Zsuzsanna Horvath

Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods

Abstract Tetrodotoxin (TTX) and its analogues are produced by marine bacteria and have been detected in marine bivalves and gastropods from European waters. The European Commission asked EFSA for a scientific opinion on the risks to public health related to the presence of TTX and TTX analogues in marine bivalves and gastropods. The Panel on Contaminants in the Food Chain reviewed the available literature but did not find support for the minimum lethal dose for humans of 2 mg, mentioned in various reviews. Some human case reports describe serious effects at a dose of 0.2 mg, corresponding to 4 μg/kg body weight (bw). However, the uncertainties on the actual exposure in the studies preclude their use for derivation of an acute reference dose (ARfD). Instead, a group ARfD of 0.25 μg/kg bw, applying to TTX and its analogues, was derived based on a TTX dose of 25 μg/kg bw at which no apathy was observed in an acute oral study with mice, applying a standard uncertainty factor of 100. Estimated relative potencies for analogues are lower than that of TTX but are associated with a high degree of uncertainty. Based on the occurrence data submitted to EFSA and reported consumption days only, average and P95 exposures of 0.00–0.09 and 0.00–0.03 μg/kg bw, respectively, were calculated. Using a large portion size of 400 g bivalves and P95 occurrence levels of TTX, with exception of oysters, the exposure was below the group ARfD in all consumer groups. A concentration below 44 μg TTX equivalents/kg shellfish meat, based on a large portion size of 400 g, was considered not to result in adverse effects in humans. Liquid chromatography with tandem mass spectroscopy (LC–MS/MS) methods are the most suitable for identification and quantification of TTX and its analogues, with LOQs between 1 and 25 μg/kg.

Re‐evaluation of alginic acid and its sodium, potassium, ammonium and calcium salts (E 400–E 404) as food additives

Abstract The present opinion deals with the re‐evaluation of alginic acid and its sodium, potassium, ammonium and calcium salts (E 400–E 404) when used as food additives. Alginic acid and its salts (E 400–E 404) are authorised food additives in the EU in accordance with Annex II and Annex III to Regulation (EC) No 1333/2008. Following the conceptual framework for the risk assessment of certain food additives re‐evaluated under Commission Regulation (EU) No 257/2010, the Panel concluded that there was no need for a numerical Acceptable Daily Intake (ADI) for alginic acid and its salts (E 400, E 401, E 402, E 403 and E 404), and that there was no safety concern at the level of the refined exposure assessment for the reported uses of alginic acid and its salts (E 400, E 401, E 402, E 403 and E 404) as food additives. The Panel further concluded that exposure of infants and young children to alginic acid and its salts (E 400, E 401, E 402, E 403 and E 404) by the use of these food additives should stay below therapeutic dosages for these population groups at which side‐effects could occur. Concerning the use of alginic acid and its salts (E 400, E 401, E 402, E 403 and E 404) in ‘dietary foods for special medical purposes and special formulae for infants’ (Food category 13.1.5.1) and ‘in dietary foods for babies and young children for special medical purposes as defined in Directive 1999/21/EC’ (Food category 13.1.5.2), the Panel further concluded that the available data did not allow an adequate assessment of the safety of alginic acid and its salts (E 400, E 401, E 402, E 403 and E 404) in infants and young children consuming the food belonging to the categories 13.1.5.1 and 13.1.5.2.

Re‐evaluation of mono‐ and di‐glycerides of fatty acids (E 471) as food additives

Abstract The EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re‐evaluating the safety of mono‐ and di‐glycerides of fatty acids (E 471) when used as a food additive. The Panel considered that it is very likely that hydrolysis of mono‐ and di‐glycerides of fatty acids by lipases in the gastrointestinal tract would occur, resulting in the release of glycerol and fatty acids. Glycerol (E 422) and fatty acids (E 570) have been re‐evaluated and the Panel concluded that there was no safety concern regarding their use as food additives. Toxicological studies with mono‐ and di‐glycerides rich in unsaturated fatty acids were considered for the re‐evaluation of E 471. No evidence for adverse effects was reported in short‐term, subchronic studies, chronic, reproductive and developmental toxicity studies. Neither carcinogenic potential nor a promotion effect in initiation/promotion was reported. The available studies did not raise any concern with regard to genotoxicity. The refined estimates were based on 31 out of 84 food categories in which E 471 is authorised. The Panel noted that the contribution of E 471 represented at the mean only 0.8–3.5% of the recommended daily fat intake. Based on the approach described in the conceptual framework for the risk assessment of certain food additives re‐evaluated under Commission Regulation (EU) No 257/2010 and taking into account the considerations mentioned above, the Panel concluded that there was no need for a numerical acceptable daily intake (ADI) and that the food additive mono‐ and di‐glycerides of fatty acids (E 471) was of no safety concern at the reported uses and use levels. The Panel recommended some modifications of the EU specifications for E 471.

Re‐evaluation of propane‐1,2‐diol alginate (E 405) as a food additive

Abstract The present opinion deals with the re‐evaluation of propane‐1,2‐diol alginate (E 405) when used as a food additive. The Panel noted that absorption, distribution, metabolism and excretion (ADME) data on propane‐1,2‐diol alginate gave evidence for the hydrolysis of this additive into propane‐1,2‐diol and alginic acid. These two compounds have been recently re‐evaluated for their safety of use as food additives (EFSA ANS Panel, 2017, 2018). Consequently, the Panel considered in this opinion the major toxicokinetic and toxicological data of these two hydrolytic derivatives. No adverse effects were reported in subacute and subchronic dietary studies with propane‐1,2‐diol alginate. The available data did not indicate a genotoxic concern for propane‐1,2‐diol alginate (E 405) when used as a food additive. Propane‐1,2‐diol alginate, alginic acid and propane‐1,2‐diol were not of concern with respect to carcinogenicity. The Panel considered that any adverse effect of propane‐1,2‐diol alginate would be due to propane‐1,2‐diol. Therefore, the acceptable daily intake (ADI) of the food additive E 405 is determined by the amount of free propane‐1,2‐diol and the propane‐1,2‐diol released from the food additive after hydrolysis. According to the EU specification, the concentration of free and bound propane‐1,2‐diol amounts to a maximum of 45% on a weight basis. On the worst‐case assumption that 100% of propane‐1,2‐diol would be systemically available and considering the ADI for propane‐1,2‐diol of 25 mg/kg body weight (bw) per day, the Panel allocated an ADI of 55 mg/kg bw per day for propane‐1,2‐diol alginate. The Panel concluded that exposure estimates did not exceed the ADI in any of the population groups from the use of propane‐1,2‐diol alginate (E 405) as a food additive. Therefore, the Panel concluded that there is no safety concern at the authorised use levels.

Re‐evaluation of glycerol esters of wood rosin (E 445) as a food additive

Abstract The present opinion deals with the re‐evaluation of glycerol esters of wood rosin (GEWR, E 445) when used as a food additive. Regarding GEWR originating from Pinus palustris (longleaf pine) and Pinus elliottii (slash pine), based on the overall toxicity database, and given the absence of reproductive and developmental toxicity data, the Panel concluded that the current acceptable daily intake (ADI) of 12.5 mg/kg body weight (bw) per day for GEWR (E 445) as established by the Scientific Committee on Food (SCF) in 1994 should be temporary pending the provision of such data. This assessment is restricted to GEWR derived from P. palustris (longleaf pine) and P. elliottii (slash pine) and with a chemical composition in compliance with GEWR used in the toxicological testing. The Panel concluded that the mean and the high exposure levels (P95) of the brand‐loyal refined exposure scenario did not exceed the temporary ADI in any of the population groups from the use of GEWR (E 445) as a food additive at the reported use levels. For GEWR originating from Pinus halepensis and Pinus brutia, the Panel noted that concentrations of the fractions of ‘glycerol monoesters’, ‘free resin acids’ and ‘neutrals’, which are considered to be of particular toxicological relevance, are not known; therefore, the evaluation of chemical equivalence with GEWR originating from P. palustris (longleaf pine) and P. elliottii (slash pine) is not possible; no data on stability were available; no toxicological data were available. Therefore, the Panel concluded that a safety assessment of GEWR originating from P. halepensis and P. brutia could not be performed. The Panel recommended the European Commission to consider an update of the definition of GEWR (E 445) in the EU specifications. It should be indicated that GEWR (E 445) (i) contain, besides the mentioned glycerol di‐ and triesters, a residual fraction of glycerol monoesters, and (ii) contain residual free resin acids and neutrals (non‐acidic other saponifiable and unsaponifiable substances).

Re‐evaluation of stannous chloride (E 512) as food additive

Abstract The Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re‐evaluating the safety of stannous chloride and stannous chloride dihydrate (E 512) as food additives. The Panel considered that adequate exposure and toxicity data were available. Stannous chloride is only permitted as food additives in one food category and no reply on the actual use level of stannous chloride (E 512) as a food additive and on its concentration in food was provided by any interested party. According to the Mintels Global New Products Database (GNPD), stannous chloride was not labelled on any products in the EU nor in Norway. The regulatory maximum level exposure assessment scenario is based on the maximum permitted levels (MPLs) for stannous chloride (E 512), which is 25 mg Sn/kg. The mean exposure to stannous chloride (E 512) from its use as a food additive was below 1.3 μg Sn/kg body weight (bw) per day for all age groups. The 95th percentile of exposure to stannous chloride (E 512) ranged from 0.0 μg Sn/kg bw per day in all groups to 11.2 μg Sn/kg bw per day in adults. Absorption of stannous chloride from the gastrointestinal tract is low there is no concern with respect to carcinogenicity and genotoxicity. Gastrointestinal irritation was reported in humans after ingestion of a bolus dose of 40 mg Sn. The Panel concluded that stannous chloride (E 512) is of no safety concern in this current authorised use and use levels.

Re‐evaluation of sodium ferrocyanide (E 535), potassium ferrocyanide (E 536) and calcium ferrocyanide (E 538) as food additives

Abstract The Panel on Food Additives and Nutrient Sources added to Food (ANS) provided a scientific opinion re‐evaluating the safety of sodium ferrocyanide (E 535), potassium ferrocyanide (E 536), and evaluating the safety of calcium ferrocyanide (E 538) as food additives. The Panel considered that adequate exposure and toxicity data were available. Ferrocyanides (E 535–538) are solely authorised in two food categories as salt substitutes. To assess the dietary exposure to ferrocyanides (E 535–538) from their use as food additives, the exposure was calculated based on regulatory maximum level exposure assessment scenario (maximum permitted level (MPL)) and the refined exposure assessment scenario. Dietary exposure to ferrocyanides was calculated based on mean and high levels consumption of salts in both the regulatory maximum level and the refined scenario. In the MPL scenario, the exposure to ferrocyanides (E 535–538) from their use as a food additive was up to 0.009 mg/kg body weight (bw) per day in children and adolescents. In the refined estimated exposure scenario, the exposure was up to 0.003 mg/kg bw per day in children and adolescents. Absorption of ferrocyanides is low and there is no accumulation in human. There is no concern with respect to genotoxicity and carcinogenicity. Reproductive studies were not available, but a no observed adverse effect level (NOAEL) of 1,000 mg sodium ferrocyanide/kg bw per day (highest dose tested) was identified from a prenatal developmental toxicity study. The kidney appeared to be the target organ for ferrocyanides toxicity and 4.4 mg sodium ferrocyanide/kg bw per day was identified as the NOAEL for the renal effects in a chronic (2‐year) study in rats. Assuming that the toxicity of this compound is due to the ferrocyanide ion only, the Panel established a group acceptable daily intake (ADI) for sodium, potassium and calcium ferrocyanide of 0.03 mg/kg bw per day expressed as ferrocyanide ion. The Panel concluded that ferrocyanides (E 535–538) are of no safety concern at the current authorised use and use levels.

Re‐evaluation of aluminium sulphates (E 520–523) and sodium aluminium phosphate (E 541) as food additives

Abstract The Panel on Food Additives and Nutrient Sources added to Food (ANS) provided a scientific opinion re‐evaluating the safety of aluminium sulphates (E 520–523) and sodium aluminium phosphate, acidic (E 541) as food additives. The Panel considered that adequate exposure and toxicity data were available. Aluminium sulphates (E 520–523) and sodium aluminium phosphate, acidic (E 541) are permitted as food additives in only a few specific products and the exposure is probably near zero. Aluminium compounds have low bioavailability and low acute toxicity. There is no concern with respect to genotoxicity and carcinogenicity. The no observed adverse effect level (NOAEL) for aluminium compounds in subchronic studies was 52 mg Al/kg body weight (bw) per day in rats and 90 mg Al/kg bw per day in dogs and the lowest NOAEL for neurotoxicity in rats was 30 mg Al/kg bw per day and for developing nervous system was 10–42 mg Al/kg bw per day in studies in mice and rats. The Panel concluded that aluminium sulphates (E 520–523) and sodium aluminium phosphate, acidic (E 541) are of no safety concern in the current authorised uses and use levels.

Re‐evaluation of polyglycerol esters of fatty acids (E 475) as a food additive

Abstract The EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re‐evaluating the safety of polyglycerol esters of fatty acids (PEFA) (E 475) when used as a food additive. In 1978, the Scientific Committee on Food (SCF) endorsed an acceptable daily intake (ADI) of 25 mg/kg body weight (bw) per day previously established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Absorption of intact PEFA in the gastrointestinal tract was extremely low. PEFA was rapidly and almost fully hydrolysed to polyglycerols and fatty acids in the gastrointestinal tract. The safety of polyglycerols and specific fatty acids has recently been assessed and no adverse effects were identified in the available studies. No adverse effects of PEFA at any dose have been observed in short‐term, subchronic or chronic toxicity studies. A no observed adverse effect level (NOAEL) of 9,000 mg/kg bw per day was identified from subchronic studies and of 2,500 mg/kg bw per day from chronic studies, the highest doses tested. No genotoxic potential of PEFA was identified from the limited information available. The reproductive toxicity studies showed no adverse effects of PEFA but had major limitations. Clinical chemistry and urinalysis, from a clinical study with limited information, did not reveal any adverse effects in volunteers receiving up to 300 mg/kg bw per day for 3 weeks. The highest exposure to PEFA used as a food additive was 2.6 and 6.4 mg/kg bw per day in children at the mean and the 95th percentile, respectively, for the non‐brand loyal scenario. Considering all the above, the Panel concluded that the food additive PEFA (E 475) was not of safety concern at the reported uses and use levels and that there was no need for a numerical ADI. The Panel recommended some modifications of the EU specifications for E 475.