Food and Chemical Toxicology 40 (2002) 1335–1373
`
`www.elsevier.com/locate/foodchemtox
`
`Review
`
`Evaluation of the health aspects of methyl paraben:
`a review of the published literature
`
`M.G. Sonia,*, S.L. Taylorb, N.A. Greenbergc, G.A. Burdocka
`aBurdock Group, 780 US HWY 1, Suite 300, Vero Beach, FL 32962, USA
`bUniversity of Nebraska, Dept of Food Science & Technology, 143 Food Industry Building, Lincoln, NE 68583, USA
`cNovartis Nutrition Corporation, 1541 Park Place Boulevard, St Louis Park, MN 55416, USA
`
`Accepted 2 February 2002
`
`Abstract
`
`Methyl paraben (CAS No. 99-76-3) is a methyl ester of p-hydroxybenzoic acid. It is a stable, non-volatile compound used as an
`antimicrobial preservative in foods, drugs and cosmetics for over 50 years. Methyl paraben is readily and completely absorbed
`through the skin and from the gastrointestinal tract. It is hydrolyzed to p-hydroxybenzoic acid, conjugated, and the conjugates are
`rapidly excreted in the urine. There is no evidence of accumulation. Acute toxicity studies in animals indicate that methyl paraben
`is practically non-toxic by both oral and parenteral routes. In a population with normal skin, methyl paraben is practically
`non-irritating and non-sensitizing. In chronic administration studies, no-observed-effect levels (NOEL) as high as 1050 mg/kg have
`been reported and a no-observed-adverse-effect level (NOAEL) in the rat of 5700 mg/kg is posited. Methyl paraben is not carci-
`nogenic or mutagenic. It is not teratogenic or embryotoxic and is negative in the uterotrophic assay. The mechanism of cytotoxic
`action of parabens may be linked to mitochondrial failure dependent on induction of membrane permeability transition accom-
`panied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation.
`Parabens are reported to cause contact dermatitis reactions in some individuals on cutaneousl exposure. Parabens have been
`implicated in numerous cases of contact sensitivity associated with cutaneous exposure; however, the mechanism of this sensitivity
`is unknown. Sensitization has occurred when medications containing parabens have been applied to damaged or broken skin.
`Allergic reactions to ingested parabens have been reported, although rigorous evidence of the allergenicity of ingested paraben is
`lacking. # 2002 Elsevier Science Ltd. All rights reserved.
`
`Keywords: Methyl paraben; Preservative; Food ingredient; Food additive; Cosmetic; Drug; Excipient; Antimicrobial; Safety
`
`Contents
`
`1. Introduction ............................................................................................................................................................................. 1336
`1.1. Description, specification, occurrence and sources.......................................................................................................... 1337
`1.2. Economic uses ................................................................................................................................................................. 1337
`1.3. Cosmetic uses .................................................................................................................................................................. 1338
`1.4. Uses in food..................................................................................................................................................................... 1338
`1.5. Pharmaceutical uses......................................................................................................................................................... 1339
`1.6. Regulatory history........................................................................................................................................................... 1340
`
`Abbreviations: Ach, acetylcholine; ADI, acceptable daily intake; CAM, chorioallantoic membrane; CAM–TB, CAM–trypan blue staining;
`CVS, crystal violet staining; DBP, dibenzo[a,i]pyrene; DNCB, dinitrochlorobenzene; DRG, dorsal root ganglion; FEMA, Flavor and Extract
`Manufacturers’ Association; GRAS, generally recognized as safe; 2HBC, 2-hydroxypropyl-b-cyclodextrin; HET–CAM, hen’s egg test–CAM; LISS,
`low-ionic-strength salt; LPS, lipopolysaccharide; MIC, minimum inhibitory concentration; NOAEL, no-observed-adverse-effect level; NOEL, no-
`observed-effect level; NRU, neutral red uptake; OTC, over-the-counter; PADI, possible average daily intake; PCB, polychlorinated biphenyls; PII,
`primary irritation index; RIPT, repeated insult patch test; SCOGS, Select Committee on GRAS Substances; SLS, sodium lauryl sulfate; SRBC, anti-
`sheep red blood cell.
`* Corresponding author. Tel.: +1-561-562-3900x104; fax: +1-561-562-3908.
`E-mail address: msoni@burdockgroup.com (M.G. Soni).
`
`0278-6915/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
`P I I : S 0 2 7 8 - 6 9 1 5 ( 0 2 ) 0 0 1 0 7 - 2
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`2. Consumption............................................................................................................................................................................ 1340
`2.1. Consumption summary ................................................................................................................................................... 1342
`
`3. Biological data ......................................................................................................................................................................... 1342
`3.1. Biochemical aspects ......................................................................................................................................................... 1342
`3.2. Absorption, distribution, metabolism and excretion ....................................................................................................... 1342
`3.3. Effects on enzymes and other biochemical parameters ................................................................................................... 1343
`
`4. Toxicological studies ................................................................................................................................................................ 1346
`4.1. Acute toxicity studies ...................................................................................................................................................... 1346
`4.1.1. Oral acute effects ................................................................................................................................................. 1346
`4.1.2. Dermal acute toxic effects ................................................................................................................................... 1347
`4.1.3. Subcutaneous acute effects .................................................................................................................................. 1347
`4.1.4.
`Intraperitoneal acute effects ................................................................................................................................ 1347
`4.1.5.
`Intraocular acute effects ...................................................................................................................................... 1347
`4.1.6.
`Intravenous acute effects ..................................................................................................................................... 1347
`4.1.7. Subconjuctival acute effects ................................................................................................................................. 1348
`4.1.8. Subarachnoid acute effects .................................................................................................................................. 1348
`4.2. Subchronic toxicity studies .............................................................................................................................................. 1348
`4.2.1. Oral short-term effects......................................................................................................................................... 1348
`4.2.2. Dermal short-term effects .................................................................................................................................... 1348
`4.2.3.
`Intrathecal short-term effects............................................................................................................................... 1349
`
`5. Long-term and carcinogenicity studies..................................................................................................................................... 1349
`5.1. Long-term studies............................................................................................................................................................ 1349
`5.2. Carcinogenicity studies .................................................................................................................................................... 1350
`5.3. Embryotoxicity and teratology studies............................................................................................................................ 1351
`5.4. Studies on genotoxicity.................................................................................................................................................... 1351
`5.4.1. Mutagenesis......................................................................................................................................................... 1351
`5.4.2. Cytotoxicity ......................................................................................................................................................... 1352
`
`6. Antimicrobial effects ................................................................................................................................................................ 1354
`
`7. Immunotoxicity and sensitivity ................................................................................................................................................ 1357
`7.1. Dermal irritation ............................................................................................................................................................. 1358
`7.2. Eye irritation ................................................................................................................................................................... 1358
`7.3. Other studies.................................................................................................................................................................... 1358
`
`8. Observations in humans ........................................................................................................................................................... 1359
`8.1. Biochemical aspects ......................................................................................................................................................... 1359
`8.2. Effects on enzymes and other biochemical parameters ................................................................................................... 1360
`8.3. Clinical observations ....................................................................................................................................................... 1360
`8.4. Sensitivity studies in humans........................................................................................................................................... 1360
`8.5. Paraben paradox ............................................................................................................................................................. 1363
`8.6. Case reports..................................................................................................................................................................... 1363
`8.7. Other clinical studies ....................................................................................................................................................... 1364
`8.8. Consumer reports ............................................................................................................................................................ 1364
`
`9. Summary .................................................................................................................................................................................. 1365
`
`References ..................................................................................................................................................................................... 1366
`
`1. Introduction
`
`Methyl paraben (Fig. 1) is one of a homologous series
`of parabens (including methyl, ethyl, butyl, heptyl and
`benzyl parabens), used singly or in combination to exert
`the intended antimicrobial affect. Parabens are particularly
`
`useful against molds and yeasts. These substances can
`have multiple biological effects, but it is generally con-
`sidered that their inhibitory effects on membrane trans-
`port and mitochondrial function processes are key for
`their actions. The parabens meet several of the criteria of
`an ideal preservative, in that they have a broad spectrum
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`M.G. Soni et al. / Food and Chemical Toxicology 40 (2002) 1335–1373
`
`1337
`
`Fig. 1. Structure of methyl paraben.
`
`of antimicrobial activity, are safe to use (i.e. relatively
`non-irritating, non-sensitizing, and of low toxicity), are
`stable over the pH range, and are sufficiently soluble in
`water to produce the effective concentration in aqueous
`phase. Antimicrobial activity of paraben increases as the
`chain length of the ester group increases, but since
`solubility decreases with increasing chain length, the
`lower esters (methyl and propyl) are the practical choi-
`ces for use in foods. Methyl paraben has been used as
`an antimicrobial preservative in foods, drugs and cos-
`metics for over 50 years. There have been several pre-
`vious safety assessments undertaken on this substance
`by several agencies, including FAO/WHO, FDA and
`FEMA. The purpose of this review is to examine the
`scientific literature describing the safety of methyl
`paraben in order to set an acceptable daily intake
`(AID).
`
`1.1. Description, specification, occurrence and sources
`
`Pure methyl paraben is a colorless crystalline or white
`powder. It is odorless or has a faint characteristic odor
`and a slight burning taste. Methyl paraben is resistant
`to hydrolysis in hot and cold water but hydrolyzes in
`alkaline solutions. It is stable in air. Aqueous solutions
`of methyl paraben buffered at pH 3 and 6 showed no
`decomposition when heated for 2 h at 100 C or for 30
`min at 120 C.
`Methyl paraben is an ester of p-hydroxybenzoic acid.
`is produced by the methanol esterification of
`It
`p-hydroxybenzoic acid in the presence of sulfuric acid.
`The materials are heated for distillation in a glass-lined
`
`Table 1
`Methyl paraben specifications (published values)
`
`reactor under reflux. The acid is then neutralized with
`caustic soda and the product is crystallized by cooling.
`The crystallized product is centrifuged, washed, dried
`under vacuum, milled and blended, all in corrosion-
`resistant equipment to avoid metallic contamination.
`Some published specifications for methyl paraben are
`summarized in Table 1.
`Aqueous solutions of methyl paraben, at pH 36, may
`be sterilized by autoclaving at 120 C for 20 min, without
`decomposition (Kibbe, 2000; Raval and Parrott, 1967).
`Aqueous solutions at pH 3–6 are stable (less than 10%
`decomposition) for up to about 4 years at room tempera-
`ture. Aqueous solutions at pH 8 or above are subject to
`rapid hydrolysis (10% or more after about 60 days of
`storage at room temperature). McCarthy (1970) reported
`that storage of methyl paraben (0.1%) in polyethylene
`bottles or in rigid polyvinyl chloride containers at 25 C
`for 12 weeks did not result in any loss of methyl paraben.
`Natural occurrence of methyl paraben has been
`reported in cloudberry, yellow passion fruit juice, white
`wine, botrytised wine and Bourbon vanilla. The amount
`of methyl paraben detected in cloudberry is around 0.15
`ppm (TNO, 2000). Goodwin et al. (1979) identified
`methyl paraben as a component of vaginal secretions of
`female dogs in estrus. Analysis of secretions at other
`points of their estrous cycle revealed no presence of
`methyl paraben. The authors of this study suggested
`that methyl paraben is a sex pheromone of dogs.
`
`1.2. Economic uses
`
`Methyl paraben is widely used as an antimicrobial
`preservative in cosmetics, food products and pharma-
`ceutical formulations. It may be used either alone, in
`combination with other parabens, or with other anti-
`microbial agents. In cosmetics, methyl paraben is the
`most frequently used antimicrobial preservative (Decker
`and Wenninger, 1987).
`
`SCOGSa (1972)
`
`Burdock (1997)
`
`Elder (1984)
`
`FCCb (1996)
`
`Small crystals or white powder
`Faint, characteristic
`0.25 g/100 ml water at 25 C
`125–128
`152.14
`
`White needles
`Odorless
`Slightly soluble
`131
`152.15
`
`Colorless crystals
`No odor
`Slightly soluble
`131
`152.16
`
`Small crystals
`Faint, characteristic
`1 g/400 ml water at 25 C
`125–128
`152.15
`
`–
`–
`
`–
`
`1 ppm
`10 ppm
`0.05%
`
`–
`10 mg/kg
`
`0.05%
`
`Physical form
`Odor
`Solubility
`Melting point (C)
`Molecular weight
`
`Inorganic impurities
`Arsenic
`Heavy metals (Pb)
`
`3 ppm
`10 ppm
`
`Residue on ignition
`
`0.05%
`
`a SCOGS, Subcommittee on GRAS Substances.
`b FCC, Food Chemical Codex.
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`
`1.3. Cosmetic uses
`
`Parabens are widely used cosmetic preservatives pre-
`sent in a large variety of products, including face, body
`and hand creams, lotions and moisturizers; eye makeup
`products; foundation and other makeup products; night
`creams and lotions; cleansing products; hair condi-
`tioners; bubble baths; shampoos; mud packs; underarm
`deodorants; skin lighteners; and sachets (Nikitakis,
`1988). Methyl paraben and propyl paraben are the most
`commonly used preservatives in cosmetics (Berke et al.,
`1982; Gruvberger et al., 1998; Soni et al., 2001). Para-
`bens are found in all types of formulations and have a
`use in over 13,200 formulations (Elder, 1984). Con-
`centrations of parabens are usually less than 0.3%, with
`the most common preservative system containing 0.3%
`methyl paraben and 0.1% propyl paraben but may
`range up to 1%. Parabens formulate well because they
`have no perceptible odor or taste, are practically
`neutral, do not produce discoloration, and do not
`cause hardening or ‘‘muddying’’ (Neidig and Burrell,
`1944).
`The popular use of paraben preservatives in cosmetics
`and toiletries arises from their low toxicity, broad spec-
`trum of activity, worldwide regulatory acceptance, bio-
`degradability, and low cost. Moreover, parabens have
`excellent chemical stability in relation to pH (effective
`between pH 4.5 and 7.5) and temperature (Blaug and
`Grant, 1974; Alexander et al., 1978). Consequently,
`products containing parabens can be autoclaved safely
`without significant loss of antimicrobial activity from
`hydrolysis (Maddox, 1982). Other advantages of para-
`bens are found in their low tendency towards absorp-
`tion in commonly used plastics of primary packaging
`material. The percent decomposition of a methyl para-
`ben solution in an autoclave for 30 min at pH 6 and 9
`was 5.5 and 49% of the initial concentration, respec-
`tively. Sunderland and Watts (1984) reported that the
`time taken for a 10% loss of the initial methyl ester
`concentration at 130.5 C and pHs of 10.59, 8.9 and
`6.58 are approximately 4 s, 3 min and 40 min, respec-
`tively. This ester is therefore unable to adequately with-
`stand a normal
`sterilization procedure unless
`the
`solution is within a pH range of 3–6 at the sterilization
`temperature.
`As the carbon number of the alkyl chain of parabens
`increases, antimicrobial activity increases, but water
`solubility decreases and oil solubility increases. Since
`microbial replication generally occurs in the water phase
`of oil/water bases, the amount of paraben dissolved in
`the water phase generally determines the preservative
`efficiency. Taking advantage of each paraben’s solubi-
`lity characteristics, various concentrations of methyl
`paraben and propyl paraben can be added to the
`base’s water and oil phases,
`respectively. These
`favorable characteristics make the combination of
`
`methyl paraben and propyl paraben the most fre-
`quently used preservative system (Jackson, 1992; Soni et
`al., 2001).
`Chemburkar and Jostlin (1975) studied the partition-
`ing of parabens, including methyl paraben, in flavoring
`oils from aqueous systems. The partitioning was depen-
`dent on the concentration of flavoring oil, the pH of the
`aqueous medium, and the nature and concentration of
`additives to the aqueous medium.
`According to the industry’s voluntary submissions to
`the FDA in 1981, the number of product formulations
`and maximum use concentrations for methyl paraben
`was 6606 and 25%, respectively (FDA, 1981). Com-
`monly, formulations contain parabens in concentrations
`up to 1%. Methyl paraben individually or with other
`parabens is used in all 13 product formulation cate-
`gories. Products containing these ingredients may con-
`tact the skin, hair and scalp, lips, mucosae (oral, ocular
`and vaginal), axillae and nails. Products containing
`parabens may be used on an occasional or daily basis
`and their use may extend over a period of years. Fre-
`quency of application and duration of exposure may be
`continuous. Methyl paraben is the most used pre-
`servative in cosmetics (Mowad, 2000).
`Rastogi et al. (1995) determined the contents of para-
`bens in cosmetic products to elucidate the concentration
`and frequency of use of different parabens to monitor
`whether the products complied with the Danish and
`EEC regulations. In an investigation of 215 cosmetic pro-
`ducts, a maximum of 0.32% methyl paraben was present
`in paraben positive cosmetics. Of all paraben-containing
`cosmetics tested, 98% contained methyl paraben. A pre-
`ferential use of methyl!ethyl!propyl!butyl!benzyl
`paraben in various groups of cosmetic products was
`reported.
`
`1.4. Uses in food
`
`their low toxicity and effective anti-
`Because of
`microbial activity, parabens, including methyl paraben,
`have been used in food for more than 50 years. Under
`FDA regulation, methyl paraben is generally recognized
`as safe (GRAS) when used as chemical preservative in
`foods, with a use limit of 0.1% (21 CFR 184.1490;
`Table 2). Types of food that may contain parabens
`include alcoholic beverages,
`frozen dairy products,
`gelatins, grain products,
`jams,
`jellies, marmalades,
`mincemeat, olives, pickles,
`relishes, preserves, pro-
`cessed fruits and vegetables,
`tomato pulp,
`tomato
`puree, catsup,
`fruit
`juices,
`soft drinks, puddings,
`seasonings, soft candy, sugar substitutes, syrups and
`sweet sauces (Smolinske, 1992). Parabens are used in
`coffee extracts, fruit juices, pickles, sauces, soft drinks,
`processed vegetables, baked goods, seasonings, sugar
`substitutes and frozen dairy products at concentrations
`of between 450 and 2000 ppm (Daniel, 1986). In a
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`M.G. Soni et al. / Food and Chemical Toxicology 40 (2002) 1335–1373
`
`1339
`
`Table 2
`CFR and FEMAa approved methyl paraben uses
`
`Source
`
`Citation number
`
`Food category
`
`Permitted functionality
`
`Use limits
`
`FDA
`
`FDA
`
`FDA
`
`FDA
`
`21 CFR 150.141 Food Standards.
`Artificially sweetened fruit jelly.
`Optional ingredient
`
`21 CFR 150.161 Food Standards.
`Artificially sweetened fruit jams.
`Optional ingredient
`
`21 CFR 172.515 Food additives.
`Permitted for direct addition to agents and
`food for human consumption.
`Subpart F- Flavoring agents and related substances.
`Synthetic flavoring substances and adjuvants
`
`21 CFR 181.23 Prior sanctioned ingredients.
`Certain substances employed in the manufacture
`of food-packaging materials.
`Antimycotics
`
`Artificially sweetened
`fruit jelly
`
`Preservative
`
`Not to exceed 0.1%
`
`Artificially sweetened
`fruit preserves and jams
`
`Preservative
`
`Not to exceed 0.1%
`
`No restriction
`
`(12) Flavoring agents
`and adjuvants
`
`CGMPa
`
`No restriction
`
`(2) Antimicrobial
`
`CGMPa
`
`FDA
`
`21 CFR 184.1490 Direct food
`substances affirmed GRAS.
`
`No restriction
`
`(2) Antimicrobial
`agent
`
`CGMPb 0.1%
`
`FEMA
`
`FEMA GRAS No. 2710
`
`Preservative
`
`0.1%
`
`a FEMA, Flavor and Extract Manufacturers’ Association.
`b CGMP, current good manufacturing practice.
`
`LSRO/FASEB (1972) report it is stated that methyl
`paraben is not reported to be used in fats and oils, pro-
`cessed fruits, or alcoholic beverages. Higuera-Ciapara
`and Nieblas (1995) reported the use of hydrogen perox-
`ide-methyl paraben for preservation and stability of
`corn tortillas held at room temperature.
`Methyl paraben is also permitted for use in certain
`standardized foods including artificially sweetened fruit
`jelly (21 CFR 150.141) and artificially sweetened fruit
`preserves and jams (21 CFR 150.161) at a level not to
`exceed 0.1% by weight of the finished food. Methyl
`paraben, propyl paraben and butyl paraben are per-
`mitted as direct food additives for use in synthetic fla-
`voring substances and adjuvants
`in the minimum
`quantities required to produce their intended effects (21
`CFR 172.515). As indirect food additives, methyl para-
`ben and propyl paraben are permitted by prior sanction
`as antimycotics in food packaging materials with no
`limit or restriction (21 CFR 181.23).
`
`1.5. Pharmaceutical uses
`
`Parabens have a long history of use in drug products.
`They were first employed as preservatives in pharma-
`ceutical products in the mid-1920s (Sabalitschka, 1930).
`Parabens have been incorporated as preservatives in a
`variety of drug formulations. Combinations of parabens
`are more active than individual parabens (Boehm and
`Maddox, 1972). Parabens are or have been used in sup-
`
`positories, anesthetics, eyewashes, pills, syrups, weight
`gaining solutions,
`injectable solutions, and contra-
`ceptives. Use concentration varies from product to pro-
`duct but seldom exceeds 1% (Neidig and Burrell, 1944;
`Hassler, 1954; Boehm and Maddox, 1972; Orth, 1980a).
`Methyl paraben is used in injections (0.065–0.25%),
`ophthalmic preparations (0.015–0.05%), oral solutions
`and suspensions (0.015–0.2%),
`topical preparations
`(0.02–0.3%) and vaginal preparations
`(0.1–0.18%)
`(Anonymous, 1998). Golomb and Shipigelman (1991)
`described the advantages of using parabens, which
`make them suitable for imparting antibacterial proper-
`ties to implanted biomaterials.
`Methyl paraben and propyl paraben are used in a
`number of over-the-counter (OTC) drugs (21 CFR
`310.545). The Ophthalmic Drug Panel of FDA’s Bureau
`of Drugs has determined that these two ingredients, if
`used alone, are unsuitable as preservatives in OTC
`ophthalmic products because they are irritating to eyes if
`used at concentrations effective against micro-organisms.
`However, eye irritation by parabens could not be con-
`firmed by the references cited in the OTC ophthalmic
`report. It was suggested that further formulation studies
`and safety testing be done on these two ingredients
`(FDA, 1980a). Other OTC panels have concluded that
`methyl paraben is a safe and effective preservative in
`concentrations of 0.1–0.2% in products for anorectal
`application and other antimicrobial uses (FDA, 1978,
`1980a,b).
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`
`Table 3
`FEMA reported usual and maximum use levels of methyl parabena
`
`Category
`
`Use level in ppm
`
`Usual
`
`Maximum
`
`Baked goods
`Milk products
`Sugar substitute
`Cheese
`Frozen dairy
`Meat products
`Soft candy
`Gelatin pudding
`Processed vegetables
`Non-alcoholic beverages
`
`0.99
`0.00
`0.50
`0.00
`0.00
`0.00
`0.00
`0.00
`1.00
`0.00
`
`a Personal communication from FEMA.
`
`0.99
`0.00
`0.50
`0.00
`0.01
`0.00
`0.01
`0.00
`1.00
`0.01
`
`Table 4
`Possible average daily intake of methyl paraben (LSRO/FASEB,
`1972)
`
`Age group
`
`Total in mg
`
`Per kg body weight
`
`Average Maximum
`
`Average
`
`Maximum
`
`0–5 Months
`6–11 Months
`12–23 Months
`2–65+ Years
`
`5
`49
`93
`222
`
`9
`108
`155
`347
`
`1
`6
`8
`4
`
`2
`14
`14
`6
`
`Calculations based on an average weight of 60 kg for an adult and the
`following estimated weights of infants by age groups: 0–5 months=5
`kg; 6–11 months=8 kg; and 12–23 months =11 kg.
`
`Methyl paraben and propyl paraben have been clas-
`sified as inactive ingredients in dentrifices, contra-
`ceptives and topical analgesics (FDA, 1979, 1980c,d)
`and in drugs for injection (via subcutaneous,
`intra-
`muscular, intravenous, intra-articular, intrabursal, intra-
`lesional and intrasynovial
`routes),
`inhalation and
`intranasal solutions, ophthalmic (ointments, solutions
`and suspensions) and other routes of administration,
`including oral, topical, rectal and vaginal (FDA, 1996).
`
`1.6. Regulatory history
`
`Methyl paraben and propyl paraben have been
`affirmed by the FDA as GRAS for direct addition to
`food (21 CFR 184.1490) in concentrations up to 0.1%
`and by prior sanction as indirect addition via packaging
`materials (21 CFR 181.23) (Table 2). Both compounds
`are used to inhibit molds and yeasts in various foods.
`They are active against Gram positive and a few Gram
`negative organisms. In addition to FDA, the Joint
`FAO/WHO Expert Committee on Food Additives
`(JECFA) and the Flavor and Extract Manufacturer’s
`Association (FEMA) have also approved the use of
`methyl paraben in food. JECFA in 1974 recommended
`that the group ADI for the methyl, ethyl and propyl
`
`esters of p-hydroxybenzoic acid was 0–10 mg/kg body
`weight/day (JECFA, 1974). Usual and maximum use
`levels of methyl paraben as FEMA food flavor ingre-
`dients are given in Table 3. The FEMA reported possi-
`ble average daily intake (PADI) of methyl paraben is
`0.22 mg.
`Use of paraben, including methyl paraben, is covered
`by an EU Directive, the ‘‘European Parliament and
`Council Directive No. 95/2/EC of February 20, 1995 on
`food additives other than colors and sweeteners’’ (Offi-
`cial Journal of the European Communities 1995, L61/1–
`40, 18.3.95). Preservation of cosmetic products with
`methyl-, ethyl-, propyl-, butyl- and benzyl paraben, with
`a maximum concentration of 0.8% (w/w), calculated as
`p-hydroxybenzoic acid is permitted by the Danish and
`EEC regulations (Howlett, 1992; Rastogi et al., 1995).
`Parabens may be present in some cosmetics labeled as
`‘‘hypoallergenic’’. Several other countries,
`including
`Canada, Japan, Norway, the Philippines, Sweden and
`Switzerland, have also approved the use of parabens as
`antimicrobial food additives. In Italy, methyl paraben
`may be used as a direct food additive. There is a close
`parallel between uses of paraben and those of sodium
`benzoate in the countries where the parabens are
`permitted.
`
`2. Consumption
`
`The major uses of parabens in the food industry are
`for cakes, pie crusts, pastries, icings, toppings and fill-
`ings (0.03–0.06% of a combination of 3:1 methyl and
`propyl parabens); soft drinks (0.03–0.05% of a 2:1 ratio
`of methyl and propyl parabens); creams and pastes
`(0.1% of a combination of parabens); jams, jellies and
`preserves (0.07% of a 2:1 ratio of methyl and propyl
`parabens); olives and pickles (0.1% of a combination of
`parabens); syrups (0.07%). According to the USDA
`food consumption data for the years 1989–1991 (Krebs-
`Smith et al., 1997), the age group 20–39 years are the
`highest consumers of jelly, jams, preserves and marma-
`lade with an intake of 56 g/day in males and 36 g/day in
`females, at the 90th percentile. The amount of methyl
`paraben consumed at the 90th percentile in jams and
`jellies at a level of 0.07% is 39 and 25 mg/day for males
`and females, respectively. These consumption data are
`further detailed below in this section.
`food manu-
`In a representative cross-section of
`facturers’ survey, the specific foods to which and at
`what concentrations methyl and propyl parabens added
`were determined (FDA, 1973). Surveys of consumer
`consumption were obtained and combined with the
`production information to obtain an estimate of the
`consumer exposure. The survey reported the total
`methyl paraben used in food in 1970 was approximately
`16 times that used in 1960.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1022, p. 006
`
`

`

`M.G. Soni et al. / Food and Chemical Toxicology 40 (2002) 1335–1373
`
`1341
`
`Table 5
`Paraben consumption via food
`
`Food
`
`Mean daily
`consumed
`over 3-day period
`(90th percentile)
`in gramsa
`
`Level
`of use
`(%)
`
`Mean daily
`amount
`consumed
`over 3-day
`period
`in grams
`
`Cake
`Piecrust
`Doughnuts and sweet rolls
`Syrup
`Pickles
`Jelly, jam, marmalade
`
`Total
`
`161
`274
`138
`130
`64
`39
`
`559
`
`0.06
`0.06
`0.06
`0.07
`0.1
`0.07
`
`0.096
`0.164
`0.082
`0.091
`0.006
`0.027
`
`–
`
`0.466
`
`a USDA, A