Exposure assessment of taste and odor standards used in the method of Flavor Profile Analysis

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Pergamon

Wal. Sci. Tech. Vol. 40, No.6. pp. 209-215, 1999 C 1999

Publishedby ElsevierScience LIdon behalfof the IAwQ Printed in GreatBritain. All rights reserved 0273-1223/99120.00 + 0.00

PII: 50273-1223(99)00559-4

EXPOSURE ASSESSMENT OF TASTE AND ODOR STANDARDS USED IN THE METHOD OF FLAVOR PROFILE ANALYSIS Linda Schweitzer and 1. H. (Mel) Suffet Department ofEnvironmentalHealth Sciences UCLA, School o/Public Health, /0833 Le Conte Avenue, Los Angeles, CA 90024, USA

ABSTRACT Information OD the toxicity of individual chemicals that have been used as known or representative odor standards in the method of Flavor Profile Analysis (FPA) was compiled for an exposure assessment. A full risk assessment was not possible since unit risk values for most of these chemicals do not exist. This study provides a recommendation as to what chemicals can be safely used as known and representat ive taste and odor standards for the next modification of the Flavor Profile:Analysis Standard Method 2170. Excluding any potential odor standard listed as possible or probable earcmogens, there would be no known risk to FPA panelists being exposed to the selected odor reference chemicals at the concentrations used in FPA. Also, the concentrations which panelists are exposed to during an FPA (20 minutes per chemical) are lower than the legal threshold limit values for 8 hour occupational exposures. However, many of the odor reference chemicals have yet to be evaluated for their carcinogenic or noncarcinogenic endpoints. Recommendations are made as to which chemicals should be avoided. C 1999 Published by Elsevier Science Ltd on behalf of the IAWQ. All rights reserved

KEYWORDS Drinking water; exposure assessment, flavor profile analysis; reference dose; taste and odor; TLV.

INTRODUCTION Information on the safety of odor reference standards is necessary in order for panel leaders to obtain informed consent from panelists and to ens~e their own safety when using these chemicals. As toxicity information becomes available for these chemicals, they need to be re-evaluated for their use in FPA. This paper investigates the safety of the chemicals listed in FPA Method 2170:I, Standard Methods for the Examination of Water and Wastewater (1995), as well as the safety of the known and representative odor standards suggested for FPA reference standards as shown in Tables IA and B from Bartels et al. (1989) . The results of this study will provide a recommendation as to what chemicals can safely be used as known and representative odor reference standards for the next modification of the FPA Standard Method 2170. Table I contains the chemicals in question. (Bartels et al., 1989). The objective of this study was to evaluate the safety of both the known and representative potential odor reference standards. This was accomplished by calculating conservative estimates of exposure and comparing these levels with the TLVs and reference doses (RIDs) - [see appendix for definitions]. 209

L. SCHWEITZER and I. H. SUFFET

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Table 1. Taste and odor standards for flavor profile analysis A. Known odor reference standards identified in raw and finished drinking water Compound geosmin

Odor Characteristics earthy, red beets

Test Cone, 300ngll

2-methylisobomeol

earthy, peat-like, brazil nut, soil chlorinous

200 ngll

free chlorine

adichloroamine trans-2-cis-6nonadienal styrene toluene cumene methylrnethacrylate m-xylene

0.5 mgll

B. Representative odor reference standards

Compound 2,3,6-trichloroanisole 2,3-diethylpyrazine 2-isopropyl-3methoxypyrazine

swimming pool, chlorinous cucumber, green vegetation model airplane glue glue, sweet solventy paste, shoe polish, solventy acrylic, plastic, solventy sweet solventy

5:1 CVN

nonanal

(WtlWt) 5 jlgIl

dimethyl sulfide

500 IIg1l 500 jig/I 100 jlgIl

Odor Characteristics leather, earthy

TestConc. 20 jlgIl

mildew, damp basement potato bin, musty (associated with decaying vegetation) hay, sweet

10 jlgIl 200 jlgIl

500 jlgIl 200 jlgIl

butyric acid trans-2-nonenal diphenyl ether

decaying vegetation, canned com putrid, sickening cucumber with skin geranium

1.5 mgll

d-Iimonene

citrusy

2mgll

200jlgll

hexanal

lettuce heart, pumpkin, green pistachio

200 jlgIl

I mgll 200 jlgIl 100 jlgIl

methyl isobutyl ketone 1,2,4-trimethylbenzene indene

paint solventy

1.0 mgll

benzaldehyde

sweet almond

Imgll

shoe polish, coal tar glue, mothballs

250 jlgIl

coumarin

Imgll

5 jlgIl

indan

varnish, coal tar

25 jlgIl

ethyl-2-methylbutyrate 2-heptanone

vanilla and black cherry fruity, pineapple

naphthalene

sweet solventy

5 jlgIl

benzofuran

shoe polish, mothballs

10 jlgIl

2-methylbenzofuran &Cis-3-hexenyl-

mothballs, sweet solventy grassy

250 jlgIl

butanol

500 jlgIl

eucalyptol (cineole)

fresh grass, green apple septic, musty

500 jlgIl

pyridine

garlicky, onion, septic, musty rancid oily, fishy

SO ngll

l-acetate bcis-3-hexene-I-01 bdirnethyl disulfide bdimethyltrisulfide atrans-2-trans-4decadienal

hexachloro1,3-butadiene 2-isobutyl-3methoxypyrazine

5 rngIl

banana-like, sweet solventy sweet, minty, vapo rub green/bell pepper, musty (associated with decaying veg.) alcohol, solventy

500 jlgIl

topical ointment for chest colds sweet, alcohol, organic

200 jlgIl

4mgll 200 jlgIl

Imgll

2mgll

IOjigIl

SO mgll

• Compounds available only in solid form and must be dissolved in methanol or ethanol. • New edition to original table b Note: since the printing of Bartels et al. (1989), the following chemicals from Table IB are now known odor reference standards and have been moved to Table IA: cis-3-hexene-I-oI, dimethyl disulfide, dimethyl trisulfide, trans-2-trans-4-decadienal.

METHODS Toxicity Infonnation Time-Weighted Averages (TWAs) and Short-Term-Exposure-Limits (STELs) were searched in RTECS and IRIS databases, representing limits set by OSHA, mOSH and/or ACGIH. Since limits were not defined for many, a search on the internet of Material Safety Data Sheets (MSDS's) from the chemical manufacturers provided TLVs set by other countries (namely France, Russia, Australia, Finland, Sweden, Thailand,

Exposure assessment oftaste and odor standards used in the method ofFPA

211

Poland). When more than one limit was available, the lowest one was reported (regardless ofsouree) to take a more conservative. protective approach to evaluating their safety. The Short-Term Exposure Limit (STEL) is probably the most relevant exposure limit for FPA panelists and researchers in the field of taste and odor. However, to be more conservative and therefore protective the TLV for an 8 hour occupational exposure was used for comparison purposes -- see exposure assessment below. Exposure assessment The maximum exposure concentration of an odor reference standard during a Flavor Profile Analysis was calculated directly from the Henry 's law constant (KH) predicted by the vapor pressure (v.p., atm.) and water solubility (mg/l) at 45°C assuming equilibrium is reached between the concentration in air and concentration in water, and assuming equal volumes of each. These assumptions are conservative, leading to a very protective estimate of exposure. T is the absolute temperature, i.e, 273 + 45 = 318 0 K and R is the universal gas constant. RT = 26.1 I atmlmol. KH =(v.p. / water solubility)! RT.

[1]

All chemicals were evaluated by making a comparison between the TLV and the exposure concentration (air concentration). The inhalation exposure for a 20 minute period in mglkgld was calculated as follows: Conc. air /0.28m 3nOkg body weight.

[2]

The 0.28 m3 is the volume of air breathed during 20 minutes based on the average adult breathing rate of 20

m3/d (Andelman, 1985). The inhalation exposure assumes that the amount absorbed by the body is 100%. This provides a conservative estimate of total exposure.

RESULTS ANDDISCUSSION Table 2 includes basic information available on the toxicity of each known or representative potential odor reference standard. For definitions and abbreviations, see Appendix. TLVs were not available for some of the compounds. Some of these chemicals are common - either in the environment or used in the food industry. Chemicals approved by the FDA are not assumed to be "non-toxic". "Additional information" includes the target organs or system affected in humans or experimental animals, whether the chemical is registered as a carcinogen, mutagenic potential as measured by the Ames test, and a reference dose when available. To reduce anxiety among panelists, we suggest that the few chemicals which are listed as being probable or possible carcinogens (or mutagens) not be used as FPA standards, particularly if safer substitutes are available. Therefore, these have been omitted from this evaluation. The following possible or probable carcinogens have been removed: indan; benzofuran; 2-methylbenzofuran; methylmethacrylate, hexachloro-1,3-butadiene;. eucalyptol; pyridine from the exposure assessment as we are recommending that they not be used in Flavor Profile Analysis. The remaining chemicals listed in Table 3 were evaluated. There are two issues to consider in evaluating the safety of these chemicals: acute exposure OVer the 20 minute period and the total or chronic exposure (in mglkgld) upon which the reference dose is used to calculate risk. Concerning the former, the acute exposure levels must be below the STEL or TLV to ensure safety. Concerning the latter, the RiD is com~ared with the maximun,t dose that a pe~on is ~xposed to on a daily basis. Below the RID, there is (theoretlcally) no measurable nsk for non-carcmogemc effects. The RID is derived from the no-observed-adverse-effect-Ievel (NOAEL) from human or animal data. Safety factors and modifying factors (to account for species differences, limitations in the studies, variability in the

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population,etc.) are applied to the NOAEL to generate the RID so that a conservativelevel is set (Pontius, 1995). For non-carcinogenic effects, only levels above the RID are believed to pose a measurable risk to those exposed (assumesdaily exposureover a lifetime). None of the above chemicalsare at levels exceedingthe TLVs. TLVs were not availablefor all chemicals. The reference dose for butanol (0.01 mg/kg/d) would not be exceeded during FPA. Oral (from drinking) reference doses for styrene and toluene are both 0.2 mg/kg/day, These also were not exceeded. Inhalation referencedoses or even oral referencedoses for most of the odor standardsare not available. Table 2. Toxicityinformationof odor referencestandards CAS # Compound 19700-21-1 geosmin 2-methylisobomeol 2371-42-8 free chlorine 7782-50-5 dichloroamine l-dodecanol 112-53-8 heptanal trans-2-cis-6-nonadienal 557-48-2 styrene 100-42-5 98-82-8 cumene toluene 105-88-3 95-47-6 m-xylene methylisobutyl ketone (MIDK) 108-10-1 1,2,4-trimethyl benzene 95-63-6 indene 95-13-6 indan 496-11-7 methylmethacrylate naphthalene 91-20-3 2-methyl-benzofuran 4265-25-2 benzofuran 271-89-6 cis-3-hexenyl-I-acetate cis-J-hexene-Lol 928-96-1 2,3,6-trichloroanisole 87-40-1 2,3-diethylpyrazine 15707-24-1 2-isopropyl-3-methoxypyrazine 25773-40-4 nonanal 124-19-6 dimethylsulfide 75-18-3 dimethyldisulfide 624-92-0 dimethyltrisulfide butyric acid 107-92-6 trans-2-nonenal 18829-56-6 diphenylether 101-84-8 hexanal d-limonene 5989-27-5 benzaldehyde 100-52-7 Ethyl-2-methyl butyrate 2-heptanone Hexachloro-l,3-butadiene 2-isobutyl-3-methoxypyrazine trans-2-trans-4-decadienal butanol Eucalyptol (cineole) pyridine

7452-79-1 110-43-0 87-68-3 24683-00-9 25152-84-5 71-36-3 470-82-6 110-86-1

TLV-TWA 0.5 ppm

10 ppm 50 ppm 50 ppm 50 ppm 50 ppm 50 ppm 10 ppm 0.05 ppm 10 ppm

Additional Information natuIallyin water. (-) Ames test naturallyin water. (-) Ames test' e.g. used in swimmingpools

+ Ames,CNS

Reproductive Toxicant CNS reproductive toxicant,fetotoxic, CNS low toxicityexpectedbased on SARs carcinogen carcinogen probablynot carcinogenic carcinogen- RTECs carcinogen- RTECs

5 ppm 1 ppm 0.5 ppm currentlyunderreview I mglm3 consideredvery toxic by inhalation consideredlow oral toxicity 1 ppm "safe and approvedby FDA" approvedby FDA - oil of almond CNS, 01, kidney 400 ppm 50 ppm 0.02 ppm 50 ppm 5 ppm

low oral toxicity suspectedcarcinogen CNS, liver, kidney possible carcinogen CNS, possiblemutagen

Exposure assessment of tasteandodorstandards used in the method ofFPA

213

The method of flavor profile analysis (FPA) requires small whiffs (inhalation) of water samples containing low concentrations of these chemicals. The flask containing the sample is briefly opened during the smell and then closed after smelling. Although the duration of each whiff is usually on the order of seconds, for the exposure assessment, a total time of 20 minutes was allowed for smelIing one sample which is a very conservative value. The exposure concentrations for FPA are in most cases far less than the legal exposure limits. The legal exposure limits take into consideration long term exposure over hours at a time and years of occupational exposures. Compare that with the FPA method which involves occasional exposures (once a week) for brief periods of time. The human nose has such a sensitive detection ability, that only very low concentrations are needed to perceive the odor. The calculations of exposure in this analysis are conservative, meaning higher that expected actual exposure, so as to be protective. Yet, the concentrations are very low. Thus, although many of these chemicals have not been thoroughly evaluated for their potential carcinogenicity, actual risk for cancer at these exposure levels is expected to be infinitesimal. Table 3. Exposure assessment

Compound

TLV-TWA (ppm)

bAirConc. (ppm)

Inhalation Exposure (mglkgld) •

geosmin 5.9E-3 3E-4 2-methylisobomeol 1.3E-3 6.2 E-S 0.5 S.3E-6 4.2E-7 free chlorine dichloroamine 4.2E-7 trans-2-cis-6-nonadienal 10 3.IE-4 1.5E-5 styrene 50 0.12 0.01 SO 0.10 om toluene cumene 50 0.49 0.02 m-xylene 50 0.03 0.002 methylisobutyl ketone 50 0.04 0.002 1,2,4-trimethyl-benzene 5.30 0.25 indene 10 0.01 3.2E-4 naphthalene 10 S.IE-5 3.9E-6 cis-3-hexenyl-l-acetate 0.05 0.002 S 0.001 S.5E-S cis-3-hexene-l-ol 2,3,6-trichloroanisole 1 l.3E-9 6.3E-11 2,3-diethylpyrazine 4.1E-5 2E-6 2.isopropyl-3-methoxypyrazine 0.5 3.6E-6 2E-7 om 5E-4 nonanal dimethyl sulfide 0.02 0.001 dimethyl disulfide 0.002 IE-4 dimethyltrisulfide 6.4E-5 3E-6 butyric acid 6.3E-S 3E-6 trans-2-nonenal 0.004 2E-4 diphenyl ether 4.SE-S 2.2E-6 d-limonene US 0.06 hexanal 0.002 SE-S benzaldehyde 0.002 SE-S ethyl-2-methyl-butyrate 400 0.001 4E-5 2-heptanone 50 0.002 SE-5 2-isobutyl-3-methoxypyrazine 7.7E-6 4E-7 Trans-2-trans-4-decadienal 0.92 0.04 butanol 50 1.9E-4 9E-6 • assumes that the exposure time to smell one sample is 20 minutes of constant breathing. The decision to eliminate those chemicals listed as probable or possible carcinogens is based on perception of risk. The old theory of the "no threshold of effects" for carcinogens is based on the premise that an

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exposure to even one molecule of a carcinogen can cause a mutation in DNA which is the first step in carcinogenesis. The dose-response curve under this hypothesis is a linear extrapolation of risk to a zero carcinogen dose (Hrudey and Krewski, 1995). However, this hypothesis is out-dated and generally not accepted in the scientific community (Hrudey and Krewski, 1995). In summation. as stated by Hrudey and Krewski (1995), (their) "calculations suggest that, within a realistic concept of safety, there is a safe level of exposure". Furthermore, humans are constantly exposed to carcinogens in food, air, and water, and the elimination of exposure to all levels ofcarcinogens is impossible. CONCLUSIONS The following chemicals have been recommended for discontinued use as odor reference standards because of their carcinogenic potential: indan; benzofuran; 2-methylbenzofuran; methyJrnethacrylate; hexachloro1,3-butadiene; eucalyptol; pyridine. In addition, methyl isobutyl ketone should also not be used due to its fetotoxicity. This recommendation is a political one based on risk perception (i.e. based on our experience of panelists' complaints). Based on the data available, the remaining FPA taste and odor standards which we evaluated should be less controversial. These recommended FPA standards pose no known risk to panelists. The results of this study provide a recommendation as to what chemicals to include in the next version of FPA Standard Method 2170. APPENDIX Definitions and abbreviations Ames Test: a test for mutagenicity of a compound. Correlates with ability to cause cancer. CNS: has effects on the central nervous system. IRIS: (Integrated Risk Information Systems) - CD ROM and on-line. PEL: Permissible Exposure Limit : An allowable exposure level in workplace air averaged over an 8-hour shift (e.g. 8 hours at 100 ppm, where 100 ppm is the TWA). RID : Reference Dose: An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RID is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RIDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RIDs are not applicable to nonthreshold effects such as cancer. RTECS: (Registry of Toxic Chemical Substances) on microfiche and on-line. SARs: Structure-Activity Relationships. Based on chemicals with similar structure (where information is available on their toxicity), the toxicity ofthe not-yet-studied chemical can be predicted by the SARs. STEL: Short-Term Exposure Limit - the maximum concentration to which workers can be exposed for up to 15 minutes continually; no more than four exposures are allowed per day and there must be at least 60 minutes between exposure periods. The daily TLV-TWA may not be exceeded. TLV: Threshold limit value - A concentration ofa substance to which most workers can be exposed without adverse effects. The TLV may be expressed as a TWA or STEL. TWA: Time-Weighted Average - An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour work week.

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REFERENCES Andelman, 1. (1985). Inhalation exposure in the home to volatile organic contaminants of drinking water, TheScienceofthe Total Environ., 47, 443460. AWWA (1995). Advancesin Taste-and-Odor Treatment and Control. American Water Works Association Research Foundation and Lyonnaise des Eaux, I.H. Suffel, J. Mallevialle, and E. Kawczynski, eds. AWWA, Denver, Co. Bartels, J. H. M., Brady, B. M. and Suffel, I. H. (1989). Tasteand Odorin Drinking WaterSupplies-Phase 1&11. American Water Works Association Research Foundation. Hrudy, S. and Krewski, D. (1995). Is there a safe level of exposure to a carcinogen? Environ. Sci. Technol., 29, 370A-375A. IRIS. Integrated Risk Information System. USEPA. Online database; TOXNET system. Pontius, F. W. (1995) . Setting standards : risk assessment issues, J. AWWA, 87(7), 10-16. StandardMethods for the Examination ofWaterand Wastewater (1995). 19th edn, American Public Health Association!American Water Works AssociationlWaler Environment Federation, Washington D.C., USA. UNIFACS (1989) . Chemdata Compound Property Processor, version I. Prepared by Research Triangle Institute, USEPA, Research Triangle Park, NC. RTECS· Registry of Toxic Effects of Chemical Substances (1992). National Institute of Occupational Safety and Health, Centers for Disease Control. Washington D.C.: U.S. Dept. of Health and Human Services: Superintendent of Documents on CD ROM and microfiche.