The EFSA ANS Panel provides a scientific opinion on the safety of aspartame (E 951). Aspartame is a sweetener authorised as a food additive in the EU. In previous evaluations by JECFA and the SCF, an ...ADI of 40 mg/kg bw/day was established based on chronic toxicity in animals. Original reports, previous evaluations, additional literature and data made available following a public call were evaluated. Aspartame is rapidly and completely hydrolysed in the gastrointestinal tract to phenylalanine, aspartic acid and methanol. Chronic and developmental toxicities were relevant endpoints in the animal database. From chronic toxicity studies in animals, a NOAEL of 4000 mg/kg bw/day was identified. The possibility of developmental toxicity occurring at lower doses than 4000 mg/kg in animals could not be excluded. Based on MoA and weight‐of‐evidence analysis, the Panel concluded that developmental toxicity in animals was attributable to phenylalanine. Phenylalanine at high plasma levels is known to cause developmental toxicity in humans. The Panel concluded that human data on developmental toxicity were more appropriate for the risk assessment. Concentration‐response modelling was used to determine the effects of aspartame administration on plasma phenylalanine using human data after phenylalanine administration to normal, PKU heterozygote or PKU homozygote individuals. In normal and PKU heterozygotes, aspartame intakes up to the ADI of 40 mg/kg bw/day, in addition to dietary phenylalanine, would not lead to peak plasma phenylalanine concentrations above the current clinical guideline for the prevention of adverse effects in fetuses. The Panel concluded that aspartame was not of safety concern at the current aspartame exposure estimates or at the ADI of 40 mg/kg bw/day. Therefore, there was no reason to revise the ADI of aspartame. Current exposures to aspartame ‐ and its degradation product DKP ‐ were below their respective ADIs. The ADI is not applicable to PKU patients.
Indigo carmine (E 312) was re‐evaluated in 2014 by the EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). The ANS Panel confirmed the acceptable daily intake (ADI) of 5 mg/kg body ...weight (bw) per day for indigo carmine allocated by JECFA (1975). The ANS Panel indicated that the ADI was applicable to a material with a purity of 93% pure colouring and manufactured using processes resulting in comparable residuals as material used in the Borzelleca et al. studies (1985, 1986) and Borzelleca and Hogan (1985) which were the basis for deriving the ADI. The ANS Panel considered that any extension of the ADI to indigo carmine of lower purity and/or manufactured using a different process would require new data to address the adverse effects on the testes observed in the Dixit and Goyal (2013) study. Following a European Commission call for data to submit data to fill the data gaps, an IBO submitted technical and toxicological data. Considering the technical data, the EFSA Panel on Food Additives and Flavourings (FAF Panel) recommended some modifications of the existing EU specifications for E 132, mainly to lower the limits for toxic elements. Considering the toxicological data, an IBO has submitted a 56‐day dietary study to address the adverse effects on testes using a material with 88% purity. The results of this study submitted did not confirm the severe adverse effects observed in the Dixit and Goyal study. Considering all the available information, the Panel confirmed the ADI of 5 mg/kg bw per day for indigo carmine (E 132) disodium salts, meeting the proposed revisions of the specifications (85% minimum for the colouring matter). The Panel concluded that there is no safety concern for the use of indigo carmine (E 132) disodium salts at the reported use levels and submitted analytical data.
The ANS Panel provides a scientific opinion re‐evaluating the safety of Indigo Carmine (E132). The Panel observed that Indigo Carmine was poorly absorbed and does not raise concern for genotoxicity. ...No adverse effects in subacute, chronic, reproduction and developmental toxicity studies, and no modifications of haematological and biological parameters in chronic toxicity studies have been identified at doses less than or equal to 500 mg/kg bw/day. The only report of an adverse effect was in testis with a LOAEL of 17 mg/kg bw/day which would give rise to a safety concern if confirmed. The Panel considered that this study has shortcomings since it is not clear to the Panel whether the adverse effects observed were due to the food additive itself or to impurities and/or contaminants present in the material tested and/or to the conduct of the study. The Panel considered that the current ADI of 5 mg/kg bw/day for Indigo Carmine was applicable to a material with the same purity and manufacturing process as material used in studies without adverse effects on testis (93% pure colouring and 7% volatile matter) and concluded that any extension of this ADI to Indigo Carmine of lower purity and/or manufactured using a different process would require new data which would need to address the adverse effects on testis. The Panel noted that at the MPL, exposure estimates of Indigo Carmine would exceed the ADI for toddlers and children at the high level. Exposure estimates using the available usage and analytical data did not show an exceedance of the ADI for any population groups.
The EFSA ANS Panel provides a scientific opinion re‐evaluating the safety of vegetable carbon (E 153). Vegetable carbon has been evaluated previously by the SCF (1977, 1983) and by JECFA (1970, 1977, ...1987). Neither Committee established an ADI for vegetable carbon, but the SCF concluded that vegetable carbon could be used in food. The Panel was not provided with a newly submitted dossier and based its evaluation on previous evaluations and additional literature. The Panel considered the available toxicological data too limited to establish an ADI for vegetable carbon. The Panel noted that data on the genotoxicity and carcinogenicity of carbon blacks of hydrocarbon origin has been related to the PAHs content of these substances. However, the Panel noted that the margins of exposure for benzoapyrene exposure from vegetable carbon were considerably higher than those estimated from the dietary benzoapyrene exposure. The Panel concluded that at the reported use levels vegetable carbon (E 153) containing less than 1.0 µg/kg of residual carcinogenic PAHs expressed as benzoapyrene is not of safety concern. This was also based on the long history of safe use as a medicinal substance and the knowledge that vegetable carbon is an inert substance which is essentially not absorbed from the gastrointestinal tract following oral administration. The Panel considered that it may be appropriate to introduce in the specifications for vegetable carbon a requirement for residual carcinogenic PAHs expressed as benzoapyrene using a validated analytical method of appropriate sensitivity (e.g. LOD of 0.1 µg/kg). The estimated dietary exposure of European children to vegetable carbon ranged from 3 to 29.7 mg/kg bw/day at the mean, and from 15.3 to 79.1 mg/kg bw/day at the 95th/97.5th percentile. The dietary exposure of UK adults was 3.8 mg/kg bw/day at the mean, and 28.1 mg/kg bw/day for high level (97.5th percentile) consumers.
The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion re‐evaluating the safety of lutein (E 161b). Lutein has been previously evaluated by the EU Scientific ...Committee for Food (SCF) in 1975 and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2006. JECFA established a group Acceptable Daily Intake (ADI) of 0–2 mg/kg body weight (bw) for lutein from Tagetes erecta and zeaxanthin. The SCF could not establish an ADI, but concluded that xanthophylls prepared from natural foods by physical processes are acceptable for use in food. The Panel was not provided with a newly submitted dossier and based its evaluation on previous evaluations, additional literature that became available since then and the data available following a public call for data. New studies included a 90‐day study in rats in which no adverse effects were reported up to dose levels of 400 mg/kg bw/day. However, the Panel noted that, compared to the standard regulatory studies, the study is too limited to identify a NOAEL for the safety evaluation of lutein. The Panel concluded, based on the NOAEL of 200 mg/kg bw/day (the highest dose level tested) in a 90‐day rat study, the absence of developmental toxicity at dose levels up to 1000 mg/kg bw/day (the highest dose level tested), the fact that lutein is not genotoxic, the fact that in 90‐day studies no effects on reproductive organs were observed, and the fact that lutein is a normal constituent of the diet, that an ADI can be derived. Given the absence of a multigeneration reproductive toxicity study and of chronic toxicity/carcinogenicity studies the Panel applies an uncertainty factor of 200 and establishes an ADI of 1 mg/kg bw/day. The Panel noted that this ADI refers to lutein derived from Tagetes erecta containing at least 80% carotenoids consisting of lutein and zeaxanthin (79 and 5% respectively). The Panel concluded that at the current levels of use Tier 3 intake estimates are above the ADI at the upper end of the range.
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 re‐evaluation of karaya ...gum (E 416) as a food additive. Karaya gum (E 416) is an authorised food additive in the EU. Karaya gum (E 416) as specified in the Commission Regulation (EU) No 231/2012 is derived from the exudates from the stems and branches of strains of Sterculia urens Roxburgh and other species of Sterculia (family Sterculiaceae) or from Cochlospermum gossypium A.P. De Candolle or other species of Cochlospermum (family Bixaceae). An acceptable daily intake (ADI) ‘not specified’ was allocated by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA), whereas the Scientific Committee for Food (SCF) allocated an ADI of 12.5 mg/kg body weight (bw) per day. Karaya gum is practically undigested and not degraded by intestinal microflora and it is most probably not or only negligibly absorbed unchanged in humans. There is no concern with respect to the genotoxicity of karaya gum from Sterculia spp. Karaya gum (E 416) from Sterculia spp. did not induce toxic effects in animals at dose levels up to 1,250 mg/kg bw per day, the highest dose tested. Karaya gum from Sterculia spp. was well tolerated in humans at dose about 100 mg/kg bw per day for 4 weeks. The Panel concluded that there is no safety concern at the refined exposure assessment for the use of karaya gum as a food additive and that there is no need for a numerical ADI for karaya gum. The Panel further concluded that exposure to karaya gum by the use of this food additive should not exceed 7,000 mg/person per day in adults, the level at which some experienced abdominal discomfort.
The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion re‐evaluating the safety of Allura Red AC (E 129). Allura Red AC has been previously evaluated by the ...Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1980 and the EU Scientific Committee for Food (SCF) in 1984 and 1989. Both committees established an Acceptable Daily Intake (ADI) of 0‐7 mg/kg body weight (bw)/day. The Panel was not provided with a newly submitted dossier and based its evaluation on previous evaluations, additional literature that became available since then and the data available following a public call for data. New studies included a study by Tsuda et al. from 2001 reporting effects on nuclear DNA migration in the mouse in vivo Comet assay, and a study by McCann et al. from 2007 that concluded that exposure to a mixture including Allura Red AC, resulted in increased hyperactivity in 8‐ to 9‐years old children. The Panel notes that Allura Red AC was negative in in vitro genotoxicity as well as in long‐term carcinogenicity studies and that the effects on nuclear DNA migration observed in the mouse in vivo Comet assay are not expected to result in carcinogenicity. The Panel also concurrs with the conclusion from a previous EFSA opinion on the McCann et al. study that the findings of the study cannot be used as a basis for altering the ADI. The Panel concluded that the present database does not give reason to revise the ADI of 7 mg/kg bw/day. The Panel also concludes that at the maximum reported levels of use refined intake estimates are generally below the ADI, although in 1‐10 years old children the high percentile of exposure (95th) can be slightly higher than the ADI at the upper end of the range.
The EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re‐evaluating the safety of β‐cyclodextrin (E 459) as a food additive. β‐Cyclodextrin is a ...non‐reducing cyclic oligosaccharide consisting of seven α‐1,4‐linked d‐glucopyranosyl units. The Scientific Committee on Food (SCF) allocated an acceptable daily intake (ADI) of 5 mg/kg body weight (bw) per day to β‐cyclodextrin (E 459) in 1996. β‐Cyclodextrin is poorly absorbed following oral administration in animals and humans. It is hydrolysed to maltose and glucose by the gut microflora and endogenous amylases in the colon; consequently, β‐cyclodextrin levels in tissues and serum are low (< 1%). β‐Cyclodextrin has a low acute oral toxicity. Short‐term and subchronic toxicity studies were available in rats and dogs. In rats, the main reported effect was an adaptive enlargement of the caecum, resulting from consumption of poorly digestible carbohydrates. From a 6‐month study in rats, a no observed adverse effect levels (NOAEL) of 600 mg/kg bw per day was identified and from a 52‐week dogs study, the NOAEL was 466 and 476 mg/kg bw per day in males and females, respectively. The Panel considered that there was no indication for genotoxicity of β‐cyclodextrin. From a chronic toxicity studies in rats, a NOAEL of 654 and 864 mg/kg bw per day in males and females, respectively, was identified. Carcinogenicity studies in mice and rats were available and no evidence for carcinogenicity was found. The Panel concluded that, based on the available toxicological database, there is no reason to revise the current ADI of 5 mg/kg bw per day for β‐cyclodextrin. Based on the available reported use and use levels, the Panel also concluded that the ADI was exceeded in the refined brand‐loyal scenario (considered the most relevant scenario) in all population groups except for infants at the mean and in all population groups at the 95th percentile.
Background
The European chemicals’ legislation REACH aims to protect man and the environment from substances of very high concern (SVHC). Chemicals like endocrine disruptors (EDs) may be subject to ...authorization. Identification of (potential) EDs with regard to the environment is limited because specific experimental assessments are not standard requirements under REACH. Evidence is based on a combination of in vitro and in vivo experiments (if available), expert judgement, and structural analogy with known EDs.
Objectives
The objectives of this study are to review and refine structural alerts for the indication of potential estrogenic and androgenic endocrine activities based on in vitro studies; to analyze in vivo mammalian long-term reproduction studies with regard to estrogen- and androgen-sensitive endpoints in order to identify potential indicators for endocrine activity with regard to the environment; to assess the consistency of potential estrogenic and androgenic endocrine activities based on in vitro assays and in vivo mammalian long-term reproduction studies and fish life-cycle tests; and to evaluate structural alerts, in vitro assays, and in vivo mammalian long-term reproduction studies for the indication of potential estrogenic and androgenic endocrine disruptors in fish.
Results
Screening for potential endocrine activities in fish via estrogenic and androgenic modes of action based on structural alerts provides similar information as in vitro receptor-mediated assays. Additional evidence can be obtained from in vivo mammalian long-term reproduction studies. Conclusive confirmation is possible with fish life-cycle tests. Application of structural alerts to the more than 33,000 discrete organic compounds of the EINECS inventory indicated 3585 chemicals (approx. 11%) as potential candidates for estrogenic and androgenic effects that should be further investigated. Endocrine activities of the remaining substances cannot be excluded; however, because the structural alerts perform much better for substances with (very) high estrogenic and androgenic activities, there is reasonable probability that the most hazardous candidates have been identified.
Conclusions
The combination of structural alerts, in vitro receptor-based assays, and in vivo mammalian studies may support the priority setting for further assessments of chemicals with potential environmental hazards due to estrogenic and androgenic activities.
The Scientific Panel on Food Additives and Nutrient Sources added to Food has re‐evaluated the safety of Erythrosine (E 127) when used as a food colouring substance. Erythrosine (E 127) is a ...xanthene‐dye which has been previously evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1990 and the EU Scientific Committee for Food (SCF) in 1989. Both committees have established an Acceptable Daily Intake (ADI) of 0‐0.1 mg/kg bw/day. Erythrosine is exclusively authorised for use in cocktail and candied cherries, and Bigarreaux cherries (94/36/EC). The Panel considered the weight‐of‐evidence still showed that the tumorigenic effects of Erythrosine in the thyroid gland of rats are secondary to its effects on thyroid function and not related to any genotoxic activity. Erythrosine‐induced rodent thyroid tumours may be considered of limited relevance to humans; an approach which is consistent with previous evaluation of Erythrosine. The Panel considered Erythrosine has a minimal effect in humans at a clinical oral dose of 200 mg daily over 14 days, while a dose of 60 mg daily was without effect (Gardner et al., 1987). The current ADI adopted by the JECFA and the SCF is based on this study. The Panel concurred with their identification of this as the critical study. The 60 mg dose was taken to be the equivalent of 1 mg/kg bw/day. By applying a safety factor of 10 to allow for the small number of subjects used in the study and its relatively short duration, an ADI of 0‐0.1 mg/kg bw per day was derived. The Panel concludes that the present database does not provide a basis to revise the ADI of 0.1 mg/kg bw/day. The Panel concluded that at the current levels of use intake estimates for adults on average is 0.0031 mg/kg bw/day and 0.01 mg/kg bw/day at the 95th percentile, and consequently are below the ADI of 0.1 mg/kg bw/day. The Panel considered there would be no safety concerns at current levels of exposure including other sources of exposure.
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