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INDEX

B. ADVERSE REACTIONS TO BENZOATES
Benzoate sensitivities can occur through ingestion of, inhalation of, and contact with benzoates. Reactions to benzoates are often “allergy-like” in character and cannot be distinguished clinically from an IgE-mediated response. The daily consumption of food additives often leads to continuous and protracted symptoms which mimic allergic reactions. The difference is that in benzoate sensitivities the symptoms occur through activation of biochemical pathways which mediate inflammation. IgE specific for the triggering agents is not involved, though the reactions may be attributed to hypersensitivity.²

Persons who have experienced Type 1 hypersensitivity reactions (atopic allergy), such as respiratory tract symptoms including asthma, or skin reactions such as hives and eczema, may be particularly vulnerable to benzoate sensitivity.⁹

The following symptoms have been linked to benzoate sensitivity, and the most recent clinical trials as well as case reports will be discussed under each:
i. Asthma
ii. Urticaria (hives) and angioedema (tissue swelling)
iii. Rhinitis (nasal congestion due to hay fever)
iv. Atopic and contact dermatitis
v. Cutaneous vasculitis
vi. Anaphylaxis

i. Asthma
The prevalence of asthmatic reactions to benzoates in the general population or select groups (such as atopic asthmatics) has not been properly defined. Several studies suggest asthma is an unusual clinical manifestation of benzoate sensitivity.

Some older studies, such as one by Freedman (1977), claim that benzoate is a common precipitator of asthma episodes in asthmatics.¹³ In 1982, Rosenhall found 8% of benzoate challenges resulted in either asthma or rhinitis.¹⁴ There are conflicting estimates of the prevalence of asthma reactions to benzoates – Hannuksela estimated it to be 11.5%¹⁵, while Weber documented the prevalence in patients with perennial asthma to be closer to 2%.¹⁶

A case report by Balatsinou et al. (2004) demonstrated a worsening of asthma due to benzoate-containing antiasthmatic drugs. The researchers discussed the fact that drug and food additives are known to induce pseudo-allergic reactions such as urticaria, eczema, asthma and rhinitis. These reactions are often under-diagnosed, above all in allergic patients treated with additive-containing drugs. Paying attention to the additives present in some drug formulations and foods may often permit more correct diagnosis.¹⁷

Nevertheless, as in the case of chronic urticaria, a benzoate-free diet may be useful in selected patients with persistent asthma. This approach has, however, not been evaluated in published controlled trials.⁶

ii. Urticaria and angioedema
The prevalence of chronic urticaria reactions to food additives has been studied frequently. Unfortunately, design problems with oral challenge studies, variable study design, a lack of adequate controls in many studies, and differences in activity or inactivity of urticaria at the time of challenge have meant that the prevalence has not been definitively elucidated.⁶

A recent randomised controlled trial, conducted in Italy, attempted to determine the incidence of sodium benzoate intolerance among subjects who experienced repeated acute urticaria with or without angioedema (n=47) following the ingestion of a sodium benzoate-containing meal or product. After a careful clinical history, subjects were diagnosed by testing serum-IgE levels to common inhalant and food allergens, and by a double-blind placebo-controlled challenge with sodium benzoate. The results showed that the percentage of repeated episodes of acute urticaria or angioedema reactions induced by sodium benzoate was in fact very low (2%). In view of these results, it is suggested that other possible causes should always be carefully evaluated in patients suspected of suffering from sodium benzoate-induced reactions.¹⁸

This study only looked at “repeated” episodes of urticaria. It is important to bear in mind that urticaria due to hypersensitivity may also present intermittently if reactions are influenced by differing doses of the offending substance; by the duration of exposure; or by differing environments in which the exposure occurred.

In another report, a 26-month-old child presented with eczema associated with allergies to egg, peanut and mites. After a period of improvement, the lesions got worse, and the child began to have urticaria as well. Some of the exacerbations followed consumption of méquitazine and cooked beets. Intolerance to benzoate was confirmed by a provocation test; the skin lesions regressed after avoidance of this additive. After 39 months of avoidance, the child tolerated the additive.¹⁹

In summary, meticulously designed studies utilising DBPCFC with benzoates suggest that these substances are uncommon as provoking or exacerbating factors in urticaria and angioedema. In selected patients, however, a trial of an additive-free diet may be warranted, followed by systematic reintroduction of additive-containing foods if significant clinical improvement has been observed. If clinically appropriate, DBPC additive challenges could be used to diagnose sensitivity to a particular additive.⁶

iii. Rhinitis
Food additives have frequently been identified anecdotally in case reports as possible causes of rhinitis. There is, however, little data from the literature on the effect of food additives, particularly benzoates, on symptoms of persistent rhinitis.^2,3

The symptoms of non-allergic rhinitis are similar to those seen in persistent allergic rhinitis, with two exceptions – eye symptoms are less frequent, and nasal blockage is more prominent.^2,3

A double-blind placebo-controlled study in 2004 attempted to evaluate the prevalence of hypersensitivity to additives in a group of subjects affected by persistent rhinitis. It specifically assessed whether non-atopic subjects with persistent rhinitis may show objective rhinitis symptoms as well as a reduction in nasal peak inspiratory flow (NPIFR) after the ingestion of various food additives, including sodium benzoate and propylhydroxybenzoate. There were 226 subjects (76 males, 150 females) between 12-60 years (mean age of 40.2 years). After a 1 month additive-free diet, subjects were placed on a 2-week additive-rich regimen, and daily symptoms were examined. This was followed by DBPCFC with 6 common food additives in the same individuals.²

It was found that 8.8% of patients reacted to sodium benzoate with typical symptoms of rhinitis and a =20% reduction in NPIFR, as proved by DBPCFC. These patients also showed improvement of rhinitis with an additive-free diet, with 2.6% of them becoming symptom-free.²

In a case report by Asero (2001) (used previously for the case study above) chronic rhinitis was found to be caused by sodium benzoate intolerance, as diagnosed by means of DBPCFC. A 33-year-old woman presented with a 7-year history of perennial rhinitis characterised by watery rhinorrhea, itching of the nasal mucosa, and episodes of sneezing paroxysm that showed little response to antihistamines or local corticosteroids. On DBPCFC, rhinitis recurred about an hour after the ingestion of 50 mg of sodium benzoate, and symptoms lasted for about 36 hours. Symptoms disappeared when the subject was placed on a benzoate-free diet and reappeared on re-challenging.²⁰

In conclusion, the data suggest that some patients with “chronic vasomotor rhinitis” may be intolerant to a particular food additive. It also demonstrates that food additives, including sodium benzoate and propylhydroxybenzoate, could be triggers or aggravating factors rather than aetiological factors, which would explain why they provoke an exacerbation of an existing chronic disease such as persistent rhinitis.²

iv. Atopic & contact dermatitis
No well designed study has implicated benzoates individually as pathogenic factors in atopic dermatitis (AD). In a recent study using multiple food additives, including benzoates, more than 50% of AD patients showed improvement on an additive-free diet and responded to DBPC-oral provocation with food additives. This suggests that at least some of the substances may be considered provoking factors in a minority of patients with AD.^6,21

Regarding contact dermatitis, reported associations with benzoates are rare.⁶

Kanerva et al. (2001) reported on a 54-year-old ship technician who had hand eczema for 7 years. The dermatitis started on the back of his hands and wrists and spread to the finger webs. It improved during a month-long period of sick leave but returned when he was back at work. At work, the technician was exposed to a number of lubricants and combustion oils. Prick tests to standard environmental allergens were negative. Patch tests were done, and a positive reaction was provoked by the approved hand ointment at the work site. Evaluation of the ingredients revealed alkylammonium amidobenzoate (Osmaron B ®) as a component of the ointment. Sensitization to Osmaron B was identified as the cause of the occupational contact dermatitis.^22,23

Another case report by Vilaplana et al (2004) discussed a 64-year-old female teacher with a prior history of episodes of itching on her right hand, progressing within 48 hours to erythema, and to oedema and blistering by day 4. Symptoms resolved in 10 days, leaving a pigmented area, which disappeared a month later. A detailed history revealed a possible link to ingestion of syrup for a throat infection. Patch testing with the components of the syrup elicited a positive result to sodium benzoate only. In a sodium benzoate provocation/challenge test, she developed the same lesions 15 hours after ingestion.²⁴

v. Cutaneous vasculitis
Occasional reports of cutaneous vasculitis have been associated with sodium benzoate ingestion.⁶

Vogt et al. (1999) reported an unusual presentation of acute leukocytoclastic vasculitis (LCV) in a 67-year-old man who had purpuric lesions almost exclusively on the upper body parts. None of the common causes of LCV could be found, but double-blind placebo-controlled oral challenge testing with common food additives revealed sodium benzoate as the causative substance. He demonstrated a strong positive response within 24 hours of ingestion of a cumulative dose of 800 mg.²⁵

vi. Anaphylaxis
Robust evidence of benzoates causing systemic anaphylaxis is lacking. There are relatively few reports of possible anaphylactic reactions from ingested benzoates in the medical literature. Given the widespread consumption of these preservatives, it can be surmised that such reactions are extremely rare.^6,26

Benzoic acid can also act as a mild irritant to the skin, eyes, and mucous membranes. Its adverse effects often increase when it is combined with other additives.

The mechanism of adverse reactions to foods containing benzoate is unknown, but evidence suggests that the cyclo-oxygenase pathway of arachidonic acid metabolism may be affected. Individuals sensitive to acetylsalicylic acid (ASA or Aspirin®)) are particularly vulnerable to benzoate sensitivity.⁹

Although numerous cases of adverse reactions to benzoates have been documented, many of the studies have lacked robust methodology, specifically blinding and placebo controls. Overall, there are very few clinical trials that have specifically assessed benzoates as causative factors in adverse clinical manifestations.

Benzoates in Unusual Skin Rashes
One study has indicated a possible causative role for benzoates in an acute inflammatory disorder known as erythema multiforme, which is characterised by lesions on the mucous membranes of the mouth, eyes, and genitals. Patch testing with a variety of food additives showed that patients in the study reacted strongly to benzoic acid. Subsequent elimination and challenge testing confirmed a role for ingested benzoates in the exacerbation and possibly the aetiology of the condition.²⁷

Benzoates and Hyperactivity
The effect of additives on hyperactivity and attention deficit disorder has been debated for many decades. In 1973, the late Dr Benjamin Feingold proposed that children were hyperactive because they were sensitive to salicylates, artificial colourings and flavourings in their food. The aim of the Feingold diet was to remove such substances from the diet. The basis of the Feingold theory was derived from his observations of allergic reactions, such as asthma caused by salicylates, in some people. When he treated the asthma by removing the salicylates from the diet, he noted a behaviour change as well as the disappearance of the asthma symptoms. Dr Feingold observed that younger children seemed to respond much sooner than older children and teenagers, and suggested that this was due to shorter periods of exposure to the chemicals. The use of this diet is extremely controversial, as it has not been clinically shown to offer any significant help to children with learning and attention difficulties.^30,31

In 2004, a double-blind placebo-controlled challenge was done in a general population sample of preschool children aged 3 years in Southampton, UK, to determine the effects of artificial food colourings and benzoate preservatives on hyperactivity. Of the 1873 children screened for hyperactivity at baseline (HA), 1246 were identified by skin prick tests as having atopy (AT). The atopic children were then divided into 4 groups: HA/AT; not-HA/AT; HA/not-AT; and not-HA/not-AT. All groups followed a diet free of artificial colourings and benzoate preservatives for 1 week. Thereafter, each group was double-blinded to crossover periods of dietary challenge and over 3 weeks received, in random order and additional to their diets, a drink containing artificial colourings (20 mg/day) and sodium benzoate (45 mg/day), or a placebo mixture, during the active phase. Behaviour was assessed by a tester blinded to the dietary status, and by parent’s ratings. Based on the parental reports, significant reductions in hyperactive behaviour were seen during the “withdrawal phase” as well as significantly increased hyperactive behaviour during the “active phase” compared to the placebo period. The study found the effects were not influenced by the presence or absence of either hyperactivity or atopy. No significant differences were seen based on objective testing in the clinic. In conclusion, general adverse effects of artificial food colouring and benzoate preservatives on the behaviour of 3-year-olds could be detected by parents but not by a simple clinic assessment, and prior hyperactivity or atopy did not make subgroups more vulnerable to the effects.³¹

Adverse reactions to benzoate-containing medications and cosmetics
Known side effects of intravenous sodium benzoate therapy include nausea, vomiting and hypokalaemia secondary to urinary loss, enhanced by the excretion of the non-absorbable substances. No serious side effects have been reported when the substance is used in recommended doses of 250 mg/kg infused over 90 minutes. However, excessive doses, as illustrated by 3 hypoammonaemic patients reported by Praphanphoj et al. (2000), can result in devastating complications. All the patients presented with altered mental status, poor respiration, a partially compensated metabolic acidosis and an increased anion gap. Two patients developed cerebral oedema and hypotension and died. The third survived after haemodialysis.¹¹

Over the past decades, declines in the prevalence of dental caries in segments of the population have been attributed mainly to increased exposure to fluoride through fluoridation of water and fluoride in dental products. An additional factor may be the increased consumption of foods and beverages containing benzoates. Sodium benzoate is also added to oral drugs for flavour and is used to treat dental plaque, due to its antibacterial properties. A recent study on rodents showed that a combination of benzoate and fluoride reduced caries activity more effectively than fluoride alone.^12,28,29

In clinical studies of topical application, benzoates produced toxic symptoms of non-immunologic contact urticaria or non-immunologic immediate contact reactions, characterised by wheals, erythema and pruritis, but only following doses far exceeding the WHO acceptable daily intake (ADI) of 5 mg/kg/day. It is unclear whether the reactions were histamine- or prostaglandin-mediated.⁸

Regarding the safety of these ingredients in the cosmetic industry, the Cosmetic Ingredient Review Expert Panel reviewed the various studies conducted to date. Although most of the studies have been on animals, the Expert Panel were satisfied that results concerning toxicity, mutagenicity, carcinogenicity, reproductive/developmental effects, and sensitisation confirm the safety of these ingredients at concentrations of up to 5% in cosmetic formulations. The exception was the use of benzyl alcohol in hair dyes. Due to the limited body area exposure, controlled exposure time and limited frequency of use, the Expert Panel was of the opinion that contact urticaria would not be a concern and that concentrations of up to 10% could be used in these products. Manufacturers should, however, consider the possibility of non-immunologic reactions when using these ingredients in cosmetic formulations for infants and children.⁸

The available data are insufficient, however, to confirm the safety of these ingredients in cosmetic products where inhalation is a possible primary route of exposure - inhalation toxicity data are still needed to complete safety assessments.⁸

In assessing benzoate sensitivity, two questions still remain unanswered:
1. What is considered the necessary duration of additive avoidance before considering reintroduction?
2. What is the natural history of benzoate sensitivity and can the sensitivity be outgrown?

C. How much benzoic acid & sodium benzoate can be safely added to products?
Based on the majority of literature reports, benzoates, even ingested in relatively high doses, seem to pose no threat and cause no adverse reactions in most individuals. However, considering the limited amount of strong clinical evidence available and the difficulty in diagnosing adverse reactions to benzoates, the actual incidence of hypersensitivity may in fact be far higher than what is currently documented. Care must therefore be taken to identify the small group of people who do present with benzoate hypersensitivity.

The US Food and Drug administration (FDA) have approved benzoates (benzoic acid and sodium benzoate) as direct food additives and awarded them with “generally recognised as safe (GRAS)” status up to a maximum concentration of 0.1%. Benzoic acid is considered more toxic than its sodium salt form. Sodium benzoate is used more often, usually at a concentration of 0.05-0.1%.^6,8,32

Benzoic acid and benzoates are permitted in a variety of products, of which each has its individual specified maximum concentration. The acceptable daily intake (ADI) for both benzoic acid and sodium benzoate, as established by the World Health Organisation, is 0-5 mg/kg body weight. The ADI represents the average amount of the substance that can be consumed daily, even for a lifetime, without health hazards. This is a level considered safe and non-toxic for the general population however, sensitive individuals may react to lower doses.^8,32

Studies to date have shown average estimated intakes of benzoates to be below or within acceptable range of the recommended ADIs. Mixed beverages and soft drinks have been documented as the main sources of daily benzoate intakes.^33,34

Considering the increasing intake of soft drinks worldwide in both adults and children, a re-evaluation by the food industry of the current use of benzoates in these products may be warranted.

In cosmetics products and other non-food products, sodium benzoate can be used without danger at maximum concentrations of 2.5% in skin-cleansing products and at 1.7% in dental hygiene products. In oral and parenteral drugs, it can be used at 0.7% and 0.5% respectively.^8,24

D. Diagnosis and laboratory tests
There is no definitive diagnostic test when it comes to benzoate sensitivity. The following methods may be helpful:
i. Patch testing: May be useful particularly when topical agents are suspected.
ii. CAST test (a measurement of sulfidoleukotriene [sLT] production): May also be useful to a degree in the clinical setting

Research by Worm et al. (2001) observed increased sulfidoleukotriene (sLT) production in the presence of a single food additive (benzoate or tartrazine) in atopic dermatitis patients with a proven food additive intolerance. The findings suggest that raised sLT production by peripheral leukocytes may contribute to the pathophysiological mechanisms of a benzoate food intolerance aggravating AD.³⁵

iii. Clinical history: A clear and detailed clinical history of the patient is essential.
iv. Double-blind placebo-controlled food additive challenge: If hypersensitivity to food additives is suspected (in individuals with persistent/intermittent and unexplained asthma, rhinitis and urticaria), the only method of proof is the DBPCFC. It also provides solid data to individuals who may be convinced of intolerance despite having no symptoms after ingestion of reasonable intakes.⁶

E. Recommended treatment & management of benzoate sensitivity
People differ in their sensitivity to additives like benzoates. Consequently, it is impossible to define a limit of benzoate intake that can apply to all individuals sensitive or intolerant to benzoate.

There are differing opinions as to whether natural sources of benzoic acid should be avoided or not, as the doses of naturally occurring benzoates may not be high enough to aggravate sensitivity. Combinations of foods containing natural benzoates may be more problematic than individual foods: e.g., yoghurt with fresh raspberries may need to be avoided. A food containing natural benzoate to which additional benzoate has been added as a preservative may also cause adverse reactions in sensitive individuals. But again, the actual quantities eaten in a normal serving may be insufficient to induce a reaction.

Summary table of sources of naturally and artificially occurring benzoates:

The general recommendation is to reduce benzoate intake by avoiding foods known to contain added benzoates – processed foods containing benzoic acid or sodium benzoate. Individuals should also be advised to avoid bleached flour and products containing hydrolysed lecithin, such as margarine, salad and cooking oils, frozen desserts, chocolate and baked goods.⁹

Labels should be carefully read, particularly when contact-induced sensitivity to cosmetic products is suspected. Synonyms for benzoic acid in cosmetic products include benzeneformic acid, benzenemethanoic acid, benzoate, carboxybenzene, dracylic acid, phenylformic acid, benzenecarboxylic acid, and phenylcarboxylic acid; synonyms used to describe sodium benzoate include sodium salt of benzenecarboxylic acid and sodium salt of phenylcarboxylic acid.⁸

In foods, benzoates can be identified on labels by either the name or by their “E-numbers”⁹:
Benzoic acid = E210
Sodium benzoate = E211
Potassium benzoate = E212
Calcium benzoate = E213
Ethylhydroxybenzoate = E214
Propylhydroxybenzoate = E216
Methylhydroxybenzoate = E218

What about Parabens?
Parabens, a class of derivatives of benzoic acid (methyl-, n-propyl-, n-butyl- and n-heptyl-esters of para-hydroxybenzoic acid), are sometimes used as preservatives in foods, and more commonly in pharmaceuticals and cosmetics. Benzoate-sensitive individuals may also react to parabens because their metabolism mimics that of benzoates – a type of cross-reactivity. There are no naturally occurring parabens. On food labels, parabens may be indicated by the terms methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, which are the forms most commonly used as food additives.^6,9

Parabens are used in processed fruits and vegetables, baked goods, fats, oils, sauces and seasonings. They may be present in foods such as frozen dairy products, sugar substitutes, cakes, pies, pastries, icings, fillings, fruit products (e.g., sauces and juices, fruit salads, syrups, preserves, jellies), syrups, olives, pickles, beers, ciders and carbonated beverages, as well as coffee extracts. Parabens have also been awarded GRAS status by the FDA, and the concentrations vary between 450-2000 ppm, with a maximum limit as a food preservative of 0.1%.^6,9

In October 2004 the European Commission proposed to ban paraben (E216) and its sodium salt (E217). Parabens are very seldom used in foods (we have never found it used in food), but are used commonly used in cosmetics and personal care products.

In Conclusion
Benzoates are used extensively as chemical preservatives in foods and beverages worldwide. They have essentially no toxicity at approved concentrations and, considering their vast consumption, are extremely well tolerated. Hypersensitivity may occur in certain vulnerable individuals either through ingested, inhaled or topically applied benzoates.

C. Comments by our editors

Prof Janice M. Joneja Ph. D., RDN Diagnosis and management of benzoate sensitivity is fraught with difficulties, as are many conditions that are triggered or exacerbated by naturally-occurring chemicals or food additives that exert their effects on the body by non-immunologically mediated mechanisms, most of which are incompletely understood. Because the physiological events that lead to sensitivity are unknown, there are no definitive tests, apart from elimination and challenge, that can identify the causative agent. The level of naturally-occurring benzoates in a number of foods has been measured by a few laboratories, and like most natural chemicals, different labs produce different results because foods from different locations, grown under varying conditions, contain levels of benzoates that can differ widely, and sometimes one lab will identify the chemical in a food while another finds none. An example of this dilemma is the case study discussed here. The test substance and the placebo were masked in orange juice. Although the juice was free from added benzoate, the statement, “Oranges also do not contain natural benzoates” is contradicted by a report of the levels of benzoates in foods (from reference below) that indicates benzoates (mg/kg) in oranges as: Navel orange 2.3 Valencia orange 0.6 Mandarin orange 0.5 Admittedly, the amount of benzoates in oranges is very small, and most fruits and vegetables contain less than 2 mg/kg as measured by these investigators. This further illustrates the problem of defining a “safe level” of natural benzoates for benzoate-sensitive people, and formulating a benzoates-restricted diet. The WHO acceptable daily intake (ADI) of 5mg/kg body weight per day would indicate that a 65 kg adult should be able to consume a total of 325 mg per day of benzoates without any problems. A person avoiding all benzoates as additives would normally consume a very low level of benzoate, so simply avoiding the chemical as an additive may be sufficient to maintain a symptom-free state without concern for the amount of natural benzoates in food. However, it is possible that an extremely benzoate-sensitive person might develop symptoms on an additive-free diet; such people need to follow a benzoate-restricted diet (see reference 9 from text). In my practice I have found that a good challenge for reactivity to natural benzoates is cinnamon; most benzoate-sensitive people develop symptoms when they consume the spice. The level of benzoates in cinnamon is 366 mg/kg (from reference below), meaning that an adult of 65 kg ingesting 1 teaspoon (2g) of cinnamon (far in excess of the average amount of the spice that is normally consumed) would ingest only 0.672 mg benzoate from that source. Nevertheless, this small quantity is sufficient to cause an adverse response in most benzoate-sensitive people, so the level of benzoate that is safe for this population must be close to zero. Reference: Heimhuber B und Herrmann K. Benzoe-, Phylessig-, 3-Phenylpropan- und Zimtsäure sowie Benzyoylglucosen in einigen Obst- und Fruchtgemüsearten. Deutsche Lebensmittel-Rundschau 1990 86 Jahr. Heft 7

Dr. Harris Steinman M.B.Ch.B. Benzoates is a commonly used preservative. Although there are not a great deal of studies elaborating on the full spectrum of adverse effects a benzoate-sensitive individual may experience (we do not even know the pathophysiological mechanism involved), it is imperative that this type of sensitivity is explored as a potential cause in patients with ongoing symptomatology. Patients with marked adverse symptoms will expect nothing less!

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D. References
1. Sampson HA. Adverse reactions to foods. In: Middleton E, Reed CE, Ellis EF, Adkinson NF, Yunginger JW, Busse WW, editors. Allergy: principles and practice, 5th edition. St Louis: Mosby-Year Book, 1998: 1162–1182.
2. Pacor ML, Di Lorenzo G, Martinelli N et al. Monosodium benzoate hypersensitivity in subjects with persistent rhinitis. Allergy. 2004 Feb; 59 (2): 192-7
3. Bousquet J, Van Cauwenberge P, Khaltaev N. Aria Workshop Group, World Health Organization. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108 (Suppl.): S147–334.
4. Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double blind placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with hypersensitivity to food and additive and/or ASA. Clin Exp Allergy 2001; 31: 1607–1614.
5. Di Lorenzo G, Pacor ML, Vignola AM, Profita M, Esposito-Pellitteri M, Biasi D et al. Urinary metabolites of histamine and leukotrienes before and after placebo-controlled challenge with ASA and food additives in chronic urticaria patients. Allergy 2002; 57:1180–1186.
6. Metcalfe D, Sampson H, Ronald A. Food allergy: adverse reactions to foods and food additives. Blackwell publishing 2003. Chapter 28 p369-375
7. Woolworths Analyzed levels of Natural Benzoates in South African products. April 2002
8. Nair B. Final report on the safety assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. Int J Toxicol. 2001; 20 Suppl 3: 23-50
9. Joneja JV. Dealing with Food Allergies. Chapter 4 p61-64 and Chapter 22 p277-285. Bull Publishing Company 2003, Boulder, Colorado USA.
10. WHO Concise International Chemical Assessment Document No. 26: http://wwwinchem.org/documents/cicads/cicads26.htm
11. Praphanphoj V, Boyadjiev SA, Waber LJ et al. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia. J Inherit Metab Dis. 2000 Mar; 23 (2): 129-36
12. Otero-Losada ME. Differential changes in taste perception induced by benzoic acid prickling. Physiol Behav. 2003 Mar; 78 (3): 415-25
13. Freedman BJ. Asthma induced by sulphur, benzoates and tartrazine contained orange drinks. Clin Allergy 1977; 7 (5): 407-415
14. Rosenhall L. Evaluation of intolerance to analgesics, preservatives and food colorants with challenge tests. Eur J Respir Dis 1982;63:410-9
15. Hannuksela M, Haahtela T. Hypersensitivity reactions to food additives. Allergy 1987;42:561-75
16. Weber RW. Food additives and allergy. Ann Allergy 1993;70(3):183-90
17. Balatsinou L, Di Gioacchino G, Sabatino G et al. Asthma worsened by benzoate contained in some antiasthmatic drugs. Int J Immunopathol Pharmacol. 2004 May-Aug; 17 (2): 225-6
18. Nettis E, Colanardi MC, Ferrannini A, Tursi A. Sodium benzoate-induced repeated episodes of acute urticaria/ angio-oedema: randomised controlled trial. Br J Dermatol. 2004 Oct; 151 (4): 898-902
19. M. Pétrus, G. Cossarizza, A. Dyan and H. Malandain Intolerance to benzoates in a 26-month old child, apparently cured after 39 months of avoidance Revue francaise d allergologie 2004;44(8):649-651
20. Asero R. Perennial rhinitis induced by benzoate intolerance. J Allergy Clin Immunol. 2001 Jan; 107 (1): 197
21. Worm M, Ehlers I, Sterry W, Zuberbier T. Clinical relevance of food additives in adult patient with atopic dermatitis. Clin Exp Allergy 2000; 30: 407-414.
22. Haapasaari K, Niinimaki A. Allergic contact dermatitis from alkylammonium amidobenzoate (Osmaron B). Contact Dermatitis 2001 Feb; 44 (2): 133-4
23. Kanerva L, Eatlander T, Jolanki R. Ocupational allergic contact dermatitis from alkylammonium amidobenzoate. Eur J Dermatol. 2001 May-Jun; 11 (3): 240-3
24. Vilaplana J, Romaguera C. Fixed drug eruption from sodium benzoate. Contact dermatitis. 2003 Dec; 49 (6): 290-1
25. Vogt T, Landthaler M, Stolz W. Sodium benzoate-induced acute leukocytoclastic vasculitis with unusual clinical appearance. Arch Dermatol.1999 Jun; 135 (6): 726-7
26. Michels A, Vandermoten G, Duchateau J et al. Anaphylaxis with sodium benzoate. Lancet 1999; 337: 1424-1425
27. Lewis MA, Lamey PJ, Forsyth A, Gall J. Recurrent erythema multiforme: a possible role of foodstuffs. Br Dent J. 1989 May 20;166(10):371-3.
28. Davis BA, Raubertas RF, Pearson SK, Bowen WH. The effects of benzoate and fluoride on dental caries in intact and desalivated rats. Caries Res. 2001 Sep-Oct; 35 (5): 331-7
29. Breitkreutz J, El-Saleh F, Kiera C et al. Paediatric drug formulations of sodium benzoate: II. Coated granules with a lipophilic binder. Eur J Pharm Biopharm. 2003 Sep; 56 (2): 255-60
30. Nutrition Information Centre, University of Stellenbosch, Department of Human Nutrition. ADHD Fact Sheet. http://www.sun.ac.za/nicus
31. Batemen B, Warner JO, Hutchison E et al. The effects of double blind, placebo controlled artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child. 2004 Jun; 89 (6): 506-511
32. Evaluation of certain food additives. Fifty first report of the Joint FAO/ WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser. 2000; 891: i-viii, 1-168
33. Yoon HJ, Cho YH, Park J et al. Assessment of estimated daily intakes of benzoates for average and high consumers in Korea. Food Addit Contam. 2003 Feb; 20 (2): 127-35
34. Tfouni SA, Toledo MC. Estimates of mean per capita daily intake of benzoic acid and sorbic acids in Brazil. Food Addit Contam. 2002 Jul; 19 (7): 647-54
35. Worm M, Vieth W, Ehlers I et al. Increased leukotriene production by food additives in patients with atopic dermatitis and proven food intolerance. Clin Exp Allergy. 2001 Feb; 31 (2): 265-73

E. CPD Questions (For South African dietitians only. Australian dietitians: where you have relevant learning goals, CPD hours related to this resource can be included in your APD log.)

2. With healthy liver function, benzoates are completely eliminated from the body at the following rate:
a. 50% of the dose within 6 hours and the remaining dose within 2-3 days
b. 75-100% of the dose within 124 hours and the remaining dose within 1 day
c. 75-100% of the dose within 6 hours and the remaining dose within 2-3 days
d. 100% of the dose within 24 hours

3. Benzoic acid may occur naturally in the following foods:
a. Yoghurt, berries, apples, prunes, apricot, Ceylon tea
b. Mincemeat, margarine, pickles, maraschino cherries, fruit juices
c. None of the above
d. All of the above

4. Benzoic acid is used in cosmetics as:
a. A preservative, a solvent, and a viscosity-decreasing agent
b. A pH adjustor
c. A pH adjuster and a preservative
d. A fragrance component and a solvent and viscosity-decreasing agent

5. A double-blind placebo-controlled study suggests that food additives could be aetiological factors rather than triggers or aggravating factors of persistent rhinitis.
a. True
b. False

6. The acceptable daily intake (ADI) for both benzoic acid and sodium benzoate, as established by the World Health Organisation, is 0-5 mg/kg body weight.
a. True
b. False

7. The E-numbers for benzoic acid, sodium benzoate, and potassium benzoate respectively are the following:
a. E216, E217, E218
b. E212, E210, E211
c. E212, E214, E216
d. E210, E211, E212
e. None of the above

8. Benzoate-sensitive individuals may also react to parabens.
a. True
b. False

Please make an "X" in the appropriate block for each question

This issue was sponsored by Abbott Laboratories S.A (PTY) LTD All Abbott products are lactose and gluten free Tel: 011-8582054