The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.
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TestSmart HPV
April 26-27, 1999
Hyatt Fair Lakes
12777 Fair Lakes Circle
Fairfax, VA 22033
A workshop of The Johns Hopkins Center for Alternatives to Animal Testing
TestSmart is a program of the Vision 20/20 forum
This workshop is partially funded through a grant by the Vira I. Heinz Endowment
Abstract for TestSmart--A Humane and Efficient Approach to Screening Information Data Sets (SIDS) Data
Concepts in Safety Evaluation of HPV Food Substances
Ian C. Munro, Ph.D., FRCPath
CanTox Inc.
Classification of HPV Food Substances
- Colors (3)
- FEMA GRAS Flavors (194)
- Foods (85)
- Food Additives (86)
- FDA GRAS Substances (37)
- Miscellaneous Food Substances (20)
Colors (3)
- C.I. Acid Blue 9, disodium salt
- C.I. Acid Yellow 23
- Sunset Yellow FCF
FEMA GRAS Flavors (194)
| alpha.-Toluenethiol | Lemon, extract (citrus limon (l.) Burm. F.) |
| 1,2-Benzisothiazolin-3-one, 1,1-dioxide, sodium salt | Linalool oxide |
| 1,2-Propanediol | Malonic acid, diethyl ester |
| 1,2-Propanediol, dibenzoate | Methanethiol |
| 1,3-Benzenediol | Methyl 2-methylthiobutyrate |
| 1,6-Octadien-3-ol, 3,7-dimethyl- | Methyl disulfide |
| 1,6-Octadien-3-ol, 3,7-dimethyl-, acetate | Methyl ketone |
| 1,6-Octadiene, 7-methyl-3-methylene- | Methyl sulfide |
| 1-Butanethiol | Mimosa, absolute (acacia decurrens willd. Var. Dealbata) |
| 1-Butanol, 2-methyl-, acetate | Myristic acid |
| 1-Decanol | Myristic acid, isopropyl ester |
| 1-Hexadecanol | Myristic acid, methyl ester |
| 1-Hexanol, 2-ethyl- | Nonanal |
| 1-Pentanol | Nonanoic acid |
| 1-Propanethiol | o-Cresol |
| 1-Propanol, 2-methyl- | Octadecanoic acid, monoester with 1,2,3-propanetriol |
| 2(10)-Pinene | Octadecanoic acid, monoester with 1,2-propanediol |
| 2(3H)-Furanone, dihydro- | Octanal |
| 2,5-Xylenol | Octanoic acid |
| 2,6-Octadien-1-ol, 3,7-dimethyl-, (E)- | Octanoic acid, methyl ester |
| 2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)- | Octyl alcohol |
| 2,6-Octadienal, 3,7-dimethyl- | Oils, orange, sweet |
| 2,6-Xylenol | Oleic acid |
| 2-Butanone | Olein, mono- |
| 2-Buten-1-ol, 3-methyl- | Palmitic acid |
| 2-Cyclohexen-1-one, 3,5,5-trimethyl- | p-Anisaldehyde |
| 2-Furaldehyde | Paraffin waxes and Hydrocarbon waxes |
| 2-Heptanone | p-Cresol |
| 2-Octanol | p-Cresol, 2,6-di-tert-butyl- |
| 2-Pentanone | p-Cymene |
| 2-Pentanone, 4-methyl- | Pentanoic acid |
| Butyl alcohol | Piperidine |
| Butylamine | p-Menth-1-en-8-ol |
| Butyraldehyde | p-Menth-1-en-8-ol, acetate |
| Butyraldehyde, 2-methyl- | p-Mentha-1,4(8)-diene |
| Butyric acid | p-Mentha-1,8-diene, (R)-(+)- |
| Butyric acid, 2-methyl- | Potassium acetate |
| Caffeine | Propionaldehyde |
| Calcium acetate | Propionaldehyde, 3-(methylthio)- |
| Camphene | Propionic acid |
| Castor oil | Propionic acid, butyl ester |
| Cinnamaldehyde | Propionic acid, methyl ester |
| Cinnamaldehyde, .alpha.-hexyl- | Propyl alcohol |
| Cinnamaldehyde, .alpha.-pentyl- | Pyridine |
| Citric acid | Salicylaldehyde |
| Citric acid, tributyl ester, acetate | Salicylic acid, benzyl ester |
| Citric acid, trisodium salt | Salicylic acid, methyl ester |
| Cyclopentaneacetic acid, 3-oxo-2-pentyl-, methyl ester | Sodium benzoate |
| Decanoic acid | Sorbic acid, potassium salt |
| D-erythro-Hex-2-enonic acid, .gamma.-lactone | Sorbitan, monostearate |
| Dodecyl alcohol | Sorbitan, monostearate, polyoxyethylene derivs. |
| Ethane, 1,1-dimethoxy- | Stearic acid |
| Ethyl alcohol | Stearic acid, butyl ester |
| Ethylene oxide | Styrene |
| Formic acid | Succinic acid, dimethyl ester |
| Formic acid, isopropyl ester | Tannins |
| Fumaric acid | Tartaric acid |
| Furfuryl alcohol | Thiazole, 4-methyl- |
| Furfuryl alcohol, tetrahydro- | Trimethylamine |
| Fusel oil | Turpentine |
| Glucitol, D- | Turpentine, oil |
| Glutamic acid, monosodium salt, L- | Undecyl alcohol |
Chemical Classification of FEMA GRAS Flavors
- Terpenoid aliphatic hydrocarbons and esters
- Cinnamyl derivatives
- Benzoic acid and related substances
- Phenethyl alcohol and related substances
- Ionone derivatives
- Alkoxypropenylbenzenes
- Acetophenone and related substances
Food (85)
| Acetic acid vinyl ester | Fatty acids, tallow |
| Castor oil, dehydrated | Fatty acids, tallow, calcium salts |
| Castor oil, hydrogenated | Fatty acids, tallow, hydrogenated |
| Castor oil, oxidized | Fatty acids, tallow, Me esters |
| Castor oil, sulfated, sodium salt | Fatty acids, tallow, sodium salts |
| Corn oil | Fatty acids, vegetable-oil |
| Corn oil, hydrogenated | Fatty acids, vegetable-oil, Me esters |
| Corn, steep liquor | Fatty acids, vegetable-oil, sodium salts |
| Cottonseed oil | Fatty acids, vegetable-oil, unsatd. |
| Cottonseed oil, hydrogenated | Fructose, D- |
| Fats and Glyceridic oils, fish, oxidized | Glycerides, C14-18 |
| Fats and Glyceridic oils, menhaden, stearins | Glycerides, C14-18 and C16-18-unsatd. |
| Fats and Glyceridic oils, vegetable, hydrogenated | Glycerides, C14-18 and C16-18-unsatd. mono- and di- |
| Fatty acids, C10-16 Fatty acids, tall-oil, potassium salts | Glycerides, C14-22 mono- |
| Fatty acids, C10-16, Me esters | Glycerides, C14-22 mono-, acetates |
| Fatty acids, C12-18, Me esters | Glycerides, C16-18 and C18-unsatd. |
| Fatty acids, C12-20 and C12-20-unsatd. | Glycerides, C16-22 and C18-unsatd. |
| Fatty acids, C14-18 | Glycerides, C8-18 and C18-unsatd. |
| Fatty acids, C14-18 and C16-18-unsatd. | Glycerides, coco mono-, sulfated, sodium salts |
| Fatty acids, C14-18 and C16-18-unsatd., Me esters | Glycerides, tallow mono-, hydrogenated |
| Fatty acids, C14-18 and C16-18-unsatd., potassium salts | Grease, catch basin |
| Fatty acids, C14-18 and C16-18-unsatd., sodium salts | Grease, poultry |
| Fatty acids, C14-18 and C16-22-unsatd. | Lanolin |
| Fatty acids, C16 and C18-unsatd. | Lard, hydrogenated |
| Fatty acids, C16-18 | Lard, oil, Me esters |
| Fatty acids, C16-18 and C18-unsatd. | Lecithins, soya |
| Fatty acids, C16-18 and C18-unsatd., Me esters | Linseed oil |
| Fatty acids, C16-18, sodium salts | Molasses |
| Fatty acids, C6-12 | Oils, glyceridic, palm kernel |
| Fatty acids, C6-12, Me esters | Oils, pine |
| Fatty acids, C6-12, sodium salts | Palm oil |
| Fatty acids, C8-18 and C18-unsatd. | Palm oil, hydrogenated |
| Fatty acids, C8-18 and C18-unsatd., Me esters | Rape oil |
| Fatty acids, C8-18 and C18-unsatd., potassium salts | Soaps, stocks, vegetable-oil |
| Fatty acids, C8-18 and C18-unsatd., sodium salts | Soybean oil |
| Fatty acids, coco | Soybean oil, epoxidized |
| Fatty acids, coco, heavy fractions | Starch, enzyme-hydrolyzed |
| Fatty acids, coco, hydrogenated | Sunflower oil |
| Fatty acids, coco, Me esters | Syrups, hydrolyzed starch |
| Fatty acids, coco, potassium salts | Syrups, hydrolyzed starch, hydrogenated |
| Fatty acids, coco, sodium salts | White mineral oil, (petroleum) |
| Fatty acids, palm-oil, sodium salts |
Classification of Food Substances
- Simple saturated aliphatic acids
- Fats and oils
- Fatty acids and their esters
- Glycerides
- Starches and sugar syrups
- Mineral oils
Food Additives (86)
| 1,2-Benzisothiazolin-3-one, 1,1-dioxide | Hydroquinone, tert-butyl- |
| 1,2-Benzisothiazolin-3-one, 1,1-dioxide, ammonium salt | Lauric acid, potassium salt |
| 1,3-Butanediol | Lignosulfonic acid, calcium salt |
| 1-Octadecanol | Magnesium stearate |
| Acetic acid, (ethylenedinitrilo)tetra-, disodium salt | Maleic acid |
| Acetic acid, (ethylenedinitrilo)tetra-, tetrasodium salt | Mannitol, D- |
| Acetic acid, nitrilotri-, trisodium salt | Methane, dichloro- |
| Acetic anhydride | Methane, dichlorodifluoro- |
| Acrolein | Methanol |
| Acrylic acid methyl ester | Morpholine |
| Aluminum stearate | Naphtha |
| Amides, coco, N,N-bis(hydroxyethyl) | Natural gas |
| Benzene | Octadecylamine |
| Benzenesulfonic acid, dodecyl-, sodium salt | Octanoic acid, sodium salt |
| Carbamic acid, dimethyldithio-, sodium salt | Oleic acid, potassium salt |
| Chloroform | Oxirane, methyl- |
| Cyclohexane | Palmitic acid, calcium salt |
| Cyclohexylamine | Palmitic acid, isopropyl ester |
| Decanoic acid, sodium salt | Pentane |
| D-gluco-Heptonic acid, monosodium salt, (2.xi.)- | Pentanedial |
| Diethylenetriamine | Peroxyacetic acid |
| Dimethylamine | Petrolatum |
| Dodecanamide, N,N-bis(2-hydroxyethyl)- | Phenol, p-(1,1,3,3-tetramethylbutyl)- |
| Ethane, 1,1,2-trichloro-1,2,2-trifluoro- | Phosphonic acid, (1-hydroxyethylidene)di- |
| Ethane, 1,2-dichloro- | Phosphonic acid, Onitrilotris(methylene) ptri-, sodium salt |
| Ethane, chloropentafluoro- | Potassium benzoate |
| Ethanol, 2-(diethylamino)- | Propane, 1-chloro-2,3-epoxy- |
| Ethanol, 2-(dimethylamino)- | Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides |
| Ethanol, 2,2',2''-nitrilotris- | Quinoline, 6-ethoxy-1,2-dihydro-2,2,4-trimethyl- |
| Ethanol, 2-amino- | Rosin |
| Ethanol, 2-butoxy- | Salicylic acid, pentyl ester |
| Ethanol, 2-ethoxy- | Sorbitan, monooleate |
| Ether, chloromethyl methyl | Stearic acid, ester with lactic acid bimol. ester, sodium salt |
| Ethylene | Stearic acid, sodium salt |
| Ethylene, trichloro- | Succinic acid, sulfo-, 1,4-bis(2-ethylhexyl) ester, sodium salt |
| Ethylenediamine | Succinic anhydride |
| Formaldehyde | Sucrose, diacetate hexaisobutyrate |
| Formamide, 1,1'-azobis- | Sulfuric acid monododecyl ester sodium salt |
| Glycols, polyethylene | Sulfuric acid, mono(2-ethylhexyl) ester, sodium salt |
| Glycols, polyethylene, dioleate | Tetradecanol |
| Glycols, polyethylene, monostearate | Xylene |
| Glycols, polypropylene | Coconut oil |
| Hexane | |
| Humic acids, sodium salts |
FDA GRAS (37)
| D-Glucose | Peanut oil |
| Lard, oil | Soybean oil, hydrogenated |
| Sucrose | Urea |
| Acetic acid, ammonium salt | Acetic acid, sodium salt |
| Carbon dioxide | Choline, chloride |
| Fats and Glyceridic oils, menhaden | Gluconic acid, .delta.-lactone, D- |
| Gluconic acid, D- | Lard |
| Linoleic acid | Maltodextrin |
| Nicotinamide | Nicotinic acid Oils, orange-juice |
| Propane, 2-methyl- | Sorbic acid |
| Benzoyl peroxide | Butane |
| Gluconic acid, monosodium salt, D- | Lecithins |
| Propane | Propionic acid, 3,3'-thiodi-, didodecyl ester |
| Propionic acid, calcium salt | Propionic acid, sodium salt |
| Sodium formate | Starch, acid-hydrolyzed |
| Stearic acid, calcium salt | Stearic acid, zinc salt |
| Succinic acid | Tall oil |
| Tallow | Tallow, hydrogenated |
Classification of Food Additives and GRAS Substances
- Simple organic acids, alcohols and aldehydes
- Common sugars and related substances
- Fatty acids, their esters and salts
- Inorganic acids (pH adjusting agents)
- Solvents and gases (used as indirects)
Miscellaneous Food Substances (20)
| Acetic acid, mercapto- | Benzoic acid, p-nitro- |
| Bone meal, steamed | Bone, ash |
| Butane, 2-methyl- | Butyric anhydride |
| Carbon | Charcoal |
| Charcoal, bone | Citric acid, sodium salt |
| Decanoic acid, methyl ester | D-erythro-Hex-2-enoinic acid, gamma-lactone, monosodium salt |
| Ethane, 1,1,1-trichloro | Formamide, N,N-dimethyl- |
| Glycol | Phenol, p-nitro-, sodium salt |
| Propane, 2,2-dimethoxy- | Stearic acid, ethylene ester |
| Terpenes and Terpenoids, sweet orange-oil | Toluene, ar-chloro- |
Natural Occurrence/Human Experience
- Many HPV substances occur naturally in foods (eg, fatty acids, glycerides, flavoring substances) or are metabolic intermediates (eg, propionic acid) - for example:
- A high percentage of flavors (415/499 = 83%)1 are food predominant (ie, natural occurrence is greater than added use).
- Many flavoring substances make an insignificant contribution to the food supply (309/499 = 62%)1
- There is no presumption of toxicity
1Stofberg and Grundschober, 1987
Structurally Related Food Substances
Many listed HPV food substances are structurally related, for example:
- FLAVORS on the HPV list can be grouped chemically,
- cinnamyl derivatives
- cinnamaldehye
- alpha-hexylcinnamaldehyde
- alpha-amylcinnamaldehye
- substituted benzyl derivatives
- pentyl salicylate
- benzyl salicylate
- benzyl acetate
- methyl salicylate
- p-methoxybenzaldehyde
- cinnamyl derivatives
- FOODS on the HPV list can be grouped into:
- fatty acids
- glycerides
- fats and oils
- FOOD ADDITIVES and GRAS substances consist of very common substances such as:
- acetic acid
- propionic acid
- their salts and esters
What Does Structure Tell Us?
- Chemical structure is typically predictive of toxicity
- Substances can be characterized by specific functional groups, or by other structural features
- Many listed substances are endogenous metabolic intermediates
- Many listed food substances are rapidly metabolized by high capacity pathways to either endogenous or innocuous substances
- With few exceptions, simple organic acids, aldehydes, alcohols and esters are rapidly metabolized to innocuous end products, the safety of which is well established or can be assumed from metabolic data
Relationship of Structure to Toxicity
- Toxicity is dependent on the chemical structure of a substance, its pharmacokinetics, and its metabolic reaction pathways
- Metabolic pathways are typically dose-dependent and govern the extent of any toxic effect
- Determinants of toxicity
- chemical structure
- pharmacokinetics
- metabolic fate
- dose
- Toxicological studies are not necessary if there is evidence that a food substance makes only a small contribution to existing metabolic pools
- Extensive toxicological testing is unnecessary for individual compounds that are closely related structurally.
- Toxicological data for a representative substance in a homologous series of compounds may be adequate to evaluate the group
- The Joint FAO/WHO Expert Committee on Food Additives (JECFA) recognizes data from one compound as representative of a homologous series in their establishment of group ADIs for similar substances (eg, benzoic acid derivatives)
Availability of Toxicological Data
- The food substances, food additives and GRAS substances listed on the HPV list have sufficient data to form the basis for FDA approval or GRAS status
- Data sources include:
- National Toxicology Program
- JECFA monographs
- peer reviewed scientific publications
- widely available industry data
Criteria Essential to Determine Testing Needs
- Nature and source of the material
- Intended use and use levels
- Chemical structure
- Structure-activity relationships
- Metabolic fate
- Similarity to substances of known biological activity
- Prior experience of human use
Conclusions
Applying these criteria, little priority can be placed on the need to further test the food substances listed in the HPV list.