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Scientific Opinion on the re-evaluation of butylated hydroxyanisole – BHA (E 320) as a food additive

EFSA Journal 2011;9(10):2392[49 pp.]. doi:10.2903/j.efsa.2011.2392
  EFSA Panel on Food Additives and Nutrient Sources added to food (ANS) Panel Members F. Aguilar, R. Crebelli, B. Dusemund, P. Galtier, J. Gilbert, D.M. Gott, U. Gundert-Remi, J. Koenig, C. Lambré, J-C. Leblanc, A. Mortensen, P. Mossesso, D. Parent-Massin, I.M.C.M. Rietjens, I. Stankovic, P. Tobback, I. Waalkens-Berendsen, R.A. Woutersen and M. Wright Acknowledgment The Panel wishes to thank the members of the ANS Working Group A on Food Additives and Nutrient Sources: N. Bemrah-Aouachria, P. Galtier, R. Guertler, U. Gundert-Remi, C. Lambré, J-C. Larsen, J-C. Leblanc, P. Mossesso, D. Parent-Massin, I.M.C.M. Rietjens, I. Stankovic, C. Tlustos, P. Tobback, and M. Wright for the preparatory work on this scientific opinion. Contact ans@efsa.europa.eu
Type: Opinion of the Scientific Committee/Scientific Panel On request from: European Commission Question number: EFSA-Q-2011-00343 Adopted: 21 September 2011 Published: 12 October 2011 Affiliation: European Food Safety Authority (EFSA), Parma, Italy
Abstract

The Panel on Food Additives and Nutrient Sources added to Food (ANS) delivers a scientific opinion re-evaluating the safety of butylated hydroxyanisole (BHA) (E 320). BHA is a synthetic antioxidant authorised as a food additive in the EU that was previously evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) several times, the latest in 1989 and the EU Scientific Committee for Food (SCF) in 1989. Both committees established an ADI of 0.5 mg/kg bw/day, with that of the SCF being classified as temporary. Both ADIs were based on proliferative changes in the rat forestomach. 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 an EFSA public call for data. The Panel concluded that BHA does not raise concern with respect to genotoxicity. A large number of long-term toxicity and carcinogenicity studies with BHA have been performed, demonstrating proliferative changes in the forestomach with BMDL10 values in the rat of 115 and 83 mg/kg bw/day. The Panel concluded that the present database does give reason to revise the ADI. The Panel considered that forestomach hyperplasia in rodents may no longer be relevant for human risk assessment. Based on a NOAEL of 100 mg/kg bw/day for growth retardation, increased mortality and behavioural effects in rat pups at higher dose levels, and using an uncertainty factor of 100 the Panel established an ADI of 1.0 mg/kg bw/day. This NOAEL also covers the BMDL10 values for forestomach hyperplasia observed in the rat. The Panel also concluded that at the current levels of use refined intake estimates are generally below the ADI of 1.0 mg/kg bw/day.

© European Food Safety Authority,2011

Summary

Following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) of the European Food Safety Authority (EFSA) was asked to deliver a scientific opinion on the re-evaluation of butylated hydroxyanisole (BHA) (E 320) as a food additive.

BHA (E 320) is a synthetic antioxidant authorised as a food additive in the EU that was previously evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) several times, the latest in 1989 and the EU Scientific Committee for Food (SCF) in 1989. Both committees established an ADI of 0.5 mg/kg bw/day with the ADI of the SCF being a temporary ADI. Both ADIs were based on proliferative changes in the rat forestomach.

BHA is a mixture of two isomers with full chemical names 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole. Specifications have been defined in the EU legislation in Directive 2008/128/EC and by JECFA. The purity is specified to be not less than 98.5% of C11H16O2 and not less than 85% of the 3-tertiary-butyl-4-hydroxyanisole isomer.

In general, BHA is rapidly absorbed from the gastrointestinal (GI) tract, metabolised and excreted in the form of metabolites mainly in urine and/or faeces. The major metabolites of BHA are the glucuronides, sulphates and free phenols, including tert-butylhydroquinone (TBHQ). The proportions of the different metabolites vary in different species and also for different dose levels. The acute toxicity of BHA is low, with an LD50 in mouse and rat > 2000 mg/kg bw/day.

In general, the majority of the genotoxicity studies indicate a lack of potential for BHA to induce point mutations or to interact with or damage DNA. BHA and its metabolite TBHQ have been reported to induce chromosomal aberrations in vitro in the presence of metabolic activation. The Panel recognised that the clastogenic activity exerted in vitro by BHA and TBHQ is likely to be secondary to the formation of reactive oxygen species via pro-oxidant chemistry, and that such a mechanism of genotoxicity is considered thresholded.

A large number of long-term toxicity and carcinogenicity studies have been performed with BHA, demonstrating proliferative changes in the forestomach. The studies have included species with a forestomach (rats, mice, hamsters) and without (guinea-pigs, dogs). The Panel noted that gastric epithelial hyperplasias, papillomas and carcinomas were only seen in species with a forestomach.

The Panel concluded that the long term studies in rats reveal the lower confidence limit of the benchmark dose (BMDL10) values for forestomach hyperplasia of respectively 115 mg/kg bw/day and 83 mg/kg bw/day. Forestomach hyperplasia was the critical effect on which SCF and JECFA based their acceptable daily intake (ADI).

The Panel noted that a new reproductive and developmental toxicity study had been published since the latest SCF and JECFA evaluations. The Panel noted that the study was not performed according to OECD guidelines and that several of the endpoints studied are not part of regular OECD guidelines for testing reproductive and developmental toxicity. The Panel also noted that the decreases reported in the parameters that were stated to be affected were generally less than 10% without a clear dose response, and that the ranges reported for these parameters overlap due to large standard deviations. Thus the Panel concluded that the effects reported in this study that were statistically significant (at p<0.05) were not biologically relevant.

The Panel also noted that other studies gave a no-observed-adverse-effect level (NOAEL) for reproductive and developmental toxicity of 0.125% BHA in the diet (equivalent to a dose of at least 100 mg/kg bw/day) in rats, and a NOAEL for reproductive and teratogenic parameters of 400 mg/kg bw/day in rabbits. The NOAEL in rats defined in the study of Vorhees et al. in 1981 was based on pups showing growth retardation, increased mortality and behavioural effects at higher dose levels.

The Panel noted that forestomach hyperplasia in rats was the critical effect on which SCF and JECFA based their ADI. The Panel considered that humans do not have a forestomach and that forestomach hyperplasia in rodents may no longer be considered relevant for human risk assessment.

Overall, the Panel concluded that the present database does give reason to revise the ADI of 0.5 mg/kg bw/day.

The Panel noted the potential endocrine effect of BHA which has been investigated in a number of studies. The Panel also noted that studies on reproductive and developmental toxicity in rats gave a NOAEL of 0.125% BHA in the diet (equivalent to a dose of at least 100 mg/kg bw/day). This NOAEL was based on pups showing growth retardation, increased mortality and behavioural effects at higher dose levels. Based on a NOAEL of 100 mg/kg bw/day and using an uncertainty factor of 100 the Panel established an ADI of 1.0 mg/kg bw/day. Since the NOAEL of 100 mg/kg bw/day is in the range of the BMDL10 values for forestomach hyperplasia in rats of respectively 115 mg/kg bw/day and 83 mg/kg bw/day the Panel concluded that this NOAEL also covers the BMDL10 values for forestomach hyperplasia observed in the rat. This NOAEL was also below the dose of 500 mg/kg bw/day causing oesophageal basal cell proliferation in monkeys.

Exposure estimates to BHA at Tier 2 for children and the adult population at both the average and high level exposures are unlikely to exceed the ADI of 1.0 mg/kg bw/day.

The Panel noted that the JECFA specification for lead is < 2 mg/kg whereas the EC specification is < 10 mg/kg.

Keywords

BHA, butylated hydroxyanisole, 3-tertiary-butyl-4-hydroxyanisole, (1,1-dimethylethyl)-4-methoxyphenol, E 320, CAS 25013-16-5, food antioxidant