Normativa UEEne. 14, 2011
UE: autoridad alimentaria informa sobre el uso de “polyvinylpyrrolidone-vinyl acetate copolymer” como aditivo alimentario
Following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on polyvinylpyrrolidone-vinyl acetate (PVP/VA) copolymer when used as a food additive.
The present opinion deals with the safety of PVP/VA copolymer for use in food supplements in tablet form as a binding/coating agent in an amount of up to 10% of weight per tablet, for a tablet weight of 1000 mg.
PVP/VA copolymer is a copolymer produced by polymerisation of the monomers N-vinyl-2-pyrrolidone (NVP) and vinyl acetate (VA). The substance will be used in food supplement tablets as a binding agent and as a coating agent.
No absorption, distribution, metabolism and excretion (ADME) studies were provided by the petitioner. It is reported in literature that PVP/VA copolymer, given its high weight average molecular weight of about 24 000 to 30 000 g/mol, is only minimally absorbed after oral administration (approximately 2% of the administered dose), and that it is largely excreted intact in the faeces.
Data from a 28-day oral feeding study and from a 90-day oral feeding study, both in the rat, demonstrated that there were no effects on body weight gain, feed consumption, haematology parameters, serum chemistry and urinalyses. There were also no test-article-related effects on organ weights, macroscopic and microscopic evaluations. The No-Observed-Adverse-Effect Level (NOAEL) in both studies was determined to be 1000 mg/kg bw/day, the highest dose level tested. The Panel agreed with these NOAELs.
PVP/VA copolymer was administered in the diet to male and female Wistar rats for 24 months and to male and female pure-bred Beagle dogs for 52 weeks. No significant toxicological findings resulting from high levels of PVP/VA copolymer in the diet of both animal species were observed. From these studies, the NOAEL was estimated to be 2800 mg PVP/VA/kg bw/day for the rat, and 2500 mg PVP/VA/kg bw/day for the dog, being the highest dose levels tested. The Panel agreed with these NOAELs.
The petitioner also referred to studies in mice and rats as summarised in a review paper. However, the Panel noted that no details of the studies were provided. It was only stated that the animals were given daily an aqueous solution of 10.2 mg PVP/VA/l (equivalent to about 2.7 mg PVP/VA/kg bw/day for the mice, and to about 1.6 mg PVP/VA/kg bw/day for the rats) for a period of one year. There were no changes attributable to the copolymer in either mice or rats, including no histological changes in the internal organs.
Data from a 2-year feeding study in the rat with PVP/VA copolymer at a dose level of 450 mg PVP/VA/kg bw/day showed that no treatment-related clinical chemistry changes were observed. No treatment-related tumours or other gross pathologically detectable lesions were induced. Histopathological examination showed an increased incidence of liver congestion and fatty degeneration in the test group compared with the cellulose control group. There were no other histopathologically detectable organ changes observed. The test and control diets were tolerated without signs of toxicity. It was however noted, that the survival in both the control and test groups was poor (8-14%), reportedly due to inflammatory diseases of the respiratory tract and from otitis.
There were no reproductive or developmental toxicity data available for PVP/VA copolymer. The petitioner considers that the copolymer is not expected to have reproductive or developmental effects considering the low oral bioavailability of PVP/VA copolymer and given the presence of only low levels (≤5 mg/kg) of residual monomers (VP and VA) in the copolymer. In support of this, the Panel noted that a similar polymer produced from VA, (i.e. polyvinyl alcohol) did not show reproductive or developmental effects at doses up to 5000 mg/kg bw/day.
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 a coating level of 100 mg PVP/VA copolymer/tablet for high consumers, an anticipated exposure of 200 mg PVP/VA copolymer/day for children and 700 mg PVP/VA copolymer/day for adults, corresponding to 8 mg/kg bw/day for children and to 11.7 mg/kg bw/day for adults, can be calculated. Assuming similar levels of use and intake data of PVP/VA copolymer from pharmaceuticals, the Panel calculated the combined intake from food supplements and pharmaceutical products to be, respectively, 16 mg/kg bw/day for children, and 23.4 mg/kg bw/day for adults.
The Panel considered that the safety of the residual levels of VA and hydrazine should also be assessed.
The petitioner stated that no data on the genotoxicity of the PVP/VA copolymer were available and provided some data on the genotoxicity of the monomers (VP and VA) from which the PVP/VA copolymer is derived. The Panel noted that the safety of VP residues in certain food additives has been evaluated by the former European Commission Scientific Committee on Food (SCF) and that the mutagenicity of both monomers has already been evaluated in the course of the European chemicals evaluation. Based on these evaluations, the Panel considered that there is no concern with respect to genotoxicity of the monomers VP and VA from which the PVP/VA copolymer is derived, nor for PVP/VA copolymer itself.
Four chronic toxicity and carcinogenicity studies with the monomer VA supplied in drinking water of rats and mice for periods up to 104 weeks were also provided. From these studies the different authors concluded that VA should be considered a multipotential carcinogen for rodents. The Panel noted that VA is present in PVP/VA copolymer at a level of maximum 5 mg/kg. The Panel calculated the exposure to VA, for the highest exposure levels, based on the proposed uses to be 0.12 µg/kg bw/day for adults and to 0.08 µg/kg bw/day for children. The Panel noted that the studies provide evidence for a VA-induced animal carcinogenicity. The Panel also noted that according to the IARC evaluation, VA is considered as a possibly human carcinogen of Group 2B (IARC, 1995).
The Panel derived a lower confidence limit on the benchmark dose (BMDL10) of 440 mg/kg bw/day from the combined incidence of squamous cell carcinomas and papillomas in mice and rats induced by VA in the oral cavity as reported by Umeda et al. in 2004. Taking the total combined exposure to VA at 0.12 µg/kg bw/day for adults and 0.08 µg/kg bw/day for children, this would lead to a Margin of Exposure (MOE) of respectively 3.7 x 106 for adults and 0.6 x 107 for children, and therefore the Panel concluded that the presence of VA at levels up to 5 mg/kg is unlikely to be of safety concern.
The petitioner did not provide data on chronic toxicity and carcinogenicity of hydrazine, present in PVP/VA copolymer at levels up to a maximum of 1.0 mg/kg.
IARC evaluated hydrazine and hydrazine sulphate in 1999. Hydrazine was found to be genotoxic in vivo and a genotoxic mechanism of the carcinogenicity cannot be excluded. IARC considered that hydrazine and hydrazine sulphate are ‘reasonably anticipated to be human carcinogens’ based on sufficient evidence of carcinogenicity in experimental animals. IARC however, considered that there is inadequate evidence in humans for the carcinogenicity of hydrazine and concluded that hydrazine is ‘possibly carcinogenic to humans (Group 2B)’ (IARC, 1999).
Based on the combined exposure for the highest exposure levels, the Panel calculated the exposure to hydrazine for adults to be 0.024 μg/kg bw/day whereas the estimated potential exposure for children would be 0.016 μg/kg bw/day.
From the available data on the incidence of hepatocellular tumours induced in male CBA/Cb/Se mice exposed daily to hydrazine for 25 weeks (Biancifiori, 1970) the Panel derived a BMDL10 for hydrazine sulphate of 2.3 mg/kg bw/day and for hydrazine anhydrous of 0.57 mg/kg bw/day. Comparison of the BMDL10 of 0.57 mg kg bw/day to the estimated exposure to hydrazine resulting from its residual presence in the final product amounting to 0.024 μg/kg bw/day for adults and 0.016 μg/kg bw/day for children the Panel calculated a MOE for hydrazine sulphate of 9.6 x104 for adults and of 14 x 104 to for children. For hydrazine anhydrous these values become 2.3 x 104 for adults and 3.6 x 104 for children. Given that these Margins of Exposure are above 10 000 and considering the opinion of the EFSA Scientific Committee (EFSA, 2005), the Panel concluded that the residual levels of hydrazine, proposed to be up to a maximum of 1.0 mg/kg in the final product, are unlikely to be of safety concern.
The Panel noted that no data on reproductive and developmental toxicity of PVP/VA were provided and that the overall toxicological database on PVP/VA is too limited to derive an acceptable daily intake (ADI). However, the Panel noted the limited absorption and the lack of toxicity observed at the highest doses tested in the available repeated-dose toxicity studies.
The NOAELs derived from the available studies were: 1000 mg/kg bw/day from a 28-day oral feeding study in the rat, 1000 mg/kg bw/day from a 90-day oral feeding study in the rat, 2800 mg/kg bw/day from a 24-month feeding study in the rat and 2500 mg/kg bw/day from a 52-week feeding study in the dog. All the NOAELs in the studies were the highest doses tested. Using this range of NOAELs and taking into account the combined intake of PVP/VA copolymer from its use in food supplements and pharmaceuticals, the Panel calculated a Margin of Safety (MOS) varying from at least 43 to 120 for adults, and 63 to 175 for children. Given the lack of absorption of PVP/VA, the fact that the MOS values are based on NOAELs that were the highest dose levels tested and that the exposures estimates were worst case assumptions, the Panel considered these MOS values sufficient.
In conclusion the Panel noted that, in the absence of data on reproductive and developmental toxicity, chronic effects in the gastrointestinal tract following oral administration cannot be excluded. Therefore, the Panel considered that an ADI should not be established and that a MOS approach is appropriate. The Panel considered the calculated Margins of Safety for PVP/VA copolymer sufficient.
The Panel concluded that the residual level of hydrazine, proposed to be up to a maximum of 1.0 mg/kg in the final product, is unlikely to be of safety concern.
Overall, the Panel concluded that the use of PVP/VA copolymer in solid food supplements as a binding/coating agent is unlikely to be of safety concern at the proposed uses and use levels provided.
The Panel however, considered that it would be prudent to lower the level of hydrazine as far as reasonably achievable.