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This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization. First draft prepared by Dr A. Wibbertmann, Dr J. Kielhorn, Dr G. Koennecker, Dr I. Mangelsdorf, and Dr C. Melber, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization Geneva, 2000 The

International Programme on Chemical Safety (IPCS)

, established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The

Inter-Organization Programme for the Sound Management of

was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Benzoic acid and sodium benzoate. (Concise international chemical assessment document ; 26) 1.Benzoic acid - toxicity 2.Sodium benzoate - toxicity 3.Risk assessment 4.Environmental exposure ternational Programme on Chemical Safety II.Series ISBN 92 4 153026 X (NLM Classification: QD 341.A2) ISSN 1020-6167 The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. (c) World Health Organization 2000 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany, provided financial support for the printing of this publication.


Concise International Chemical Assessment Documents (CICADs) are the latest in a family of publications from the International Programme on Chemical Safety (IPCS) -- a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of chemicals. CICADs are concise documents that provide summaries of the relevant scientific information concerning the potential effects of chemicals upon human health and/or the environment. They are based on selected national or regional evaluation documents or on existing EHCs. Before acceptance for publication as CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their completeness, accuracy in the way in which the original data are represented, and the validity of the conclusions drawn. The primary objective of CICADs is characterization of hazard and dose-response from exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that information considered critical for characterization of the risk posed by the chemical. The critical studies are, however, presented in sufficient detail to support the conclusions drawn. For additional information, the reader should consult the identified source documents upon which the CICAD has been based. Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 170

for advice on the derivation of health-based tolerable intakes and guidance values.

International Programme on Chemical Safety (1994)

Assessing human health risks of chemicals: deriviation of

guidance values for health-based exposure limits

. Geneva, World Health Organization (Environmental Health Criteria 170). While every effort is made to ensure that CICADs represent the current status of knowledge, new information is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new information that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.

The flow chart shows the procedures followed to produce a CICAD. These procedures are designed to take advantage of the expertise that exists around the world -- expertise that is required to produce the high-quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment. The first draft is based on an existing national, regional, or international review. Authors of the first draft are usually, but not necessarily, from the institution that developed the original review. A standard outline has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS to ensure that it meets the specified criteria for CICADs. The second stage involves international peer review by scientists known for their particular expertise and by scientists selected from an international roster compiled by IPCS through recommendations from IPCS national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are required to take reviewers comments into account and revise their draft, if necessary. The resulting second draft is submitted to a Final Review Board together with the reviewers comments. The CICAD Final Review Board has several important functions: - to ensure that each CICAD has been subjected to an appropriate and thorough peer review; - to verify that the peer reviewers comments have been addressed appropriately; - to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and - to approve CICADs as international assessments. Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation. Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

This CICAD on benzoic acid and sodium benzoate was prepared by the Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany. The two compounds are being considered together because it is undissociated benzoic acid that is responsible for its antimicrobial activity. As benzoic acid itself is only slightly soluble in water, sodium benzoate -- which, under acid conditions, converts to undissociated benzoic acid -- is often used instead. This CICAD was based on reviews compiled by the German Advisory Committee on Existing Chemicals of Environmental Relevance (BUA, 1995), the US Food and Drug Administration (US FDA, 1972a), and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (WHO, 1996) to assess potential effects of benzoic acid and sodium benzoate on the environment and on humans. A comprehensive literature search of relevant databases was conducted in September 1999 to identify any relevant references published subsequent to those incorporated in these reports. Information on the preparation and peer review of the source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Sydney, Australia, on 21-24 November 1999. Participants at the Final Review Board meeting are listed in Appendix 3. The International Chemical Safety Card (ICSC 0103) for benzoic acid, produced by the International Programme on Chemical Safety (IPCS, 1993), has also been reproduced in this document (Appendix 4). Benzyl acetate, its hydrolysis product, benzyl alcohol, and the oxidation product of this alcohol, benzaldehyde, are extensively metabolized to benzoic acid in experimental animals and humans. Therefore, toxicological data on these precursors were also utilized in the assessment of the potential health effects of benzoic acid. Benzoic acid (CAS No.

) is a white solid that is slightly soluble in water. Sodium benzoate (CAS No.

) is about 200 times more soluble in water. Benzoic acid is used as an intermediate in the synthesis of different compounds, primarily phenol (>50% of the amount produced worldwide) and caprolactam. Other end products include sodium and other benzoates, benzoyl chloride, and diethylene and dipropylene glycol dibenzoate plasticizers. Sodium benzoate is primarily used as a preservative and corrosion inhibitor (e.g., in technical systems as an additive to automotive engine antifreeze coolants). Benzoic acid and sodium benzoate are used as food preservatives and are most suitable for foods, fruit juices, and soft drinks that are naturally in an acidic pH range. Their use as preservatives in food, beverages, toothpastes, mouthwashes, dentifrices, cosmetics, and pharmaceuticals is regulated. The estimated global production capacity for benzoic acid is about 600 000 tonnes per year. Worldwide sodium benzoate production in 1997 can be estimated at about 55 000-60 000 tonnes. Benzoic acid occurs naturally in many plants and in animals. It is therefore a natural constituent of many foods, including milk products. Anthropogenic releases of benzoic acid and sodium benzoate into the environment are primarily emissions into water and soil from their uses as preservatives. Concentrations of naturally occurring benzoic acid in several foods did not exceed average values of 40 mg/kg of food. Maximum concentrations reported for benzoic acid or sodium benzoate added to food for preservation purposes were in the range of 2000 mg/kg of food. After oral uptake, benzoic acid and sodium benzoate are rapidly absorbed from the gastrointestinal tract and metabolized in the liver by conjugation with glycine, resulting in the formation of hippuric acid, which is rapidly excreted via the urine. To a lesser extent, benzoates applied dermally can penetrate through the skin. Owing to rapid metabolism and excretion, an accumulation of the benzoates or their metabolites is not to be expected. In rodents, the acute oral toxicity of benzoic acid and sodium benzoate is low (oral LD

values of >1940 mg/kg body weight). In cats, which seem to be more sensitive than rodents, toxic effects and mortality were reported at much lower doses (about 450 mg/kg body weight). Benzoic acid is slightly irritating to the skin and irritating to the eye, while sodium benzoate is not irritating to the skin and is only a slight eye irritant. For benzoic acid, the available studies gave no indication of a sensitizing effect; for sodium benzoate, no data were identified in the literature. In short-term studies with rats, disorders of the central nervous system (benzoic acid/sodium benzoate) as well as histopathological changes in the brain (benzoic acid) were seen after feeding high doses (

1800 mg/kg body weight) over 5-10 days. Other effects included reduced weight gain, changes in organ weights, changes in serum parameters, or histopathological changes in the liver. The information concerning long-term oral exposure of experimental animals to benzoic acid is very limited, and there is no study available dealing specifically with possible carcinogenic effects. From a limited four-generation study, only a preliminary no-observed-(adverse-)effect level (NO(A)EL) of about 500 mg/kg body weight per day can be derived. With sodium benzoate, two long-term studies with rats and mice gave no indication of a carcinogenic effect. However, the documentation of effects is inadequate in most of these studies; therefore, no reliable NO(A)EL values can be derived. Data on its precursors support the notion that benzoic acid is unlikely to be carcinogenic. Benzoic acid tested negative in several bacterial assays and in tests with mammalian cells, while

studies were not identified. Sodium benzoate was also inactive in Ames tests, whereas tests with mammalian cells gave consistently positive results. In one

study (dominant lethal assay with rats), a positive result was obtained. At present, a genotoxic activity of sodium benzoate cannot be ruled out entirely. For benzoic acid, two limited studies gave no indication of adverse reproductive or developmental effects. With sodium benzoate, several studies on different species have been performed, and embryotoxic and fetotoxic effects as well as malformations were seen only at doses that induced severe maternal toxicity. In a dietary study in rats, a NO(A)EL of about 1310 mg/kg body weight was established. Data on its precursors support the notion that benzoic acid is unlikely to have adverse reproductive effects at dose levels not toxic to the mother. In humans, the acute toxicity of benzoic acid and sodium benzoate is low. However, both substances are known to cause non-immunological contact reactions (pseudoallergy). This effect is scarce in healthy subjects; in patients with frequent urticaria or asthma, symptoms or exacerbation of symptoms was observed. A provisional tolerable intake of 5 mg/kg body weight per day can be derived, although benzoates at lower doses can cause non-immunological contact reactions (pseudoallergy) in sensitive persons. As there are no adequate studies available on inhalation exposure, a tolerable concentration for exposure by inhalation cannot be calculated. From their physical/chemical properties, benzoic acid and sodium benzoate emitted to water and soil are not expected to volatilize to the atmosphere or to adsorb to sediment or soil particles. From the results of numerous removal experiments, the main elimination pathway for both chemicals should be biotic mineralization. Data from laboratory tests showed ready biodegradability for both substances under aerobic conditions. Several isolated microorganisms (bacteria, fungi) have been shown to utilize benzoic acid under aerobic or anaerobic conditions. From the experimental data on bioconcentration, a low to moderate potential for bioaccumulation is to be expected. From valid test results available on the toxicity of benzoic acid and sodium benzoate to various aquatic organisms, these compounds appear to exhibit low to moderate toxicity in the aquatic compartment. The lowest EC

value of 9 mg/litre (cell multiplication inhibition) reported in a chronic study was observed in the cyanobacterium

values for the other aquatic species tested were in the range of 60-1291 mg/litre. Immobilization of

has been demonstrated to be pH dependent, with a lower 24-h EC

(102 mg/litre) at acidic pH. For the freshwater fish golden ide

of 460 mg/litre has been determined. Developmental effects have been found in frog

embryos at a concentration of 433 mg/litre (96-h EC

for malformation). For sodium benzoate, exposure of juvenile stages of aquatic organisms in a multispecies test (including

values of greater than100 mg/litre. A 96-h LC

of 484 mg/litre has been determined in the freshwater fish fathead minnow

Owing to the limited available data on exposure levels in water, a quantitative risk characterization with respect to aquatic organisms in surface waters could not be performed. Taking into account the rapid biodegradability, the low to moderate bioaccumulation potential, the low toxicity to most aquatic species, and the rapid metabolism of these substances, benzoic acid and sodium benzoate will -- with the exception of accidental spills -- pose only a minimal risk to aquatic organisms. The few available data indicate that benzoic acid and sodium benzoate have only a low toxicity potential in the terrestrial environment. Except for the antimicrobial action of benzoic acid, characterized by minimum microbiocidal concentrations ranging from 20 to 1200 mg/litre, no data on toxic effects of benzoic acid on terrestrial organisms were available. For sodium benzoate, bacterial and fungal growth were inhibited in a pH-dependent manner by concentrations ranging from 100 to 60 000 mg/litre. Owing to the lack of measured exposure levels, a sample risk characterization with respect to terrestrial organisms could not be performed.


COOH; benzenecarboxylic acid, phenyl carboxylic acid [E 210 (EU No. Regulation on Labelling of Foodstuffs)]; molecular weight 122.13) is a white solid that starts to sublime at 100C, with a melting point of 122C and a boiling point of 249C. Its solubility in water is low (2.9 g/litre at 20C), and its solution in water is weakly acid (dissociation constant at 25C = 6.335 10

4.19). It is soluble in ethanol and very slightly soluble in benzene and acetone. It has an octanol/water partition coefficient (log

) of 1.9. Its vapour pressure at 20C ranges from 0.11 to 0.53 Pa. Its calculated Henrys law constant at 20C was given as 0.0046-0.022 Pa.m

/mol (BUA, 1995). Additional physical and chemical properties are presented in the International Chemical Safety Card reproduced in this document (Appendix 4). Sodium benzoate (CAS No.

Na; benzoic acid, sodium salt [E 211 (EU No. Regulation on Labelling of Foodstuffs)]; molecular weight 144.11) has a melting point above 300C. It is very soluble in water (550-630 g/litre at 20C) and is hygroscopic at a relative humidity above 50%. Its pH is about 7.5 at a concentration of 10 g/litre water. It is soluble in ethanol, methanol, and ethylene glycol. Dry sodium benzoate is electrically charged by friction and forms an explosive mixture when its dust is dispersed in air (Maki & Suzuki, 1985).

Analytical methods for the determination of benzoic acid include spectrophotometric methods, which need extensive extraction procedures and are not very specific; gas chromatographic (GC) methods, which are more sensitive and specific but need lengthy sample preparation and derivatization prior to determination; and high-performance liquid chromatography (HPLC), which has a high specificity and minimum sample preparation and does not require derivatization. A direct determination of benzoic acid in air by flash desorption at 240C with helium into capillary-GC gave a detection limit of 0.1 ppm (0.5 mg/m

) in a 20-litre sample (=10 g benzoic acid). This method has been developed and used for monitoring occupational exposure (Halvorson, 1984). A method for the determination of benzoic acid in solid food at 0.5-2 g/kg levels involves extraction with ether into aqueous sodium hydroxide and methylene chloride, conversion to trimethylsilyl esters, and detection by GC and flame ionization (Larsson, 1983; AOAC, 1990). For margarine, a method using HPLC and ultraviolet (UV) detection has been described with prior extraction with ammonium acetate/acetic acid/methanol (Arens & Gertz, 1990). When benzoic acid is used as a preservative in soft drinks and fruit drinks, other additives, colouring agents, and other acids (e.g., sorbate) may interfere with its analysis. Liquid chromatographic methods were developed to overcome this (e.g., Bennett & Petrus, 1977; Puttemans et al., 1984; Tyler, 1984). For the sensitive determination of benzoic acid in fruit-derived products, a clean-up pretreatment with solid-phase extraction followed by liquid chromatography with UV absorbance detection is described (Mandrou et al., 1998). The detection limit is 0.6 mg/kg, with a range of quantification of 2-5 mg/kg. For soft drinks, a simultaneous second-order derivative spectrophotometric determination has been developed (detection limit 1 mg/litre) (Castro et al., 1992). Sodium benzoate was measured in soya sauce, fruit juice, and soft drinks using HPLC with a UV spectrophotometric detector. Before injection, all samples were filtered (Villanueva et al., 1994). GC determination of low concentrations (down to 10 ng/ml) of benzoic acid in plasma and urine was preceded by diethyl ether extraction and derivatization with pentafluorobenzyl bromide (Sioufi & Pommier, 1980). Detection was by

Ni electron capture. HPLC methods have been developed for the simultaneous determination of benzoic acid and hippuric acid -- the metabolite of sodium benzoate that is eliminated in the urine -- that require no extraction step (detection limit for both, 1 g/ml; Kubota et al., 1988). Hippuric acid and creatinine levels have been determined simultaneously by HPLC, and measured hippuric acid levels corrected for urinary creatinine excretion (Villanueva et al., 1994).


4.1 Natural sources of benzoic acid

Benzoic acid is produced by many plants as an intermediate in the formation of other compounds (Goodwin, 1976). High concentrations are found in certain berries (see section 6.1). Benzoic acid has also been detected in animals (see section 6.1). Benzoic acid therefore occurs naturally in many foods, including milk products (Sieber et al., 1989, 1990).

From data provided by the German producers, emissions of benzoic acid from industrial processes were less than 525 kg per year into the atmosphere, less than 3 tonnes per year into the River Rhine, and 8 tonnes per year into sewage or water purification plants (BUA, 1995). No data were available from other countries. Other anthropogenic releases of benzoic acid and sodium benzoate into the environment are emissions into water and soil from their uses as preservatives in food, toothpastes, mouthwashes, dentifrices, and cosmetics. There were no data available on the emission of benzoic acid from the disposal of antifreeze mixtures and waterborne cooling systems and other miscellaneous industrial uses. The amount of benzoic acid emitted to air from car exhaust gases as an oxidation product is not quantifiable from the available data.


5.1 Transport and distribution between media

(Oussi et al., 1998). However, benzoic acid adsorbed on silica gel (SiO

) and irradiated with UV light (lambda > 290 nm) for 17 h showed 10.2% photodegradation (Freitag et al., 1985). This may be due to a photocatalytic effect, which was also observed with other oxides, notably zinc oxide (ZnO) and titanium dioxide (TiO

). When benzoic acid was irradiated with sunlight in aqueous suspensions of zinc or titanium dioxide, 67% (after 2-3 h) or 90% (after 24 h) of the applied amount was mineralized (Kinney & Ivanuski, 1969; Matthews, 1990).

An einstein is a unit of light energy used in photochemistry, equal to Avogadros number times the energy of one photon of light of the frequency in question. Indirect photolysis by reaction with hydroxyl radicals is expected to be low. Hydroxyl radical rate constants

) for benzoic acid and its anion have been estimated to be approximately 0.5 10

/s, respectively (Palm et al., 1998). Standardized tests on ready (MITI, 1992) or inherent (Zahn & Wellens, 1980) biodegradation showed benzoic acid to be readily biodegraded. The degrees of aerobic degradation were as follows: MITI I 85% (100 mg/litre; (MITI, 1992) test 2 weeks; OECD No. 301C) Zahn-Wellens >90% (508 mg/litre; (Zahn & Wellens, test 2 days) 1980) Easy degradation of benzoic acid to methane and carbon dioxide was also observed in different non-standardized experiments using sewage sludge as inoculum (BUA, 1995). Benzoic acid was found to be degraded by adapted anaerobic sewage sludge at 86-93% after 14 days (Nottingham & Hungate, 1969), by aerobic activated sludge (adapted) at >95% after 5-20 days (Pitter, 1976; Lund & Rodriguez, 1984), and by unadapted aerobic activated sludge at 61-69% after 2-3 days with a preceding lag time of 2-20 h (Urano & Kato, 1986). The use of a synthetic sewage inoculated with laboratory bacterial cultures led to complete degradation of benzoic acid after 14 days under anaerobic conditions (Kameya et al., 1995). A greater variability in degradation (0-100%) was seen in tests using environmental matrices (e.g., rain, lake water, seawater, soil, etc.). It depended mainly on substance concentration and time for acclimation (see Table 1). Test durations exceeding 2 days resulted in removal of

40% when initial concentrations were below 20 mg/litre. A rapid mineralization occurred in groundwater and subsurface soil samples. In groundwater, a half-life of 41 h has been found for benzoic acid (initial concentration 1-100 g/litre; metabolized to

) under aerobic conditions (Ventullo & Larson, 1985). Half-lives of 7.3 h and 18.2 h, respectively, have been observed for aerobic and anaerobic degradation of benzoic acid (initial concentration 1 mg/kg dry weight; metabolized to

) in subsurface soils of septic tank tile fields (Ward, 1985). Anaerobic degradation of benzoic acid (initial concentration 250 mg carbon/litre) in a methanogenic microcosm (consisting of aquifer solids and groundwater) required 4 weeks of adaptation, followed by nearly complete depletion after 8 weeks of incubation (Suflita & Concannon, 1995). Several isolated microorganisms have been shown to utilize (and therefore probably degrade) benzoic acid under aerobic or anaerobic conditions. They include, among others, fungal species such as

and other yeast-like fungi (Kocwa-Haluch & Lemek, 1995), the mould

(Hofrichter & Fritsche, 1996), and bacteria, such as

several strains of denitrifying pseudomonads (Fuchs et al., 1993; Elder & Kelly, 1994; Harwood & Gibson, 1997), and

(Sharak Genthner et al., 1997). Although benzoic acid is primarily metabolized to hippuric acid in rats (see section 7), some other species do excrete other metabolites, such as dibenzoylornithine (hen), benzoylglutamic acid (Indian fruit bat), benzoylarginine (tick, insects), or benzoyltaurine (southern flounder,

(Parke, 1968; Goodwin, 1976; James & Pritchard, 1987).

/s (Palm et al., 1998). Sodium benzoate was readily biodegradable under aerobic conditions in several standard test systems: Modified 84% (100 mg/litre; (King & Painter, MITI test 10 days) 1983) Modified 80-90% (50 mg/litre; (Salanitro et a