Comparison of Estimated Daily Intakes of Flavouring Substances With No-observed-effect Levels

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Food and Chemical Toxicology 44 (2006) 758–809

Comparison of estimated daily intakes of flavouring substanceswith no-observed-effect levels

I.C. Munro *, B. Danielewska-Nikiel

CANTOX Health Sciences International, 2233 Argentia Road, Suite 308, Mississauga, Ont., Canada L5N 2X7

Received 23 September 2005; accepted 18 October 2005

Abstract

This study was conducted to determine the margins of safety between no-observed-effect levels (NOELs) and estimates of daily intakefor 809 flavouring substances evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) between 2000 and 2004.Estimates of daily intake were calculated using two methods, the maximized survey-derived daily intake (MSDI) and the possible averagedaily intake (PADI). The MSDI estimates were based on the production volume of flavouring agents as reported by industry, whereasthe higher more conservative PADI estimates were derived by multiplying the anticipated average use level of a flavouring substance ineach of 33 food categories by the average amount of food consumed daily from that food category and summing the intake over all 33food categories. These intake estimates were used to calculate the margins of safety for the flavouring agents to determine whether ade-quate margins of safety would still exist in the event that the MSDIs used by JECFA to evaluate the safety of flavouring substancesunderestimated daily intakes. Based on the calculation of the margins of safety using the MSDI values, 99.9% of the 809 flavouring sub-stances evaluated by JECFA have margins of safety of greater than 100. In comparison, 98% of flavouring substances have margins ofsafety of greater than 100 when the margins of safety were calculated from PADI values. The results indicate that if the MSDI estimatesused by JECFA for the evaluation of the safety of flavouring substances were underestimated, a wide margin of safety exists for all but afew of the flavouring substances even when intakes were estimated from PADI values.� 2005 Elsevier Ltd. All rights reserved.

Keywords: Flavouring substances; Margin of safety; MSDI; NOEL; PADI

1. Introduction

There are over 2800 flavouring substances presentlyused by the food industry in Europe and the United States.The safety evaluation of such a large number of substanceshas presented regulatory bodies with a unique challenge

0278-6915/$ - see front matter � 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.fct.2005.10.008

Abbreviations: ADI, Acceptable Daily Intake; EPA, US EnvironmentalProtection Agency; FEMA, Flavor and Extract Manufacturers� Associ-ation; GLP, Good Laboratory Practice; GRAS, Generally Recognized asSafe; JECFA, Joint FAO/WHO Expert Committee on Food Additives;MSDI, Maximized Survey-Derived Daily Intake; mTAMDI, modifiedTheoretical Added Maximum Daily Intake; NOEL, No-Observed-EffectLevel; NTP, National Toxicology Program; PADI, Possible AverageDaily Intake; WHO, World Health Organization.

* Corresponding author. Tel.: +1 905 542 2900; fax: +1 905 542 1011.E-mail address: [email protected] (I.C. Munro).

and it became evident several years ago that it would beimpracticable to evaluate each compound individuallyusing traditional toxicological approaches. Moreover,given the self-limiting nature of these substances due totheir potent organoleptic properties, flavouring substancesare typically consumed in very low amounts.

In 1996 the Joint FAO/WHO Expert Committee onFood Additives (JECFA) began a programme of evaluat-ing the safety of flavouring agents used in food. Theprocedure used by JECFA for the safety evaluation of fla-vouring substances integrates data on intake, metabolism,and structure–activity relationships with toxicity data(JECFA, 1998). To perform these evaluations, flavouringsubstances are first compiled into groups of structurallyrelated materials. The members of these groups wouldbe expected to have common routes of metabolism and

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I.C. Munro, B. Danielewska-Nikiel / Food and Chemical Toxicology 44 (2006) 758–809 759

similar toxicity. According to the JECFA safety evaluationapproach, substances with simple structures, which areknown or presumed to be readily metabolized to innocuousproducts, can be evaluated without toxicity data via theA-side of the procedure. Substances for which metabolismis not well defined or are expected to be metabolized to reac-tive products, require toxicity data to perform the safetyevaluation in accordance with the B-side of the procedure.Since not all members of a congeneric group have metabo-lism or toxicity data, the safety evaluation of substanceslacking these data depends upon the availability of suchdata for other well-tested members of the group. Usingthe safety evaluation procedure, JECFA has evaluatedapproximately 1450 flavouring agents since the process firstbegan.

A study was conducted in 2000 comparing no-observed-effect levels (NOELs) with intakes for 592 flavouring sub-stances evaluated by JECFA during the period from 1996to 1998 to establish margins of safety for these substances(Munro and Kennepohl, 2001). Since NOELs were notavailable for all of these substances, NOELs for structurallyrelated substances were used for those lacking such data.This study demonstrated that 98% of flavouring agentshad margins of safety in excess of 1000.

Since 2000, JECFA has evaluated a further 809 flavour-ing substances. It was therefore considered appropriatethat the earlier study be extended to compare the NOELsfor these 809 substances with their estimated intakes. Inthe original study, per capita intakes were estimated fromannual production data for flavours and calculated accord-ing to procedures used by JECFA (1998). This procedurealso is known as the maximized survey-derived daily intake(MSDI) (Arcella and Leclercq, 2005). This practice wascontinued for the present study but, in addition, an exag-gerated intake also was calculated. This higher estimatedintake, known as the possible average daily intake (PADI)(Woods and Doull, 1991; Smith et al., 2001), makes theassumption that a flavouring agent is used at the averageuse level in all foods within a category of foods in whichthe flavour was anticipated to be used by industry at thetime it was evaluated for Generally Recognized as Safe(GRAS) status by the Expert Panel of the Flavor andExtract Manufacturers� Association (FEMA). The PADIprovides a substantial overestimate of actual intake, andis equivalent to the modified theoretical added maximumdaily intake (mTAMDI) (Arcella and Leclercq, 2005). Thishigher more conservative estimation of intake was used todetermine if, under a worst-case scenario, margins of safetyare still adequate to ensure safety.

1 The greatest concentration or amount of an agent, found by study orobservation, that causes no detectable, usually adverse, alteration ofmorphology, functional capacity, growth, development, or lifespan of thetarget (WHO, 1987).

2. Materials and methods

To compare intake estimates of specific flavouring substances withrepresentative NOELs, intake and toxicology data were considered for atotal of 30 congeneric groups of flavouring substances, which were eval-uated by JECFA at the annual meetings held in 2000, 2001, 2002, 2003,and 2004. These 30 groups, which are listed below, included a total of 822individual flavouring agents; however, the evaluation of 13 substances was

not completed by JECFA due to lack of data demonstrating use of thesecompounds as flavouring agents.

Flavouring substances evaluated by JECFA in 2000 (55th meeting)

1. Cinnamyl alcohol and related substances (55)2. Furfuryl alcohol and related substances (15)3. Phenol and phenol derivatives (48)4. Pulegone and related substances (6)


1. Pyrazine derivatives (41)2. Aromatic substituted secondary alcohols, ketones and related esters (37)3. Benzyl derivatives (37)4. Hydroxy- and alkoxy-substituted benzyl derivatives (45)5. Aliphatic acyclic diols, triols and related substances (20)6. Aliphatic acetals (10)


1. Alicyclic primary alcohols, aldehydes, acids and related esters (26)2. Phenethyl alcohol, aldehyde, acid and related acetals and esters (43)3. Sulfur-containing heterocyclic compounds (30)4. Sulfur-substituted furan derivatives (33)5. Alicyclic ketones, secondary alcohols and related esters (25)6. Aliphatic secondary alcohols, ketones and related esters (39)

Flavouring substances evaluated by JECFA in 2003 (61st meeting)

1. Alicyclic, alicyclic-fused and aromatic-fused ring lactones (16)2. Aliphatic, alicyclic, linear a,b-unsaturated di- and trienals and related

alcohols, acids and esters (26)3. Aliphatic branched-chain saturated and unsaturated alcohols, alde-

hydes, acids and related esters (32)4. Aliphatic and aromatic ethers (29)5. Hydroxypropenylbenzenes (9)6. Linear and branched-chain aliphatic unsaturated, unconjugated alco-

hols, aldehydes, acids and related esters; additional compounds (20)7. Simple aliphatic and aromatic sulfides and thiols; additional com-

pounds (12)

Flavouring substances evaluated by JECFA in 2004 (63rd meeting)

1. Pyridine, pyrrole and quinoline derivatives (22)2. Aliphatic and alicyclic hydrocarbons (20)3. Aromatic hydrocarbons (5)4. Aliphatic, linear a,b-unsaturated aldehydes, acids and related alcohols,

acetals and esters (37)5. Monocyclic and bicyclic secondary alcohols, ketones and related esters

(32)6. Tetrahydrofuran and furanone derivatives (18)7. Phenyl-substituted aliphatic alcohols and related aldehydes and esters

(21)

Additionally, in 2004 JECFA also evaluated a group of amino acids; how-ever, in light of their wide spread occurrence in food, amino acids were notconsidered in this study.

As in the previous study (Munro and Kennepohl, 2001), every effortwas made to select a NOEL as defined1 by the World Health Organization(WHO, 1987) based on a good quality toxicological study [e.g., good

760 I.C. Munro, B. Danielewska-Nikiel / Food and Chemical Toxicology 44 (2006) 758–809

laboratory practice (GLP), multiple dose levels, long term, etc.]. Themajority of studies used in this comparison of NOELs to estimated intakevalues were selected from studies considered at the JECFA meetings andpresented in the JECFA monographs published subsequent to eachmeeting (WHO Food Additive Series). For a few flavouring substances,more recent toxicological data had become available since JECFA�sevaluation. Where appropriate, these data were used to derive NOELs forthe calculation of the margins of safety.

The evaluation of flavouring agents by JECFA according to the�Procedure for the Safety Evaluation of Flavouring Agents� does not inevery case require use of toxicity data. Depending on the structural classthat the compound is assigned to, its metabolic fate and intake levels, theevaluation may proceed without the need for a NOEL. For example,substances determined at the outset of the evaluation to be metabolized toinnocuous products may not require toxicity data. In cases where notoxicity data were available for a compound, representative NOELs wereselected from NOELs identified for a structurally related substance ormetabolite in accordance with JECFA practices.

For some substances multiple NOELs were identified as a result ofstudies conducted in more than one species and sex, and/or extending overdifferent treatment periods or utilizing various routes of exposure. In theseinstances, a range of NOELs was available for some members of a series ofstructurally related compounds. In such cases, the most appropriateNOEL, representative of the structurally related group, was chosen as thebasis for the margin of safety calculation. In cases where only a single doselevel study or a study of very short-term duration (i.e., 14 days) wasavailable for a compound, more suitable NOELs for structurally relatedcompounds where selected whenever possible.

For comparative purposes, both MSDI and PADI values were used tocalculate the margins of safety. Intake estimates based on the MSDI2

approach were selected directly from European and US poundage surveyestimates presented to JECFA and used in their evaluation of the safety ofthe flavouring agents. The MSDI values for the 809 compounds wereobtained from the JECFA reports covering the period from 2000 to 2004.The MSDI calculations were based on the assumption that 10% of theEuropean or US population are consumers or �eaters� of the flavouringagent. Without exception, the highest intake estimate (i.e., Europe or US)was used as a basis for comparison with the corresponding NOEL.

The estimates of intake based on the PADI calculation were derived bymultiplying the anticipated average use level of a flavouring substance ineach of 33 food categories (e.g., baked goods, meat products, etc.) by theaverage amount of food consumed daily from that food category andsumming the intake over all 33 food categories (NRC, 1972). The antici-pated average use level is the level of use requested by industry at the timethe substance was submitted to FEMA for GRAS evaluation. Addition-ally, it was assumed that the flavouring substance was added to all typesand brands of foods in the entire food category and, not just a specific foodwithin that food category (Oser and Hall, 1977). For example, if a flavourwas reported to have an anticipated use at a specified concentration in anybakery product, the assumption was made in calculating the PADI that it isused at that concentration in all baked goods regardless of type. Thisapproach of estimating intake further assumes that all foods within a foodcategory in which the flavour was anticipated to be used are consumeddaily. The PADI values used in this study were provided by FEMA.

For each substance the NOEL and intake estimates were tabulated,and the margins of safety were calculated according to the following:

Margin of safety ¼ NOEL ðmg=kg body weight=dayÞ=Intake ðmg=kg body weight=dayÞ

2 Daily per capita intake (PCI · 10) = annual poundage data in kg/[population · 365 days · survey correction factor]; where it is assumedthat only 10% of the population consumes the flavouring substance(population values used; 32 · 106 and 26 · 106 for Europe and US,respectively). Depending on the survey, a correction factor of 0.6 or 0.8 isused, which assumes that only 60% and 80%, respectively, of production isreported.

3. Results

Each section discussing results for the individual conge-neric groups has been divided into two parts, with the firstoutlining parent compound NOELs and the latter identify-ing compounds for which NOELs for metabolites and/orstructurally related substances were used for the calcula-tion of the margins of safety.

Tables 1–30 list the individual flavouring substancesevaluated by JECFA with the corresponding highestestimated daily per capita intakes selected from eitherEuropean or US annual volume of production surveydata, as well as with the corresponding PADI values.The tables also include the representative NOEL for eachflavouring agent, as well as the basis for the NOEL. Addi-tionally, study details pertaining to the species, route ofexposure, treatment duration, and dose levels tested arepresented in the footnotes accompanying each respectivetable. The tables also specify instances where the NOELis the highest dose level tested in a multiple dose levelstudy or, alternatively, was the only dose level tested atwhich no adverse effects were reported. In such cases thecalculated margin of safety would be expected to representa minimum value.

3.1. Flavouring substances evaluated by JECFA at the

55th meeting in 2000

3.1.1. Cinnamyl alcohol and related flavouring agents

3.1.1.1. Parent compound NOELs. In this group of flavour-ing substances, suitable NOELs were available for cinnamylalcohol and ethyl cinnamate (Zaitsev and Rakhmanina,1974), cinnamaldehyde (NTP, 2004a), linalyl cinnamateand benzyl cinnamate (Hagan et al., 1967), a-amylcinnam-aldehyde (Carpanini et al., 1973), a-methylcinnamaldehyde(Trubek Laboratories, 1958a), and ortho-methoxycinnam-aldehyde and para-methoxy-a-methyl cinnamaldehyde(Posternak et al., 1969).

At the time of JECFA�s evaluation of this group of fla-vouring substances, only short-term toxicity studies up to16 weeks in duration, were available for cinnamaldehyde.Subsequent to the evaluation, the National ToxicologyProgram (NTP) conducted longer-term carcinogenicitystudies with trans-cinnamaldehyde in mice and rats, whichwere considered by the study authors to be more appro-priate for the calculation of the margin of safety. There-fore, while JECFA�s evaluation of cinnamaldehyde andthe related compound cinnamaldehyde ethylene glycolacetal was based on a NOEL of 620 mg/kg body weight/day, a lower NOEL of 205 mg/kg body weight/day wasused to calculated the margin of safety for cinnamalde-hyde and all related compounds in the present study.

Although evaluation of a-amylcinnamaldehyde by theCommittee was not based on toxicity data, two NOELswere identified for the compound in the JECFA report.The NOEL selected in this study was the more conservativeof the two and based on the results of a longer-term study.


Likewise, for a-methylcinnamaldehyde two studies wereidentified in the JECFA monograph; however, in one ofthe studies the compound was administered as acomponent of a mixture. Thus, the study performed withthe pure compound was considered to be a more suitablestudy as a NOEL basis for the calculation of the marginof safety.

3.1.1.2. NOELs for metabolites and/or structurally related

substances. For those flavouring substances for whichNOELs were not identified, the most conservative orappropriate NOEL for a structurally similar compoundor a metabolite of the compound was selected. Since themetabolic fate of 3-phenyl-1-propanol is comparable tothat of benzyl alcohol (see Section 3.2.3), the NOEL estab-lished for benzyl alcohol (NTP, 1989) was selected for 3-phenyl-1-propanol for the calculation of the margin ofsafety. The NOEL for benzyl alcohol also was consideredto be an appropriate NOEL basis for the 3-phenyl-l-propa-nol esters and for the structurally related compound 5-phenylpentanol.

3-Phenylpropionic acid and 3-(para-isopropylphenyl)-propionaldehyde are metabolized to benzoic acid deriva-tives. Therefore, the NOEL for benzoic acid (JECFA,1974, 1983) (see Section 3.2.3) was determined to be appro-priate as the NOEL basis for 3-phenylpropionic acid, itsesters, 3-phenylpropionaldehyde, which oxidizes to 3-phenylpropionic acid, and 3-(para-isopropylphenyl)-propionaldehyde.

The results for this group of flavouring substances of thecomparison of the intake estimates with NOELs are shownin Table 1.

3.1.2. Furfuryl alcohol and related substances

All compounds in this group of flavouring agents evalu-ated by JECFA required toxicological data. In keepingwith JECFA�s evaluation, the NOELs presented by theCommittee for furfural (Jonker, 2000), 2-benzofurancar-boxaldehyde (Posternak et al., 1969), and 2-phenyl-3-car-bethoxyfuran (Posternak et al., 1969) also were selectedto calculate the margins of safety in this study. Based ona common metabolic fate, the furfural NOEL served asthe basis for JECFA�s evaluation of the safety of theremaining compounds in this congeneric group and wastherefore also selected for the calculation of the marginsof safety in this study. The results for this group of flavour-ing substances of the comparison of the intake estimateswith NOELs are summarized in Table 2.

3.1.3. Phenol and phenol derivatives

3.1.3.1. Parent compound NOELs. In this group of flavour-ing substances, suitable NOELs were available for severalcompounds, including phenol (NCI, 1980a), ortho-cresoland meta-cresol (NTP, 1992a), para-cresol (EPA, 1988b),para-ethylphenol (Posternak et al., 1969), 2,6-xylenol and3,4-xylenol (Maasik, 1970), thymol (Hagan et al., 1967),

resorcinol (NTP, 1992b), 2,6-dimethoxyphenol (Posternaket al., 1969), 4-(para-hydroxyphenyl)-2-butanone (Gauntet al., 1970), and 2-phenylphenol (Wahle et al., 1997). 4-(para-Hydroxyphenyl)-2-butanone was the only com-pound, which was evaluated by the Committee based ontoxicity data. In keeping with the evaluation, the NOELselected by JECFA also was presently used for the calcula-tion of the margin of safety (Gaunt et al., 1970). An accept-able daily intake (ADI) of 0.4 mg/kg body weight/day,based on a NOEL of 39 mg/kg body weight/day (Wahleet al., 1997), was established for 2-phenylphenol when eval-uated at the Joint FAO/WHO Meeting on Pesticide Resi-dues (JMPR) in 1999. In keeping with the rationalepresented by the Committee, this NOEL also was main-tained for the calculation of the margin of safety in thisstudy.

A number of studies of equal duration were identifiedfor ortho-cresol in the JECFA report. In comparison to aNOEL based on the results of a gavage study (EPA,1988a), albeit lower (i.e., 180 mg/kg body weight/day), theNOEL for ortho-cresol obtained from a NTP feeding studywas considered by the authors of this study to be a moreappropriate representative NOEL (NTP, 1992a) for thecalculation of the margin of safety based on the dietaryroute of administration.

The NTP conducted a 13-week rat feeding study with amixture of meta- and para-cresol (60:40) (NTP, 1992a).Since no other studies were available for meta-cresol,the NOEL derived from this NTP study, adjusted forthe proportion of meta-cresol present in the mixture,was selected for the calculation of the margin of safety.For para-cresol, a lower NOEL was available fromanother 13-week study in which rats were administeredthe substance via gavage (EPA, 1988b). Although theroute of administration utilized in the NTP study is morerepresentative of the use of para-cresol as a flavouringagent, given that the substance was administered as partof a mixture in the NTP study, the study conducted bythe US Environmental Protection Agency (EPA) was con-sidered to be more appropriate for the determination ofan appropriate NOEL.


substances. For a number of flavouring substances in thisgroup, studies were not conducted with the parent com-pound and thus NOELs for structural relatives or metab-olites were selected for the calculation of the margin ofsafety. For several of the compounds in this group themargins of safety were calculated based on a NOEL forthe structurally related flavouring substance, eugenol.Eugenol was evaluated by JECFA in 1982, at which pointan ADI of 2.5 mg/kg body weight/day was establishedbased on the results of a rat carcinogenicity study(NTP, 1983).

A study abstract presenting results which supported aNOEL of 125 mg/kg body weight/day was identified forphenyl salicylate; however, a full study report was not

Table 1Cinnamyl alcohol and related substances—comparison of intake estimates to NOEL

JECFAno.

Flavouring substance NOEL(mg/kg bw/d)

MSDIa PADI Reference NOEL basis

Intake(mg/kg bw/day)

Marginof safety


Marginof safety

636 3-Phenyl-1-propanol 400b 0.001 400,000 0.018 22,222 NTP (1989)1 Benzyl alcohol637 3-Phenylpropyl formate 400b 0.00001 40,000,000 0.028 14,286 NTP (1989)1 Benzyl alcohol638 3-Phenylpropyl acetate 400b 0.0007 571,429 0.035 11,429 NTP (1989)1 Benzyl alcohol639 3-Phenylpropyl propionate 400b 0.000005 80,000,000 0.014 28,571 NTP (1989)1 Benzyl alcohol640 3-Phenylpropyl isobutyrate 400b 0.0003 1,333,333 0.04 10,000 NTP (1989)1 Benzyl alcohol641 3-Phenylpropyl isovalerate 400b 0.000001 400,000,000 0.0033 121,212 NTP (1989)1 Benzyl alcohol642 3-Phenylpropyl hexanoate 400b 0.000007 57,142,857 0.011 36,364 NTP (1989)1 Benzyl alcohol643 Methyl 3-phenylpropionate 500b 0.00005 10,000,000 0.029 17,241 JECFA (1974, 1983)2 Benzoic acid644 Ethyl 3-phenylpropionate 500b 0.00002 25,000,000 0.03 16,667 JECFA (1974, 1983)2 Benzoic acid645 3-Phenylpropionaldehyde 500b 0.0003 1,666,667 0.016 31,250 JECFA (1974, 1983)2 Benzoic acid646 3-Phenylpropionic acid 500b 0.0003 1,666,667 0.0069 72,464 JECFA (1974, 1983)2 Benzoic acid647 Cinnamyl alcohol 54b 0.03 1800 0.03 1800 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol649 Cinnamyl formate 54b 0.0003 180,000 0.0082 6585 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol650 Cinnamyl acetate 54b 0.005 10,800 0.034 1588 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol651 Cinnamyl propionate 54b 0.0004 135,000 0.027 2000 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol652 Cinnamyl butyrate 54b 0.00005 1,080,000 0.018 3000 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol653 Cinnamyl isobutyrate 54b 0.0004 135,000 0.013 4154 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol654 Cinnamyl isovalerate 54b 0.0001 540,000 0.017 3176 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol760 Cinnamyl benzoate 54b 0.00001 5,400,000 0.051 1059 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol655 Cinnamyl phenylacetate 54b 0.00005 1,080,000 0.062 871 Zaitsev and Rakhmanina (1974)3 Cinnamyl alcohol656 Cinnamaldehyde 205b 1 205 1.22 168 NTP (2004a)4 Cinnamaldehyde657 Cinnamic acid 205b 0.0007 292,857 1.32 155 NTP (2004a)4 Cinnamaldehyde658 Methyl cinnamate 80b 0.05 1600 0.02 4000 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate659 Ethyl cinnamate 80b 0.002 40,000 0.17 471 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate660 Propyl cinnamate 80b 0.00007 1,142,857 0.024 3333 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate661 Isopropyl cinnamate 80b 0.0003 266,667 0.0097 8247 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate19 Allyl cinnamate 80b 0.00009 888,889 0.022 3636 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate663 Butyl cinnamate 80b 0.000006 13,333,333 0.031 2581 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate664 Isobutyl cinnamate 80b 0.00005 1,600,000 0.017 4706 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate665 Isoamyl cinnamate 80b 0.0001 800,000 0.029 2759 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate666 Heptyl cinnamate 80b 0.0009 88,889 0.025 3200 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate667 Cyclohexyl cinnamate 80b 0.000006 13,333,333 0.071 1127 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate668 Linalyl cinnamate 500b 0.0001 5,000,000 0.0066 75,758 Hagan et al. (1967)6 Linalyl cinnamate669 Terpinyl cinnamate 80b 0.000009 8,888,889 0.018 4444 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate670 Benzyl cinnamate 500b 0.001 500,000 0.051 9804 Hagan et al. (1967)7 Benzyl cinnamate671 Phenethyl cinnamate 80b 0.0008 100,000 0.014 5714 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate672 3-Phenylpropyl cinnamate 80b 0.0006 133,333 0.037 2162 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate673 Cinnamyl cinnamate 80b 0.0006 133,333 0.08 1000 Zaitsev and Rakhmanina (1974)5 Ethyl cinnamate676 a-Amylcinnamyl formate 290b 0.00002 14,500,000 0.012 24,167 Carpanini et al. (1973)8 a-Amylcinnamaldehyde677 a-Amylcinnamyl acetate 290b 0.00005 5,800,000 0.018 16,111 Carpanini et al. (1973)8 a-Amylcinnamaldehyde678 a-Amylcinnamyl isovalerate 290b 0.000009 32,222,222 0.008 36,250 Carpanini et al. (1973)8 a-Amylcinnamaldehyde679 3-Phenyl-4-pentenal 205b 0.00004 5,125,000 0.0068 30,147 NTP (2004a)4 Cinnamaldehyde680 3-(para-Isopropylphenyl)-propionaldehyde 500b 0.000002 250,000,000 0.033 15,152 JECFA (1974, 1983)2 Benzoic acid681 a-Amylcinnamaldehyde dimethyl acetal 290b 2.00 · 10�7 1450,000,000 0.01 29,000 Carpanini et al. (1973)8 a-Amylcinnamaldehyde

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enyl

pen

tan

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400b

0.00

0002

200,

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000

0.03

411

,765

NT

P(1

989)

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684

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3)8

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exp

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500

mg/

kg

bw

/day

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anet

al.,

1967

);8ra

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320

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arp

anin

iet

al.,

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);9ra

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iet,

90d

ays,

58,

120,

or

220

mg/

kg

bw

/day

(Tru

bek

Lab

ora

tori

es,

1958

a);

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iet,

90d

ays,

47/5

7(M

/F)

mg/

kg

bw

/day

(Po

ster

nak

etal

.,19

69);

11ra

t,d

iet,

90d

ays,

2.4/

2.7

(M/F

)m

g/k

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ost

ern

aket

al.,

1969

).a

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hes

tin

tak

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tim

ate

was

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fro

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no

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erca

pit

ain

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mu

ltip

led

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sth

ath

adn

oad

vers

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valu

eth

eref

ore

isn

ot

atr

ue

NO

EL

bu

tra

ther

the

hig

hes

td

ose

test

edat

wh

ich

no

adve

rse

effec

tsw

ere

ob

serv

ed.

Th

eac

tual

NO

EL

may

be

hig

her

.


available for review and as such the inadequate level ofdetail presented in the abstract limited the usefulness of thisstudy. Instead, since phenyl salicylate is an ester expectedto hydrolyze to phenol and salicylic acid, the NOEL wasbased on a structurally similar ester, methyl salicylate(Webb and Hansen, 1963) (see Section 3.2.4).

For 4-(1,1-dimethyl)ethylphenol, a single-dose leveltrial demonstrating adverse effects at a relatively high-dose level (i.e., 1800 mg/kg body weight/day) was the onlyavailable study for review. Thus, a NOEL could not beestablished on the basis of this study and instead theNOEL was based on the structurally related compound,para-cresol.

Margins of safety for all other compounds in thisgroup of flavouring substances were evaluated based onsuitable NOELs for structurally similar compounds orcompounds with a comparable metabolic fate. The resultsfor this group of flavouring substances of the compari-son of the intake estimates with NOELs are shown inTable 3.

3.1.4. Pulegone and related substancesAll compounds in this group of flavouring agents were

evaluated on the B-side of the procedure for the safetyevaluation of flavouring agents. Accordingly, toxicity datawere required for all flavouring substances. AlthoughJECFA�s evaluation of pulegone and related compoundswas based on a rat study in which following 90-daygavage administration of peppermint oil containingapproximately 1.1% pulegone, cyst-like spaces wereobserved in the brain tissue of high-dose animals (i.e.,100 mg peppermint oil/kg body weight/day), two addi-tional 28-day oral toxicity rat studies were conducted withpulegone itself. In one of the two studies a NOEL of20 mg/kg body weight/day was established based on theappearance of cerebral tissue variations at higher doselevels (Thorup et al., 1983). In contrast, in the other studyno histological changes were observed in the white matterof the cerebellum at dose levels of up to 160 mg/kg bodyweight/day (Mølck et al., 1998). Mølck et al. (1998) sug-gested that the cyst-like spaces may have been artefactsoccurring as a result of inappropriate tissue fixation tech-niques, rather than adverse effects related to pulegone tox-icity per se. It is therefore questionable whether the effectsare in fact relevant to the evaluation of pulegone safety inhumans. Furthermore, it is well known that vacuolationof the cerebellum occurs in rats with increasing age(Burek, 1978; Greaves and Faccini, 1984). Therefore, inthis study the margins of safety for pulegone, as well asfor the structurally related compound isopulegol, itsesters, and menthofuran were based on the NOEL of20 mg/kg body weight/day established on the basis ofthe results of the toxicity study conducted with pulegoneitself. Table 4 presents a summary of the comparison ofthe intake estimates with NOELs for this group of fla-vouring substances.

Table 2Furfuryl alcohol and related substances—comparison of intake estimates to NOEL

JECFAno.

Flavouring substance NOEL(mg/kgbw/day)


Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

451 Furfuryl alcohol 60 0.004 15,000 0.13 462 Jonker (2000)1 Furfural739 Furfuryl acetate 60 0.0004 150,000 0.11 545 Jonker (2000)1 Furfural740 Furfuryl propionate 60 0.00008 750,000 0.0065 9231 Jonker (2000)1 Furfural741 Furfuryl pentanoate 60 0.0002 300,000 0.0037 16,216 Jonker (2000)1 Furfural742 Furfuryl octanoate 60 0.0001 600,000 0.011 5455 Jonker (2000)1 Furfural743 Furfuryl 3-methyl butanoate 60 0.00002 3,000,000 0.0076 7895 Jonker (2000)1 Furfural450 Furfural 60 0.009 6667 0.21 286 Jonker (2000)1 Furfural745 5-methyl furfural 60 0.003 20,000 0.012 5000 Jonker (2000)1 Furfural746 Methyl-2-furoate 60 0.0006 100,000 0.015 4000 Jonker (2000)1 Furfural747 Propyl-2-furoate 60 0.000002 30,000,000 0.0036 16,667 Jonker (2000)1 Furfural748 Amyl-2-furoate 60 0.000002 30,000,000 0.018 3333 Jonker (2000)1 Furfural749 Hexyl-2-furoate 60 0.000002 30,000,000 0.03 2000 Jonker (2000)1 Furfural750 Octyl-2-furoate 60 0.00005 1,200,000 0.013 4615 Jonker (2000)1 Furfural751 2-Benzofurancarboxaldehyde 25b 2.00 · 10�8 1,250,000,000 0.009 2778 Posternak et al.

(1969)22-Benzofurancarboxaldehyde

752 2-Phenyl-3-carbethoxyfuran 13b 0.00003 433,333 0.01 1300 Posternak et al.(1969)3

2-Phenyl-3-carbethoxyfuran

Species, route of exposure, study duration, dose levels tested: 1rat, diet (microencapsulated), 13 weeks, 30, 60, 90, or 180 mg/kg bw/day (Jonker, 2000);2rat, diet, 90 days, 25/27 mg/kg bw/day (M/F) (Posternak et al., 1969); 3rat, diet, 90 days, 13 mg/kg bw/day (Posternak et al., 1969).

a Highest intake estimate was selected from European or US per capita intake data.b Study performed with either a single dose or multiple doses that had no adverse effect; the value therefore is not a true NOEL but rather the highest

dose tested at which no adverse effects were observed. The actual NOEL may be higher.




3.2.1. Pyrazine derivatives

3.2.1.1. Parent compound NOELs. None of the compoundsin this group required toxicity data for JECFA�s evaluationof their safety. With the exception of a carcinogenicitystudy performed with pyrazinamide, a compound structur-ally related to pyrazine, no other long-term studies wereavailable for this group of compounds. Evaluated in rats,pyrazinamide was considered to be not carcinogenicfollowing administration at dose-levels of up to 1000 mg/kg body weight/day (NCI, 1977). Although in female micethe carcinogenicity of the substance could not be fully eval-uated, in males there was also no evidence of carcinogenic-ity at dose levels of up to 1500 mg/kg body weight/day.

Suitable NOELs based on the results of shorter-termstudies, typically 90–91 days in duration, were, however,available in the JECFA monograph for a series of com-pounds in this group, including 2-ethyl-5-methylpyrazine(Oser, 1969a), 2-ethyl-3-methylpyrazine (Posternak et al.,1969), 2,3-diethylpyrazine (Posternak et al., 1969), 2,3,5-trimethylpyrazine (Oser, 1969b), 2-ethyl-3,(5 or 6)-dim-ethylpyrazine (Oser, 1969c), 3-ethyl-2,6-dimethylpyra-zine (Posternak et al., 1975), 2,3,5,6-tetramethylpyrazine(Oser, 1969d), 5-methyl-6,7-dihydro-5H-cyclopentapyr-azine (Wheldon et al., 1967), 2-acetylpyrazine (Posternaket al., 1975), methoxypyrazine (Osborne et al., 1981), 2-methoxy-3,(5 or 6)-methylpyrazine (Posternak et al.,1969), (cyclohexylmethyl)pyrazine (Babish and Re, 1978),2-pyrazinylethanethiol (Posternak et al., 1975), pyrazi-

nylmethyl methyl sulfide (Posternak et al., 1975), (3,5 or6)-(methylthio)-2-methylpyrazine (Posternak et al., 1975),5-methylquinoxaline (Posternak et al., 1969), and 5,6,7,8-tetrahydroquinoxaline (Oser, 1970a).

For all remaining compounds in this group for whichNOELs were not available, the margins of safety were cal-culated based on NOELs derived for other structurallysimilar compounds in this group of flavouring substances.A summary of the comparison of the intake estimates withNOELs for this group of flavouring substances is presentedin Table 5.

3.2.2. Aromatic substituted secondary alcohols, ketones

and related esters

3.2.2.1. Parent compound NOELs. The evaluation of thecompounds in this group of flavouring agents by the Com-mittee was not based on toxicity data; however, the Com-mittee had evaluated a-methylbenzyl alcohol in 1993 andassigned an ADI of 0.1 mg/kg body weight/day on thebasis of a 13-week oral rat study, which demonstrated aminimal-effect-level of 93 mg/kg body weight/day (NTP,1990). Although 2-year toxicity studies also were available,these were conducted at higher dose levels at which chronicprogressive nephropathy was observed in male, but notfemale rats, and both male and female mice. In keepingwith the determination of the ADI by JECFA, the NOELof 93 mg/kg body weight/day was used as the basis for thecalculation of the margin of safety for the alcohol and, withthe exception of a-methylbenzyl acetate for which a sepa-rate NOEL was identified (Gaunt et al., 1974), its relatedesters, as well as other structurally related compounds.

Table 3Phenol and phenol derivatives—comparison of intake estimates to NOEL

JECFAno.




Marginof safety


Marginof safety

690 Phenol 250 0.0001 2,500,000 0.012 20,833 NCI (1980a)1 Phenol691 ortho-Cresol 250 0.005 50,000 0.021 11,905 NTP (1992a)2 ortho-Cresol692 meta-Cresol 150 0.000002 75,000,000 0.021 7143 NTP (1992a)3 meta-Cresol693 para-Cresol 50 0.00002 2,500,000 0.023 2174 EPA (1988b)4 para-Cresol694 para-Ethylphenol 0.2b 0.00007 2857 0.023 9 Posternak et al. (1969)5 para-Ethylphenol695 ortho-Propylphenol 250 0.00002 12,500,000 0.0033 75,758 NTP (1992a)2 ortho-Cresol696 para-Propylphenol 50 0.000002 25,000,000 3.33 · 10�5 1,501,502 EPA (1988b)4 para-Cresol697 2-Isopropylphenol 250 0.0003 833,333 0.0033 75,758 NTP (1992a)2 ortho-Cresol733 4-(1,1-Dimethyl)ethylphenol 50 2.00 · 10�7 250,000,000 0.0012 41,667 EPA (1988b)4 para-Cresol734 Phenyl acetate 250 2.00 · 10�7 1,250,000,000 0.012 20,833 NCI (1980a)1 Phenol698 ortho-Tolyl acetate 250 0.0007 357,143 0.065 3846 NTP (1992a)2 ortho-Cresol699 para-Tolyl acetate 50 0.001 50,000 0.041 1220 EPA (1988b)4 para-Cresol700 ortho-Tolyl isobutyrate 250 0.000002 125,000,000 0.029 8621 NTP (1992a)2 ortho-Cresol701 para-Tolyl isobutyrate 50 0.000007 7,142,857 0.018 2778 EPA (1988b)4 para-Cresol702 para-Tolyl-3-methyl butyrate 50 0.000007 7,142,857 0.0036 13,889 EPA (1988b)4 para-Cresol703 para-Tolyl octanoate 50 0.00002 2,500,000 0.012 4167 EPA (1988b)4 para-Cresol704 para-Tolyl laurate 50 0.000005 10,000,000 0.02 2500 EPA (1988b)4 para-Cresol705 para-Tolyl phenylacetate 50 0.00001 5,000,000 0.024 2083 EPA (1988b)4 para-Cresol706 2,5-Xylenol 0.06 0.00002 3000 0.0086 7 Maasik (1970)6 2,6-Xylenol707 2,6-Xylenol 0.06 0.00003 2000 0.012 5 Maasik (1970)6 2,6-Xylenol708 3,4-Xylenol 0.14 0.0001 1400 0.0095 15 Maasik (1970)7 3,4-Xylenol737 2,3,6-Trimethylphenol 0.06 0.000005 12,000 0.0027 22 Maasik (1970)6 2,6-Xylenol709 Thymol 500b 0.003 166,667 0.059 8475 Hagan et al. (1967)8 Thymol710 Carvacrol 500b 0.0003 1,666,667 0.079 6329 Hagan et al. (1967)8 Thymol711 para-Vinylphenol 0.2b 0.0001 2000 0.01 20 Posternak et al. (1969)5 para-Ethylphenol712 Resorcinol 100 0.00002 5,000,000 0.015 6667 NTP (1992b)9 Resorcinol713 Guaiacol 250 0.0009 277,778 0.011 22,727 NTP (1983)10 Eugenol714 ortho-(Ethoxymethyl)phenol 250 0.00003 8,333,333 0.012 20,833 NTP (1992a)2 ortho-Cresol715 2-Methoxy-4-methylphenol 250 0.0006 416,667 0.031 8065 NTP (1983)10 Eugenol716 4-Ethylguaiacol 250 0.0001 2,500,000 0.042 5952 NTP (1983)10 Eugenol717 2-Methoxy-4-propylphenol 250 0.004 62,500 0.0008 312,500 NTP (1983)10 Eugenol718 Guaiacyl acetate 250 0.000002 125,000,000 0.034 7353 NTP (1983)10 Eugenol719 Guaiacyl phenylacetate 250 0.00003 8,333,333 0.016 15,625 NTP (1983)10 Eugenol720 Hydroquinone monoethyl ether 50 0.000007 7,142,857 0.01 5000 EPA (1988b)4 para-Cresol721 2,6-Dimethoxyphenol 6b 0.0002 30,000 0.015 400 Posternak et al. (1969)11 2,6-Dimethoxyphenol722 4-Methyl-2,6-dimethyoxyphenol 6b 7.00 · 10�7 8,571,429 0.00055 10,909 Posternak et al. (1969)11 2,6-Dimethoxyphenol723 4-Ethyl-2,6-dimethoxyphenol 6b 0.00002 300,000 0.00055 10,909 Posternak et al. (1969)11 2,6-Dimethoxyphenol724 4-Propyl-2,6-dimethoxyphenol 6b 0.000002 3,000,000 0.00055 10,909 Posternak et al. (1969)11 2,6-Dimethoxyphenol725 2-Methoxy-4-vinylphenol 250 0.00005 5,000,000 0.057 4386 NTP (1983)10 Eugenol726 2-Allyl-2,6-dimethoxyphenol 250 0.0001 2,500,000 0.00035 714,286 NTP (1983)10 Eugenol727 2-Hydroxyacetophenone 250 0.000002 125,000,000 0.00045 555,556 NTP (1992a)2 ortho-Cresol736 Phenyl salicylate 50 0.0002 250,000 0.23 217 Webb and Hansen (1963)12 Methyl salicylate

(continued on next page)

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.


Two 90-day oral rat toxicity studies were identified forbenzophenone. In the study conducted by Freeman et al.(1994) adverse effects were observed at the lowest doselevel administered (i.e., 120 mg/kgbody weight/day) and,therefore, a NOEL could not be established; however,in the other study, no adverse effects were reported ata dose level of 19 mg/kg body weight/day (Burdocket al., 1991), which accordingly was selected as the repre-sentative NOEL for the calculation of the margin ofsafety.

Several studies were conducted with benzoin, andalthough short-term studies demonstrated some adverseeffects, no statistically significant effects were observed in2-year-long mouse and rat studies on the basis of which aNOEL of 25 mg/kg body weight/day was established(NCI, 1980b).

Additionally, suitable NOELs also were identified in theJECFA report for acetophenone (Hagan et al., 1967), a-methylphenethyl butyrate (Posternak et al., 1969), 1-(para-methoxyphenyl)-1-penten-3-one (Oser et al., 1965),1-phenyl-1-propanol (Brown et al., 1955), a-isobutylphen-ethyl alcohol (Ford et al., 1983), 1-phenyl-1,2-propanedi-one (Posternak et al., 1969), methyl b-napthyl ketone(Oser et al., 1965), and 4-(para-methoxyphenyl)-2-buta-none (Trubek Laboratories, 1956) in this group of flavour-ing agents.


substances. Given their metabolism to hippuric acid andstructural analogy, margins of safety for ethyl benzoylace-tate and ethyl 2-acetal-3-phenylpropionate were calculatedbased on the NOEL for benzoic acid (JECFA, 1974, 1983)(see Section 3.2.3). Margins of safety for the remainingcompounds in this group of flavouring substances werecalculate on the basis of suitable NOELs selected for otherstructurally related compounds in this group. Table 6presents a summary of the comparison of the intakeestimates with NOELs for this group of flavouring subs-tances.

3.2.3. Benzyl derivatives

3.2.3.1. Parent compound NOELs. In keeping with theCommittee�s evaluation, a NOEL available from a two-generation study for the hydrolysis product methoxyetha-nol (Gulati et al., 1990a,b) was selected as the NOEL basisfor the calculation of the margin of safety of benzyl2-methoxyethyl acetal, which was the only flavouring sub-stance in this group requiring toxicity data for the evalua-tion of its safety by the Committee.

In 1996, JECFA maintained the group ADI of 5 mg/kg body weight for benzoic acid, benzoate salts, benzal-dehyde, benzyl acetate, benzyl alcohol and benyl benzo-ate, expressed as benzoic acid equivalents, establishedin 1970 and 1973 for benzoic acid and its salts on thebasis of a NOEL of 500 mg/kg body weight/day observedin rats (JECFA, 1974, 1983); however, whenever an

Table 4Pulegone and related substances—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

755 Isopulegol 20 0.0002 100,000 0.049 408 Thorup et al. (1983)1 Pulegone756 Isopulegyl acetate 20 0.00002 1,000,000 0.022 909 Thorup et al. (1983)1 Pulegone753 Pulegone 20 0.00003 666,667 0.1 200 Thorup et al. (1983)1 Pulegone754 Isopulegone 20 0.00002 1,000,000 0.036 556 Thorup et al. (1983)1 Pulegone757 para-Mentha-1,4(8)-dien-3-one 20 0.00003 666,667 0.0098 2041 Thorup et al. (1983)1 Pulegone758 Menthofuran 20 0.0004 50,000 0.04 500 Thorup et al. (1983)1 Pulegone

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 28 days, 20, 80, or 160 mg/kg bw/day (Thorup et al., 1983).a Highest intake estimate was selected from European or US per capita intake data.


appropriate NOEL was available for a parent benzylcompound it was used for the calculation of the corres-ponding margin of safety. The results for this group offlavouring substances of the comparison of the intakeestimates with NOELs are shown in Table 7a.

Benzyl alcohol has been studied extensively in a series ofNTP short- and long-term mouse and rat oral toxicitystudies (NTP, 1989). Under the conditions of the 2-yearstudies, no evidence of carcinogenic activity and no othertoxicologically significant adverse effects were observed inmale or female mice and rats administered up to 200 and400 mg benzyl alcohol/kg body weight/day via gavage.Although in comparison to controls, a 50% reductionwas observed in the survival of female rats at both dose lev-els, deaths were attributed to gavage error rather than tocompound-related toxicity. Accordingly, based on theresults of the rat study a NOEL of 400 mg/kg body -weight/day was selected for benzyl alcohol for the calcula-tion of the margin of safety.

For benzyl acetate the NOEL was selected based on theresults of a 2-year rat feeding study (NTP, 1993a). Theresults of both the rat and mouse feeding studies were incontrast to those reported in prior gavage studies, in whichsome benzyl acetate-related evidence of carcinogenicity wasreported; however, as noted by the Committee, the resultsof the feeding studies are more relevant to the safety assess-ment of flavouring agents.

The NOEL for benzaldehyde was selected based on theresults of a 13-week oral toxicity study conducted in rats(Hagan et al., 1967). Although longer-term gavage studieswere available for benzaldehyde, which produced someevidence of carcinogenicity, these were considered by theCommittee as not appropriate for evaluation of agentsfor oral consumption.

Additionally, suitable NOELs also were identified forglyceryl tribenzoate and propylene glycol dibenzoate (Car-son, 1972b), and tolualdehyde (Oser et al., 1965). Althoughthe NOEL for tolualdehyde was based on a single-doselevel study, the NOEL was confirmed in a 13-week ratgavage study in which no adverse effects were observed ata higher dose level (250 mg/kg body weight/day) (Brantomet al., 1972).


substances. A 6-month gavage study was available formethyl benzoate; however, the NOEL for benzoic acidbased on the results of a feeding study was deemed to bemore appropriate for the calculation of the margin ofsafety. Likewise, although a 14-day single-dose level studywas conducted with 2,4-dimethylbenzaldehyde (DeGrootet al., 1974), given the short treatment duration, the studywas not deemed appropriate as a basis for the calculationof the margin of safety for the compound. Thus, the NOELfor benzaldehyde was selected for the calculation of themargin of safety for 2,4-dimethylbenzaldehyde.

For all other compounds the most appropriate NOELfor a structurally related flavouring substances evaluatedin this group was selected as the NOEL basis for the calcu-lation of the margin of safety. In cases where more thanone NOEL was suitable, the more conservative NOELwas selected. Although the margin of safety for benzylphenylacetate was calculated on the basis of the NOELfor benzyl alcohol, in comparison to either the MSDI orPADI, margins of safety for the compound of at least1000 would still be available if the calculation was basedon the more conservative NOEL of 120 mg/kg body -weight/day for phenethyl alcohol (Johannsen and Pur-chase, 1969) (see Section 3.3.2). Similarly, although thebenzoic acid NOEL served as the basis for the calculationof the margin of safety for cis-3-hexenyl benzoate, using themore conservative NOEL of 130 mg/kg body weight/dayfor cis-3-hexen-1-ol (Gaunt et al., 1969), margins of safetyof well-above 1000 would still exist for cis-3-hexenyl benzo-ate compared to either estimate of intake.

Additionally, since all compounds in this group of fla-vouring substances are expected to be metabolized to ben-zoic acid or its derivatives, Table 7b presents the margins ofsafety for the benzyl derivatives when calculated on thebasis of the MSDI and PADI intakes expressed as benzoicacid equivalents. As summarized in Table 7b, margins ofsafety of greater than 100 exist for the total intake of ben-zoic acid equivalents obtained from the consumption ofbenzoic acid derivatives at intake levels estimated usingthe MSDI and PADI approach when compared to theNOEL of 500 mg/kg body weight/day for benzoic acid.

Table 5Pyrazine derivatives—comparison of intake estimates to NOEL

JECFAno.



Intake (mg/kgbw/day)

Marginof safety


Marginof safety

761 2-Methylpyrazine 17b 0.0003 56,667 0.013 1308 Oser (1969a)1 2-Ethyl-5-methylpyrazine762 2-Ethylpyrazine 17b 0.0001 170,000 0.097 175 Oser (1969a)1 2-Ethyl-5-methylpyrazine763 2-Propylpyrazine 17b 0.000002 8,500,000 0.0042 4048 Oser (1969a)1 2-Ethyl-5-methylpyrazine764 2-Isopropylpyrazine 17b 0.000002 8,500,000 0.0042 4048 Oser (1969a)1 2-Ethyl-5-methylpyrazine765 2,3-Dimethylpyrazine 17b 0.0003 56,667 0.076 224 Oser (1969a)1 2-Ethyl-5-methylpyrazine766 2,5-Dimethylpyrazine 17b 0.0004 42,500 0.12 142 Oser (1969a)1 2-Ethyl-5-methylpyrazine767 2,6-Dimethylpyrazine 17b 0.00003 566,667 0.089 191 Oser (1969a)1 2-Ethyl-5-methylpyrazine768 2-Ethyl-3-methylpyrazine 5.2b 0.001 5200 0.013 400 Posternak et al. (1969)2 2-Ethyl-3-methylpyrazine769 2-Ethyl-6-methylpyrazine 17b 0.000007 2,428,571 0.011 1545 Oser (1969a)1 2-Ethyl-5-methylpyrazine770 2-Ethyl-5-methylpyrazine 17b 0.00008 212,500 0.014 1214 Oser (1969a)1 2-Ethyl-5-methylpyrazine771 2,3-Diethylpyrazine 1.8b 0.00003 60,000 0.011 164 Posternak et al. (1969)3 2,3-Diethylpyrazine772 2-Methyl-5-isopropylpyrazine 17b 0.000007 2,428,571 0.0098 1735 Oser (1969a)1 2-Ethyl-5-methylpyrazine773 2-Isobutyl-3-methylpyrazine 17b 7.00 · 10�7 24,285,714 0.012 1417 Oser (1969a)1 2-Ethyl-5-methylpyrazine774 2,3,5-Trimethylpyrazine 17b 0.002 8500 0.019 895 Oser (1969b)4 2,3,5-Trimethylpyrazine775 2-Ethyl-3,(5 or 6)-dimethylpyrazine 17b 0.0007 24,286 0.023 739 Oser (1969c)4 2-Ethyl-3,(5 or 6)-

dimethylpyrazine776 3-Ethyl-2,6-dimethylpyrazine 12b 0.00003 400,000 0.0014 8571 Posternak et al. (1975)5 3-Ethyl-2,6-dimethylpyrazine777 2,3-Diethyl-5-methylpyrazine 12b 0.00002 600,000 0.0039 3077 Posternak et al. (1975)5 3-Ethyl-2,6-dimethylpyrazine778 2,5-Diethyl-3-methylpyrazine 12b 2.00 · 10�7 60,000,000 0.0047 2553 Posternak et al. (1975)5 3-Ethyl-2,6-dimethylpyrazine779 3,5-Diethyl-2-methylpyrazine 12b 2.00 · 10�7 60,000,000 0.0047 2553 Posternak et al. (1975)5 3-Ethyl-2,6-dimethylpyrazine780 2,3,5,6-Tetramethylpyrazine 50b 0.0003 166,667 0.011 4545 Oser (1969d)6 2,3,5,6-Tetramethylpyrazine781 5-Methyl-6,7-dihydro-5H-cyclopentapyrazine 50 0.00008 625,000 0.00038 131,579 Wheldon et al. (1967)7 5-Methyl-6,7-dihydro-5H-

cyclopentapyrazine782 6,7-Dihydro-2,3-dimethyl-5H-cyclopentapyrazine 50 2.00 · 10�7 250,000,000 0.0033 15,152 Wheldon et al. (1967)7 5-Methyl-6,7-dihydro-5H-

cyclopentapyrazine792 2-Isobutyl-3-methoxypyrazine 17b 0.00003 566,667 0.0026 6538 Oser (1969a)1 2-Ethyl-5-methylpyrazine784 2-Acetylpyrazine 8.2b 0.002 4100 0.0049 1673 Posternak et al. (1975)8 2-Acetylpyrazine950 2-Acetyl-3-methylpyrazine 8.2b 0.000002 4,100,000 0.007 1171 Posternak et al. (1975)8 2-Acetylpyrazine785 2-Acetyl-3-ethylpyrazine 8.2b 0.00002 410,000 0.00046 17,826 Posternak et al. (1975)8 2-Acetylpyrazine786 2-Acetyl-3,(5 or 6)-dimethylpyrazine 8.2b 0.00002 410,000 0.027 304 Posternak et al. (1975)8 2-Acetylpyrazine787 Methoxypyrazine 14 0.00007 200,000 0.1 140 Osborne et al. (1981)9 Methoxypyrazine788 2-Methoxy-3,(5 or 6)-methylpyrazine 45b 0.0002 225,000 0.013 3462 Posternak et al. (1969)10 2-Methoxy-3,(5 or 6)-

methylpyrazine789 2-Ethyl-3,(5 or 6)-methoxypyrazine 45b 0.00002 2,250,000 0.048 938 Posternak et al. (1969)10 2-Methoxy-3,(5 or 6)-

methylpyrazine790 2-Methoxy-3,(5 or 6)-isopropylpyrazine 45b 0.000002 22,500,000 0.00033 136,364 Posternak et al. (1969)10 2-Methoxy-3,(5 or 6)-

methylpyrazine791 2-Methoxy-3-(1-methylpropyl)-pyrazine 45b 0.00002 2,250,000 0.00016 281,250 Posternak et al. (1969)10 2-Methoxy-3,(5 or 6)-

methylpyrazine783 (Cyclohexylmethyl)pyrazine 0.44b 2.00 · 10�7 2,200,000 0.00029 1517 Babish and Re (1978)11 (Cyclohexylmethyl)pyrazine793 2-Methyl-3,(5 or 6)-ethoxypyrazine 45b 2.00 · 10�7 225,000,000 0.0021 21,429 Posternak et al. (1969)10 2-Methoxy-3,(5 or 6)-

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3.2.4. Hydroxy- and alkoxy-substituted benzyl derivatives

3.2.4.1. Parent compound NOELs. Numerous short- andlong-term studies were performed with vanillin. No toxico-logically significant adverse effects were reported in any ofthe studies. Thus, for vanillin the representative NOEL wasselected on the basis of the longest-term rat study available(Hagan et al., 1967) and was consistent with that chosen bythe Committee. For ethyl vanillin, a NOEL of 500 mg/kg body weight/day was identified (Hooks et al., 1992)which the Committee also used to establish an ADI of3 mg/kg body weight/day in 1995. In keeping with the eval-uation of methyl salicylate by the Committee, 50 mg/kg bo-dy weight/day (Webb and Hansen, 1963) was selected asthe representative NOEL for the calculation of the marginof safety. The Committee also assigned an ADI of 0.5 mg/kg body weight/day for methyl salicylate on the basis ofthis NOEL in 1967. The margins of safety for piperonalwere calculated on the basis of a NOEL (Bar and Griepen-trog, 1967), which also was used by the Committee to setan ADI of 2.5 mg/kg body weight/day for piperonal in1967.

None of the remaining compounds evaluated in thisgroup of flavouring agents required toxicity data; how-ever, appropriate NOELs for the calculation of themargin of safety were provided in the JECFA reportfor isoamyl salicylate (Drake et al., 1975), para-methoxy-benzaldehyde (FDA, 1954), and methyl ortho-meth-oxybenzoate (van Miller and Weaver, 1987). Althoughthe NOEL selected for methyl ortho-methoxybenzoatewas based on the results of a 14-day rat study (vanMiller and Weaver, 1987), the NOEL for the structurallyrelated compound, butyl para-hydroxybenzoate demon-strates absence of toxicity following longer-term adminis-tration and at higher dose levels.


substances. The evaluation of butyl para-hydroxybenzoatewas not finalized at the 2001 meeting pending additionaldata to demonstrate its use as a flavouring agent; however,a long-term oral toxicity mouse study was identified in theJECFA monograph on the basis of which a NOEL of900 mg/kg body weight/day was established (Inai et al.,1985). The NOEL for butyl para-hydroxybenzoate wasconsidered to be appropriate for the calculation of the mar-gin of safety for the structurally related compounds methylanisate and ethyl para-anisate.

For the remaining compounds, NOELs were chosenbased on structural similarity to other compounds in thisgroup, as well as benzoic acid, benzaldehyde, and benzylalcohol (see Section 3.2.3). The margin of safety for ani-syl phenylacetate was calculated using the benzyl alcoholNOEL. Although margins of safety for anisyl phenylace-tate would be slightly lower using the more conservativeNOEL for phenethyl alcohol (Johannsen and Purchase,1969) (see Section 3.3.2), they would still be well above100 in comparison to either the MSDI or PADI. Resultsof the comparison of the intake estimates with NOELs

Table 6Aromatic substituted secondary alcohols, ketones and related esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

799 a-Methylbenzyl alcohol 93 0.001 93,000 0.03 3100 NTP (1990)1 a-Methylbenzyl alcohol800 a-Methylbenzyl formate 93 0.000007 13,285,714 0.051 1824 NTP (1990)1 a-Methylbenzyl alcohol801 a-Methylbenzyl acetate 15 0.01 1500 0.02 750 Gaunt et al. (1974)2 a-Methylbenzyl acetate802 a-Methylbenzyl propionate 93 0.0004 232,500 0.069 1348 NTP (1990)1 a-Methylbenzyl alcohol803 a-Methylbenzyl butyrate 93 0.00002 4,650,000 0.018 5167 NTP (1990)1 a-Methylbenzyl alcohol804 a-Methylbenzyl isobutyrate 93 0.0005 186,000 0.012 7750 NTP (1990)1 a-Methylbenzyl alcohol805 para,a-Dimethylbenzyl alcohol 93 0.00002 4,650,000 0.013 7154 NTP (1990)1 a-Methylbenzyl alcohol806 Acetophenone 1000b 0.003 333,333 0.092 10,870 Hagan et al. (1967)3 Acetophenone807 4-Methylacetophenone 1000b 0.0006 1,666,667 0.017 58,824 Hagan et al. (1967)3 Acetophenone808 para-Isopropylacetophenone 1000b 0.000007 142,857,143 0.0088 113,636 Hagan et al. (1967)3 Acetophenone809 2,4-Dimethylacetophenone 1000b 0.000005 200,000,000 0.053 18,868 Hagan et al. (1967)3 Acetophenone810 Acetanisole 1000b 0.002 500,000 0.17 5882 Hagan et al. (1967)3 Acetophenone813 1-(para-Methoxyphenyl)-2-propanone 1000b 0.000003 333,333,333 0.025 40,000 Hagan et al. (1967)3 Acetophenone814 a-Methylphenethyl butyrate 3.1b 0.000002 1,550,000 0.014 221 Posternak et al. (1969)4 a-Methylphenethyl butyrate815 4-Phenyl-2-butanol 3.1b 0.00002 155,000 0.0067 463 Posternak et al. (1969)4 a-Methylphenethyl butyrate816 4-Phenyl-2-butyl acetate 3.1b 0.0001 31,000 0.05 62 Posternak et al. (1969)4 a-Methylphenethyl butyrate817 4-(para-Tolyl)-2-butanone 110b 0.000007 15,714,286 0.0065 16,923 Trubek Laboratories (1956)5 4-(para-Methoxyphenyl)-2-butanone818 4-(para-Methoxyphenyl)-2-butanone 110b 0.01 11,000 0.061 1803 Trubek Laboratories (1956)5 4-(para-Methoxyphenyl)-2-butanone819 4-Phenyl-3-buten-2-ol 13b 0.00003 433,333 0.013 1000 Oser et al. (1965)6 1-(para-Methoxyphenyl)-1-penten-3-one820 4-Phenyl-3-buten-2-one 13b 0.0001 130,000 0.016 813 Oser et al. (1965)6 1-(para-Methoxyphenyl)-1-penten-3-one821 3-Methyl-4-phenyl-3-buten-2-one 13b 0.000002 6,500,000 0.055 236 Oser et al. (1965)6 1-(para-Methoxyphenyl)-1-penten-3-one822 1-Phenyl-1-propanol 420b 0.000005 84,000,000 0.012 35,000 Brown et al. (1955)7 1-Phenyl-1-propanol823 a-Ethylbenzyl butyrate 93 0.000005 18,600,000 0.047 1979 NTP (1990)1 a-Methylbenzyl alcohol824 Propiophenone 420b 5.00 · 10�7 840,000,000 0.0016 262,500 Brown et al. (1955)7 1-Phenyl-1-propanol825 a-Propylphenethyl alcohol 93 0.00002 4,650,000 0.013 7154 NTP (1990)1 a-Methylbenzyl alcohol826 1-(para-Methoxyphenyl)-1-penten-3-one 13b 0.002 6500 0.011 1182 Oser et al. (1965)6 1-(para-Methoxyphenyl)-1-penten-3-one834 Ethyl benzoylacetate 500b 0.002 250,000 0.053 9434 JECFA (1974, 1983)8 Benzoic acid835 Ethyl 2-acetal-3-phenylpropionate 500b 0.000007 71,428,571 0.1 5000 JECFA (1974, 1983)8 Benzoic acid827 a-Isobutylphenethyl alcohol 10 0.0005 20,000 0.042 238 Ford et al. (1983)9 a-Isobutylphenethyl alcohol828 4-Methyl-1-phenyl-2-pentanone 10 0.0002 50,000 0.022 455 Ford et al. (1983)9 a-Isobutylphenethyl alcohol829 1-(4-Methoxyphenyl)-4-methyl-l-penten-3-one 13b 0.0006 21,667 0.023 565 Oser et al. (1965)6 1-(para-Methoxyphenyl)-1-penten-3-one830 3-Benzyl-4-heptanone 10 0.00002 500,000 0.034 294 Ford et al. (1983)9 a-Isobutylphenethyl alcohol833 1-Phenyl-1,2-propanedione 17b 0.0001 170,000 0.014 1214 Posternak et al. (1969)10 1 -Phenyl-1,2-propanedione811 Methyl b-naphthyl ketone 33b 0.0008 41,250 0.0028 11,786 Oser et al. (1965)11 Methyl b-naphthyl ketone831 Benzophenone 19b 0.0004 47,500 0.0055 3455 Burdock et al. (1991)12 Benzophenone832 1,3-Diphenyl-2-propanone 19b 0.000002 9,500,000 0.048 396 Burdock et al. (1991)12 Benzophenone836 Benzoin 25b 0.0004 62,500 0.037 676 NCI (1980b)13 Benzoin

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 13 weeks, 93, 190, 380, 750, or 1000 mg/kg bw/day (NTP, 1990); 2rat, gavage, 13 weeks, 15, 50, or 150 mg/kg bw/day (Gauntet al., 1974); 3rat, diet, 100, 250, or 1000 mg/kg bw/day (Hagan et al., 1967); 4rat, diet, 90 days, 3.1/3.5 (M/F) mg/kg bw/day (Posternak et al., 1969); 5rat, diet, 90 days, 56 or 110 mg/kg bw/day (TrubekLaboratories, 1956); 6rat, diet, 90 days, 13/15 (M/F) mg/kg bw/day (Oser et al., 1965); 7rat, diet, 4 months, 420/480 (M/F) mg/kg bw/day (Brown et al., 1955); 8rat, diet, 16 weeks to life-long, 250 or500 mg/kg bw/day (JECFA, 1974, 1983); 9rat, diet, 90 days, 10, 40, or 160 mg/kg bw/day (Ford et al., 1983); 10rat, diet, 90 days, 18/17 (M/F) mg/kg bw/day (Posternak et al., 1969); 11rat, diet, 90 days,33/37 (M/F) mg/kg bw/day (Oser et al., 1965); 12rat, diet, 90 days, 19/22 (M/F) mg/kg bw/day (Burdock et al., 1991); 13rat, diet, 104 weeks, 12/25 or 25/50 (M/F) mg/kg bw/day (NCI, 1980b).

a Highest intake estimate was selected from European or US per capita intake data.b Study performed with either a single dose or multiple doses that had no adverse effect; the value therefore is not a true NOEL but rather the highest dose tested at which no adverse effects were

observed. The actual NOEL may be higher.

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Table 7aBenzyl derivatives—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

25 Benzyl alcohol 400b 0.3 1333 0.7 571 NTP (1989)1 Benzyl alcohol841 Benzyl formate 400b 0.0008 500,000 0.038 10,526 NTP (1989)1 Benzyl alcohol23 Benzyl acetate 510b 0.02 25,500 0.056 9107 NTP (1993a)2 Benzyl acetate842 Benzyl propionate 400b 0.002 200,000 0.057 7018 NTP (1989)1 Benzyl alcohol843 Benzyl butyrate 400b 0.005 80,000 0.048 8333 NTP (1989)1 Benzyl alcohol844 Benzyl isobutyrate 400b 0.0004 1,000,000 0.078 5128 NTP (1989)1 Benzyl alcohol845 Benzyl isovalerate 400b 0.0003 1,333,333 0.023 17,391 NTP (1989)1 Benzyl alcohol846 Benzyl trans-2-methyl-2-butenoate 400b 5.00 · 10�7 800,000,000 0.012 33,333 NTP (1989)1 Benzyl alcohol847 Benzyl 2,3-dimethylcrotonate 400b 0.00002 20,000,000 0.098 4082 NTP (1989)1 Benzyl alcohol848 Benzyl acetoacetate 400b 0.000003 133,333,333 0.08 5000 NTP (1989)1 Benzyl alcohol24 Benzyl benzoate 400b 0.07 5714 0.17 2353 NTP (1989)1 Benzyl alcohol849 Benzyl phenylacetate 400b 0.001 400,000 0.036 11,111 NTP (1989)1 Benzyl alcohol22 Benzaldehyde 500b 0.6 833 0.8 625 Hagan et al. (1967)3 Benzaldehyde837 Benzaldehyde dimethyl acetal 500b 0.000005 100,000,000 0.32 1563 Hagan et al. (1967)3 Benzaldehyde838 Benzaldehyde glyceryl acetal 500b 0.005 100,000 0.36 1389 Hagan et al. (1967)3 Benzaldehyde839 Benzaldehyde propylene glycol acetal 500b 0.002 250,000 0.77 649 Hagan et al. (1967)3 Benzaldehyde850 Benzoic acid 500b 0.006 83,333 0.57 877 JECFA (1974, 1983)4 Benzoic acid851 Methyl benzoate 500b 0.004 125,000 0.032 15,625 JECFA (1974, 1983)4 Benzoic acid852 Ethyl benzoate 500b 0.002 250,000 0.062 8065 JECFA (1974, 1983)4 Benzoic acid853 Propyl benzoate 500b 0.000005 100,000,000 0.034 14,706 JECFA (1974, 1983)4 Benzoic acid854 Hexyl benzoate 500b 0.006 83,333 0.016 31,250 JECFA (1974, 1983)4 Benzoic acid855 Isopropyl benzoate 500b 0.000005 100,000,000 0.00023 2,173,913 JECFA (1974, 1983)4 Benzoic acid856 Isobutyl benzoate 500b 0.00002 25,000,000 0.034 14,706 JECFA (1974, 1983)4 Benzoic acid857 Isoamyl benzoate 500b 0.002 250,000 0.047 10,638 JECFA (1974, 1983)4 Benzoic acid858 cis-3-Hexenyl benzoate 500b 0.0001 5,000,000 0.0048 10,4167 JECFA (1974, 1983)4 Benzoic acid859 Linalyl benzoate 500b 0.0002 2,500,000 0.0021 238,095 JECFA (1974, 1983)4 Benzoic acid860 Geranyl benzoate 500b 0.00007 7,142,857 0.11 4545 JECFA (1974, 1983)4 Benzoic acid861 Glyceryl tribenzoate 600 0.0008 750,000 0.38 1579 Carson (1972a)5 Glyceryl tribenzoate862 Propylene glycol dibenzoate 2500b 0.0002 12,500,000 0.14 17,857 Carson (1972b)6 Propylene glycol dibenzoate863 Methylbenzyl acetate (mixed ortho, meta, para) 400b 0.00005 8,000,000 0.0005 800,000 NTP (1989)1 Benzyl alcohol864 para-Isopropylbenzyl alcohol 400b 0.000005 80,000,000 0.16 2500 NTP (1989)1 Benzyl alcohol865 4-Ethylbenzaldehyde 500b 0.0001 5,000,000 0.029 17,241 Hagan et al. (1967)3 Benzaldehyde866 Tolualdehyde (mixed ortho, meta, para) 36b 0.02 1800 0.095 379 Oser et al. (1965)7 Tolualdehyde (mixed ortho, meta, para)867 Tolualdehyde glyceryl acetal 500b 0.00002 25,000,000 0.078 6410 Hagan et al. (1967)3 Benzaldehyde868 Cuminaldehyde 500b 0.002 250,000 0.093 5376 Hagan et al. (1967)3 Benzaldehyde869 2,4-Dimethylbenzaldehyde 500b 0.000007 71,428,571 0.0034 147,059 Hagan et al. (1967)3 Benzaldehyde840 Benzyl 2-methoxyethyl acetal 6 0.00002 300,000 0.012 500 Gulati et al. (1990a,b)8 Methoxyethanol

Species, route of exposure, study duration, dose levels tested: 1rat, 2 years, gavage, 200 or 400 mg/kg bw/day (NTP, 1989); 2rat, 2 year, diet, 130/145, 260/290, or 510/575 (M/F) mg/kg bw/day (NTP,1993a); 3rat, diet, 16 or 27–28 weeks, 50 (27–28 weeks) or 500 (16 weeks) mg/kg bw/day (Hagan et al., 1967); 4rat, diet, 16 weeks to life-long, 250 or 500 mg/kg bw/day (JECFA, 1974, 1983); 5 rat, oral,90 days, 120, 600, or 2600 mg/kg bw/day (Carson, 1972a); 6rat, diet, 90 days, 130, 630, or 2500 mg/kg bw/day (Carson, 1972b); 7rat, diet, 90 days, 36/43 (M/F) mg/kg bw/day (Oser et al., 1965); 8rat,continuous breeding (>120 days/>20 days), 3/5, 6/15, or 12/500 mg/kg bw/day (Gulati et al., 1990a,b).



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Table 7bBenzoic acid Equivalents—comparison of intake estimates to NOEL

JECFAno.



Intakeb

(mg/kgbw/day)

Marginof safety

Intakeb

(mg/kgbw/day)

Marginof safety

25 Benzyl alcohol 500c 0.34 1471 0.79 633 JECFA (1974, 1983)1 Benzoic acid841 Benzyl formate 500c 0.00072 694,444 0.034 14,706 JECFA (1974, 1983)1 Benzoic acid23 Benzyl acetate 500c 0.016 31,250 0.046 10,870 JECFA (1974, 1983)1 Benzoic acid842 Benzyl propionate 500c 0.0015 333,333 0.042 11,905 JECFA (1974, 1983)1 Benzoic acid843 Benzyl butyrate 500c 0.0034 147,059 0.033 15,152 JECFA (1974, 1983)1 Benzoic acid844 Benzyl isobutyrate 500c 0.00027 1,851,852 0.053 9434 JECFA (1974, 1983)1 Benzoic acid845 Benzyl isovalerate 500c 0.00019 2,631,579 0.015 33,333 JECFA (1974, 1983)1 Benzoic acid846 Benzyl trans-2-methy-2-butenoate 500c 3.2 · 10�7 1,562,500,000 0.0077 64,935 JECFA (1974, 1983)1 Benzoic acid847 Benzyl 2,3-dimethylcrotonate 500c 1.2 · 10�5 41,666,667 0.059 8475 JECFA (1974, 1983)1 Benzoic acid848 Benzyl acetoacetate 500c 1.9 · 10�6 263,157,895 0.051 9804 JECFA (1974, 1983)1 Benzoic acid24 Benzyl benzoate 500c 0.04 12,500 0.98 510 JECFA (1974, 1983)1 Benzoic acid849 Benzyl phenylacetate 500c 0.00054 925,926 0.019 26,316 JECFA (1974, 1983)1 Benzoic acid22 Benzaldehyde 500c 0.69 725 0.92 543 JECFA (1974, 1983)1 Benzoic acid837 Benzaldehyde dimethyl acetal 500c 4.00 · 10�6 125,000,000 0.26 1923 JECFA (1974, 1983)1 Benzoic acid838 Benzaldehyde glyceryl acetal 500c 0.0034 147,059 0.24 2083 JECFA (1974, 1983)1 Benzoic acid839 Benzaldehyde propylene glycol acetal 500c 0.0015 333,333 0.57 877 JECFA (1974, 1983)1 Benzoic acid850 Benzoic acid 500c 0.006 83,333 0.57 877 JECFA (1974, 1983)1 Benzoic acid851 Methyl benzoate 500c 0.0036 138,889 0.029 17,241 JECFA (1974, 1983)1 Benzoic acid852 Ethyl benzoate 500c 0.0016 312,500 0.050 10,000 JECFA (1974, 1983)1 Benzoic acid853 Propyl benzoate 500c 3.7 · 10�6 135,135,135 0.025 20,000 JECFA (1974, 1983)1 Benzoic acid854 Hexyl benzoate 500c 0.0036 138,889 0.0094 53,191 JECFA (1974, 1983)1 Benzoic acid855 Isopropyl benzoate 500c 3.7 · 10�6 135,135,135 0.00017 2,941,176 JECFA (1974, 1983)1 Benzoic acid856 Isobutyl benzoate 500c 1.4 · 10�5 35,714,286 0.023 21,739 JECFA (1974, 1983)1 Benzoic acid857 Isoamyl benzoate 500c 0.0013 384,615 0.030 16,667 JECFA (1974, 1983)1 Benzoic acid858 cis-3-Hexenyl benzoate 500c 6.0 · 10�5 8,333,333 0.0029 172,414 JECFA (1974, 1983)1 Benzoic acid859 Linalyl benzoate 500c 9.5 · 10�5 5,263,158 0.00099 505,051 JECFA (1974, 1983)1 Benzoic acid860 Geranyl benzoate 500c 3.3 · 10�5 15,151,515 0.052 9615 JECFA (1974, 1983)1 Benzoic acid861 Glyceryl tribenzoate 500c 0.00073 684,932 0.34 1471 JECFA (1974, 1983)1 Benzoic acid862 Propylene glycol dibenzoate 500c 0.00017 2,941,176 0.12 4167 JECFA (1974, 1983)1 Benzoic acid863 Methylbenzyl acetate (mixed ortho, meta, para) 500c 3.7 · 10�5 13,513,514 0.00037 1,351,351 JECFA (1974, 1983)1 Benzoic acid864 para-Isopropylbenzyl alcohol 500c 4.1 · 10�6 121,951,220 0.13 3846 JECFA (1974, 1983)1 Benzoic acid865 4-Ethylbenzaldehyde 500c 9.1 · 10�5 5,494,505 0.026 19,231 JECFA (1974, 1983)1 Benzoic acid866 Tolualdehyde (mixed ortho, meta, para) 500c 0.02 25,000 0.096 5208 JECFA (1974, 1983)1 Benzoic acid867 Tolualdehyde glyceryl acetal 500c 1.3 · 10�5 38,461,538 0.049 10,204 JECFA (1974, 1983)1 Benzoic acid868 Cuminaldehyde 500c 0.0016 312,500 0.077 6494 JECFA (1974, 1983)1 Benzoic acid869 2,4-Dimethylbenzaldehyde 500c 6.4 · 10�6 78,125,000 0.0031 161,290 JECFA (1974, 1983)1 Benzoic acid840 Benzyl 2-methoxyethyl acetal 500c 1.2 · 10�5 41,666,667 0.0070 71,429 JECFA (1974, 1983)1 Benzoic acidTotal Benzoic acid equivalents 500c 1.1 455 4.9 102 JECFA (1974, 1983)1 Benzoic acid

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 16 weeks to life-long, 250 or 500 mg/kg bw/day (JECFA, 1974, 1983).a Highest intake estimate expressed as benzoic acid equivalents was selected from European or US per capita intake data.b Intake estimate expressed as benzoic acid equivalents.c Study performed with either a single dose or multiple doses that had no adverse effect; the value therefore is not a true NOEL but rather the highest dose tested at which no adverse effects were


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for this group of flavouring substances are summarized inTable 8.

3.2.5. Aliphatic acyclic diols, triols and related substances

3.2.5.1. Parent compound NOELs. The evaluation of allcompounds in this group of flavouring agents proceededvia the A-side of the Procedure; however, for a few mem-bers of this group toxicological studies were included inthe JECFA monograph. Among these, a study was identi-fied in which rats were treated with the calcium salt of lacticacid. Based on the absence of any toxicologically signifi-cant adverse effects the highest dose level of 5000 mg/kg body weight/day was determined to be the NOEL forlactic acid (Maekawa et al., 1991). The NOEL for pyruval-dehyde was based on the results of a two-stage carcinogen-esis study performed in rats (Takahashi et al., 1989).Although for 2,2,4-trimethyl-1,3-oxacyclopentane, 3-oxo-tetradecanoic acid glyceride, and 3-oxodecanoic acidglyceride, the NOELs selected for the calculation of themargins of safety were based on 14-day toxicity studies,absence of toxicity following longer treatment periodsand at higher dose levels is supported by the NOEL of10,000 mg/kg body weight/day obtained for the structur-ally related compound glycerol (Hine et al., 1953; AtlasChemicals Co., 1969).


substances. Although the evaluation of glycerol was notfinalized at the time of the evaluation of this group pendingavailability of additional data verifying use of this com-pound as a flavouring agent, a NOEL established for glyc-erol was used as the NOEL basis for the calculation of themargins of safety for several structurally related com-pounds in this group of flavouring agents. Likewise, theevaluation of propylene glycol also was not finalized; how-ever, the NOEL presented for propylene glycol on the basisof which the Committee established an ADI of 25mg/kg body weight/day in 1973, was considered to beappropriate for the calculation of the margins of safetyfor the structurally related compounds 1,2-di[(l-ethoxy)eth-oxy]propane and 4-methyl-2-pentyl-1,3-dioxolan.

The NOEL for lactic acid also was selected for thecalculation of the margins of safety for its related esters,as well as for pyruvic acid, which is reduced to lactic acid.Using the more conservative cis-3-hexen-l-ol NOEL of130 mg/kg body weight/day (Gaunt et al., 1969), the mar-gins of safety for cis-3-hexenyl lactate would be slightlyreduced, but still maintained at levels of well above 1000compared to either the MSDI or PADI. The NOEL forpyruvaldehyde also was determined to be appropriate forthe calculation of the margin of safety for the related pyru-vic acid esters, ethyl pyruvate and isoamyl pyruvate. Asummary of the results of the comparison of the intake esti-mates with NOELs for this group of flavouring is presentedin Table 9.

3.2.6. Aliphatic acetals

3.2.6.1. Parent compound NOELs. All of the compoundsevaluated in this group of flavouring agents were predictedto be metabolized to innocuous products and the evalua-tion of their safety proceeded in the absence of toxicitydata; however, a suitable NOEL for citral diethyl acetalwas included in the JECFA report (Trubek Laboratories,1958b), which was used to calculate the margin of safety.


substances. With the exception of citral diethyl acetal, noother short- or long-term studies were available for anyof the remaining members in this group of flavouring sub-stances; however, since all compounds were predicted to bemetabolized to innocuous products, in evaluating thesafety of these compounds the Committee reviewed dataon the component hydrolysis products and metabolites.The margins of safety were therefore calculated using themost conservative NOEL identified for the metabolites.Suitable NOELs, however, were not always available forall of the metabolic products. In particular, appropriateNOELs were not identified for methanol, 1-heptanal, 4-heptenal, and 2,6-nonadienal, and instead the margins ofsafety were calculated based on suitable NOELs for relatedcompounds (i.e., formic acid, hexyl alcohol, cis-3-hexen-1-ol, and trans,trans-2,4-decadienal, respectively). For thisgroup of flavouring substances the expected metabolicproducts for each compound, as well as the results of thecomparison of the intake estimates with NOELs are pre-sented in Table 10.



3.3.1. Alicyclic primary alcohols, aldehydes, acids and

related esters

3.3.1.1. Parent compound NOELs. In this group of flavour-ing agents, suitable NOELs were available for only two ofthe compounds (i.e., 2,2,3-trimethylcyclopent-3-en-1-ylacetaldehyde and para-mentha-l,8-dien-7-ol). For para-mentha-1,8-dien-7-ol (i.e., perillyl alcohol) several short-and long-term studies were identified. Although toxicitystudies were performed, which demonstrated absence ofany adverse effects at dose levels of up to 4000 mg/kg -body weight/day, a more conservative NOEL was chosenbased on the results of 90-day rat and dog studies (NCI,1996).


substances. The NOEL for benzoic acid (JECFA, 1974,1983) (see Section 3.2.3) was selected as the NOEL basisfor several structurally related compounds in this groupof flavouring substances for which compound-specificNOELs were not identified. Likewise, the margin of safetyfor the ester cylcohexaneethyl acetate was based on theNOEL for phenethyl alcohol (Johannsen and Purchase,1969) (see Section 3.3.2), which is structurally similar to

Table 8Hydroxy- and alkoxy-substituted benzyl derivatives—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

955 4-Hydroxybenzyl alcohol 400b 0.0001 4,000,000 0.027 14,815 NTP (1989)1 Benzyl alcohol956 4-Hydroxybenzaldehyde 500b 0.001 500,000 0.034 14,706 Hagan et al. (1967)2 Benzaldehyde957 4-Hydroxybenzoic acid 500b 0.0003 1,666,667 0.27 1852 JECFA (1974, 1983)3 Benzoic acid958 2-Hydroxybenzoic acid 500b 5.00 · 10�7 1,000,000,000 0.023 21,739 JECFA (1974, 1983)3 Benzoic acid871 Anisyl alcohol 400b 0.003 133,333 0.049 8163 NTP (1989)1 Benzyl alcohol872 Anisyl formate 400b 0.0008 500,000 0.035 11,429 NTP (1989)1 Benzyl alcohol873 Anisyl acetate 400b 0.005 80,000 0.054 7407 NTP (1989)1 Benzyl alcohol874 Anisyl propionate 400b 0.00008 5,000,000 0.055 7273 NTP (1989)1 Benzyl alcohol875 Anisyl butyrate 400b 0.0006 666,667 0.04 10,000 NTP (1989)1 Benzyl alcohol876 Anisyl phenylacetate 400b 0.000002 200,000,000 0.026 15,385 NTP (1989)1 Benzyl alcohol877 Veratraldehyde 500b 0.002 250,000 0.0039 128,205 Hagan et al. (1967)2 Benzaldehyde878 para-Methoxybenzaldehyde 500b 0.01 50,000 0.23 2174 FDA (1954)4 para-Methoxybenzaldehyde879 para-Ethoxybenzaldehyde 500b 0.000002 250,000,000 0.016 31,250 FDA (1954)4 para-Methoxybenzaldehyde880 Methyl ortho-methoxybenzoate 94b 0.001 94,000 0.094 1000 van Miller and

Weaver (1987)5Methyl ortho-methoxybenzoate

881 2-Methoxybenzoic acid 500b 2.00 · 10�7 2,500,000,000 0.0072 69,444 JECFA (1974, 1983)3 Benzoic acid882 3-Methoxybenzoic acid 500b 2.00 · 10�7 2,500,000,000 0.0047 106,383 JECFA (1974, 1983)3 Benzoic acid883 4-Methoxybenzoic acid 500b 0.000002 250,000,000 0.008 62,500 JECFA (1974, 1983)3 Benzoic acid884 Methyl anisate 900b 0.00002 45,000,000 0.023 39,130 Inai et al. (1985)6 Butyl para-hydroxybenzoate885 Ethyl para-anisate 900b 0.0002 4,500,000 0.038 23,684 Inai et al. (1985)6 Butyl para-hydroxybenzoate886 Vanillyl alcohol 1000b 0.0001 10,000,000 0.029 34,483 Hagan et al. (1967)7 Vanillin889 Vanillin 1000b 2.5 400 0.65 1538 Hagan et al. (1967)7 Vanillin959 4-Hydroxy-3-methoxybenzoic acid 500b 0.0005 1,000,000 0.0068 73,529 JECFA (1974, 1983)3 Benzoic acid890 Vanillin acetate 1000b 0.00003 33,333,333 0.045 22,222 Hagan et al. (1967)7 Vanillin891 Vanillin isobutyrate 1000b 0.001 1,000,000 0.023 43,478 Hagan et al. (1967)7 Vanillin897 Salicylaldehyde 500b 0.002 250,000 0.034 14,706 Hagan et al. (1967)2 Benzaldehyde898 2-Hydroxy-4-methyl benzaldehyde 500b 0.00002 25,000,000 0.0025 200,000 Hagan et al. (1967)2 Benzaldehyde899 Methyl salicylate 50 0.7 71 0.62 81 Webb and Hansen

(1963)8Methyl salicylate

900 Ethyl salicylate 50 0.03 1667 0.087 575 Webb and Hansen(1963)8

Methyl salicylate

901 Butyl salicylate 50 2.00 · 10�7 250,000,000 0.0049 10,204 Webb and Hansen(1963)8

Methyl salicylate

902 Isobutyl salicylate 50 0.0001 500,000 0.047 1064 Webb and Hansen(1963)8

Methyl salicylate

903 Isoamyl salicylate 4.7 0.0008 5875 0.0073 644 Drake et al. (1975)9 Isoamyl salicylate904 Benzyl salicylate 50 0.0005 100,000 0.031 1613 Webb and Hansen

(1963)8Methyl salicylate

905 Phenethyl salicylate 50 0.00007 714,286 0.0085 5882 Webb and Hansen(1963)8

Methyl salicylate

907 ortho-Tolyl salicylate 50 0.0005 100,000 0.00013 384,615 Webb and Hansen(1963)8

Methyl salicylate

774I.C

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the ester�s metabolic product, cyclohexaneethanol. Sincecyclohexaneacetic acid is expected to be metabolized tosuccinic acid, the NOEL selected for the structurallyrelated compound monosodium succinate (Maekawaet al., 1990) by Munro and Kennepohl (2001) was deter-mined to be an appropriate NOEL basis for the calculationof the margin of safety for cyclohexaneacetic acid.

Margins of safety for the remaining compounds in thisgroup of flavouring agents were based on the NOELs iden-tified for either 2,2,3-trimethylcyclopent-3-en-1-yl acetalde-hyde or para-mentha-1,8-dien-7-ol. As such, thecalculation of the margin of safety for 2,6,6-trimethylcyclo-hexa-1,3-dienyl methanal using the NOEL for para-men-tha-1,8-dien-7-ol was in keeping with the rational of theCommittee, which based the safety evaluation of this com-pound also on the para-mentha-1,8-dien-7-ol NOEL. Theresults for this group of flavouring substances are presentedin Table 11.

3.3.2. Phenethyl alcohol, aldehyde, acid and related

acetals and esters

3.3.2.1. Parent compound NOELs. In this group of flavour-ing agents, appropriate NOELs were presented in theJECFA report for para-isopropylphenylacetaldehyde (Pos-ternak et al., 1969), ethyl (para-tolyloxy) acetate (Posternaket al., 1969), sodium 2-(4-methoxyphenoxy)propanoate(Hill and Wood, 1986), phenethyl alcohol (Johannsenand Purchase, 1969), phenethyl senecioate (Posternaket al., 1969), and phenethyl phenylacetate (Hagan et al.,1967).


substances. For all other flavouring substances in thisgroup, margins of safety were calculated based on theNOELs selected for structurally similar compounds in thisgroup for which appropriate NOELs were available. Themargin of safety for 2-phenoxyethyl isobutyrate, whichwas this group�s only flavouring substance requiring toxic-ity data for its safety evaluation, was calculated based onthe same NOEL as that chosen by the Committee. Table12 presents a summary of the comparison of the intakeestimates with NOELs for this group of flavouring subs-tances.

3.3.3. Sulfur-containing heterocyclic compounds

3.3.3.1. Parent compound NOELs. Although a few com-pounds in this group were predicted to be metabolized toinnocuous agents, for the most part flavouring sub-stances in this group were evaluated via the B-side of theprocedure. As such, several suitable NOELs were availablefor compounds in this group of flavouring agents, includ-ing 2- or 4-isobutyl-2,6-dimethyldihydro-1,3,5-dithiazine(Rush, 1989a,b), 2- or 4-isopropyl-4,6-dimethyldihydro-1,3,5-dithiazine (Rush, 1989a,b), 2-thienyl disulfide(Morgareidge and Oser, 1970a), 2-(2-butyl)-4,5-dimethyl-3-thiazoline (Babish, 1978), 2-acetylthiazole (Wheldon et al.,1970a), thiamine hydrochloride (Oser, 1964), benzothiazole

Table 9Aliphatic acyclic diols, triols and related substances—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

927 1,2-Di[(1-ethoxy)ethoxy]propane

2500b 0.002 1,250,000 0.49 5102 Gaunt et al. (1972a)1 Propylene glycol

930 Lactic acid 5000b 0.8 6250 15.4 325 Maekawa et al. (1991)2 Lactic acid931 Ethyl lactate 5000b 0.03 166,667 0.22 22,727 Maekawa et al. (1991)2 Lactic acid932 Butyl lactate 5000b 0.006 833,333 0.058 86,207 Maekawa et al. (1991)2 Lactic acid933 Potassium 2-(1 0-ethoxy)

ethoxypropanoate5000b 0.02 250,000 0.34 14,706 Maekawa et al. (1991)2 Lactic acid

934 cis-3-Hexenyl lactate 5000b 0.0006 8,333,333 0.011 454,545 Maekawa et al. (1991)2 Lactic acid935 Butyl butyryllactate 5000b 0.02 250,000 0.1 50,000 Maekawa et al. (1991)2 Lactic acid936 Pyruvic acid 5000b 0.001 5,000,000 0.11 45,455 Maekawa et al. (1991)2 Lactic acid937 Pyruvaldehyde 250b 0.002 125,000 0.025 10,000 Takahashi et al. (1989)3 Pyruvaldehyde938 Ethyl pyruvate 250b 0.0003 833,333 0.33 758 Takahashi et al. (1989)3 Pyruvaldehyde939 Isoamyl pyruvate 250b 0.0003 833,333 0.051 4902 Takahashi et al. (1989)3 Pyruvaldehyde910 3-Oxohexanoic

acid glyceride10,000b 0.004 2,500,000 0.0025 4,000,000 Hine et al. (1953);

Atlas Chemicals Co. (1969)4Glycerol

911 3-Oxooctanoicacid glyceride

10,000b 0.0006 16,666,667 0.0045 2,222,222 Hine et al. (1953);Atlas Chemicals Co. (1969)4

Glycerol

912 Heptanal glyceryl acetal(mixed 1,2 and 1,3 acetals)

10,000b 0.00007 142,857,143 0.041 243,902 Hine et al. (1953);Atlas Chemicals Co. (1969)4

Glycerol

914 3-Oxodecanoicacid glyceride

10b 0.004 2500 0.0045 2222 Gill and van Miller (1987a)5 3-Oxodecanoicacid glyceride

915 3-Oxododecanoicacid glyceride


Glycerol

916 3-Oxotetradecanoicacid glyceride

10b 0.004 2500 0.0045 2222 Gill and van Miller (1987a)5 3-Oxotetradecanoicacid glyceride

917 3-Oxohexadecanoicacid glyceride


Glycerol

928 4-Methyl-2-pentyl-1,3-dioxolan

2500b 0.000003 833,333,333 0.00074 3,378,378 Gaunt et al. (1972a)1 Propylene glycol

929 2,2,4,-Trimethyl-1,3-oxacyclopentane

38b 0.000005 7,600,000 0.0059 6441 DeGroot et al. (1974)6 2,2,4-Trimethyl-1,3-oxacyclopentane

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 2 years, 310, 630, 1,300, or 2500 mg/kg bw/day (Gaunt et al., 1972a); 2rat, diet, 2years, 2500 or 5000 mg/kg bw/day (Maekawa et al., 1991); 3rat, drinking water, 32 weeks, 250 mg/kg bw/day (Takahashi et al., 1989); 4rat, diet, 2 years,2500, 5000, or 10,000 mg/kg bw/day (Hine et al., 1953; Atlas Chemicals Co., 1969); 5rat, diet, 14 days, 10 mg/kg bw/day (Gill and van Miller, 1987a); 6rat,gavage, 14 days, 3.8 or 38 mg/kg bw/day (DeGroot et al., 1974).




(Morgareidge, 1971a), 2-methyl-5-methoxythiazole (Poster-nak et al., 1975), and 4-methyl-5-thiazoleethanol(Oser, 1964). For 2,4-dimethyl-5-vinylthiazol (Posternaket al., 1969) and 2,4-dimethyl-5-acetylthiazole (Shellenber-ger, 1971), only single-dose level studies of similar durationwere identified. In contrast to JECFA�s evaluation, thehigher NOEL for 2,4-dimethyl-5-acetylthiazole (Shellen-berger, 1971) was selected as the NOEL basis for the calcu-lation of the margins of safety for both thiazoles and anyrelated compounds. Although the calculation of themargins of safety for 2- or 4-isopropyl-2,6-dimethyldihy-dro-1,3,5-dithiazine and 2- or 4-isopropyl-4,6-dimethyldi-hydro-1,3,5-dithiazine and their related compounds(Rush, 1989a,b) was based on 14-day studies, this was con-sistent with the evaluation of these compounds by theCommittee.


substances. A number of compounds also were identified inthis group for which no toxicological data were available,but which were structurally similar to 2,4-dimethyl-5-vinyl-thiazol and 2,4-dimethyl-5-acetylthiazole. As discussedabove, the calculation of the margin of safety for thesecompounds proceeded on the basis of the NOEL for 2,4-dimethyl-5-acetylthiazole.

Additionally, another compound, thiophene, was identi-fied, which was not included in this group of JECFA-eval-uated flavouring agents, but which was determined bythe authors of this study to be structurally related to5-methyl-2-thiophene-carboxyaldehyde, 3-acetyl-(2,5-dime-thyl)thiophene, and 2-thienyl mercaptan. As such, theNOEL identified for thiophene (O�Donoghue, 1979) wasconsidered to be appropriate for the evaluations of these

Table 10Aliphatic acetals—comparison of intake estimates to NOEL

JECFAno.

Flavouring substance Metabolites NOEL(mg/kgbw/day)


Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

940 1,1-Dimethoxyethane Acetaldehyde/methanol 400b 0.001 400,000 0.015 26,667 Malorny (1969)1 Formic acid (for methanol)941 Acetal Acetaldehyde/ethanol 675b 0.01 67,500 0.19 3553 Til et al. (1988)2 Acetaldehyde947 Heptanal dimethyl acetal 1-Heptanal/methanol 230b 0.000004 57,500,000 0.015 15,333 Eibert (1992)3 Hexyl alcohol (for 1-heptanal)949 4-Heptenal diethyl acetal 4-Heptenal/ethanol 130b 7.00 · 10�7 185,714,286 0.0084 15,476 Gaunt et al. (1969)4 cis-3-Hexen-1-ol (for 4-heptenal)942 Octanal dimethyl acetal Octanal/methanol 12b 0.00002 600,000 0.034 353 Trubek Laboratories (1958c)5 Octanal946 2,6-Nonadienal diethyl acetal 2,6-Nonadienal/ethanol 34b 7.00 · 10�7 48,571,429 0.00013 261,538 Damske et al. (1980)6 trans, trans-2,4-Decadienal

(for 2,6-nonadienal)945 Decanal dimethyl acetal Decanal/methanol 7b 5.00 · 10�7 14,000,000 0.059 119 Trubek Laboratories (1958c)7 Decanal944 Citral dimethyl acetal Citral/methanol 100 0.00008 1,250,000 0.28 357 NTP (2003)8 Citral948 Citral diethyl acetal N/R 56 0.00007 800,000 0.14 400 Trubek Laboratories (1958b)9 Citral diethyl acetal943 Acetaldehyde ethyl

cis-3-hexenyl acetalAcetaldehyde/ethanol/cis-3-hexen-1-ol

130b 0c N/A 0.00017 764,706 Gaunt et al. (1969)4 cis-3-Hexen-1-ol

N/A = Not applicable; N/R = Not required.Species, route of exposure, study duration, dose levels tested: 1rat, oral, 2 years, 400 mg/kg bw/day (Malorny, 1969); 2rat, drinking water, 4 weeks, 25, 125, or 675 mg/kg bw/day (Til et al., 1988); 3dog,diet, 13 weeks, 0.5 or 1% (equivalent to �230 to 695 mg/kg bw/day) (Eibert, 1992); 4rat, drinking water, 98 days, 130/170 (M/F) mg/kg bw/day (Gaunt et al., 1969); 5rat, diet, 12 weeks, 12 mg/kg bw/day (Trubek Laboratories, 1958c); 6rat, diet, 13 weeks, 3.4, 11, or 34 mg/kg bw/day (Damske et al., 1980); 7rat, diet, 12 weeks,7 mg/kg bw/day (Trubek Laboratories, 1958c); 8rat, diet, 104 to 105 weeks,50, 100, or 210 mg/kg bw/day (NTP, 2003); 9rat, diet, 12 weeks, 56 mg/kg bw/day (Trubek Laboratories, 1958b).


observed. The actual NOEL may be higher.c MSDI reported as 0 mg/person/day.

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Table 11Alicyclic primary alcohols, aldehydes, acids and related substances—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

961 Cyclohexanecarboxylic acid 500b 0.00007 7,142,857 0.007 71,429 JECFA (1974, 1983)1 Benzoic acid962 Methyl cyclohexanecarboxylate 500b 0.000002 250,000,000 0.00017 2,941,176 JECFA (1974, 1983)1 Benzoic acid963 Ethyl cyclohexanecarboxylate 500b 0.000002 250,000,000 0.00005 10,000,000 JECFA (1974, 1983)1 Benzoic acid964 Cyclohexaneethyl acetate 120b 0.00002 6,000,000 0.026 4615 Johannsen and Purchase (1969)2 Phenethyl alcohol965 Cyclohexaneacetic acid 2500 0.000007 357,142,857 0.0013 1,923,077 Maekawa et al. (1990)3 Monosodium succinate966 Ethyl cyclohexanepropionate 500b 0.000002 250,000,000 0.062 8065 JECFA (1974, 1983)1 Benzoic acid967 2,2,3-Trimethylcyclopent-

3-en-l-yl acetaldehyde12b 0.0001 120,000 0.019 632 BIBRA (1976)4 2,2,3-Trimethylcyclopent-3-en-1-yl

acetaldehyde968 cis-5-Isopropenyl-cis-

2-methylcyclopentan-1-carboxaldehyde

12b 2.00 · 10�7 60,000,000 0.00017 70,588 BIBRA (1976)4 2,2,3-Trimethylcyclopent-3-en-1-ylacetaldehyde

969 Campholene acetate 12b 0.000001 12,000,000 0.0053 2264 BIBRA (1976)4 2,2,3-Trimethylcyclopent-3-en-1-ylacetaldehyde

970 a-Campholenic alcohol 12b 2.00 · 10�7 60,000,000 0.005 2400 BIBRA (1976)4 2,2,3-Trimethylcyclopent-3-en-1-ylacetaldehyde

971 para-Menth-1-ene-9-al 120 0.000002 60,000,000 0.015 8000 NCI (1996)5 para-Mentha-1,8-dien-7-ol972 1-para-Menthen-9-yl acetate 120 0.00002 6,000,000 0.015 8000 NCI (1996)5 para-Mentha-1,8-dien-7-ol973 para-Mentha-1,8-dien-7-al 120 0.00003 4,000,000 0.027 4444 NCI (1996)5 para-Mentha-1,8-dien-7-ol974 para-Mentha-1,8-dien-7-ol 120 0.00003 4,000,000 0.0065 18,462 NCI (1996)5 para-Mentha-1,8-dien-7-ol975 para-Mentha-1,8-dien-7-yl acetate 120 0.000007 17,142,857 0.027 4444 NCI (1996)5 para-Mentha-1,8-dien-7-ol976 1,2,5,6-Tetrahydrocuminic acid 120 2.00 · 10�7 600,000,000 0.0035 34,286 NCI (1996)5 para-Mentha-1,8-dien-7-ol977 2,6,6-Trimethylcyclohexa-

1,3-dienyl methanal120 0.00007 1,714,286 0.013 9231 NCI (1996)5 para-Mentha-1,8-dien-7-ol

978 2,6,6-Trimethyl-l-cyclohexen-1-acetaldehyde

120 0.00003 4,000,000 0.0052 23,077 NCI (1996)5 para-Mentha-l,8-dien-7-ol

979 2,6,6-Trimethyl-1 & 2-cyclohexen-1-carboxaldehyde

120 0.000007 17,142,857 1.67 · 10�5 7,185,629 NCI (1996)5 para-Mentha-1,8-dien-7-ol

980 2-Formyl-6,6-dimethylbicyclo[3.1.1]hept-2-ene

120 0.0001 1,200,000 0.00017 705,882 NCI (1996)5 para-Mentha-1,8-dien-7-ol

981 Myrtenol 120 0.000007 17,142,857 0.016 7500 NCI (1996)5 para-Mentha-1,8-dien-7-ol982 Myrtenyl acetate 120 0.000007 17,142,857 0.00033 363,636 NCI (1996)5 para-Mentha-1,8-dien-7-ol983 (6,6-Dimethylbicyclo[3.1. l]hept-

2-en-2-yl)methyl formate120 0.000007 17,142,857 0.005 24,000 NCI (1996)5 para-Mentha-1,8-dien-7-ol

984 Santalol (a and b) 120 7.00 · 10�7 171,428,571 0.024 5000 NCI (1996)5 para-Mentha-1,8-dien-7-ol985 Santalyl acetate 120 2.00 · 10�7 600,000,000 0.013 9231 NCI (1996)5 para-Mentha-1,8-dien-7-ol986 10-Hydroxymethylene-2-pinene 120 2.00 · 10�7 600,000,000 0.0058 20,690 NCI (1996)5 para-Mentha-1,8-dien-7-ol

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 16 weeks to life-long, 250 or 500 mg/kg bw/day (JECFA, 1974, 1983); 2rat, drinking water, 56 weeks, 120 mg/kg bw/day(Johannsen and Purchase, 1969); 3rat, drinking water, 13 weeks, 300, 600, 1200, 2500, 5000, or 10,000 (Maekawa et al., 1990); 4 rat/dog, gavage/gelatine capsules (oral), 90 days, 12 mg/kg bw/day(BIBRA, 1976); 5rat, gavage, 90 days, 40, 120, or 400 mg/kg bw/day (NCI, 1996).



778I.C

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un

ro,

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nielew

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9

Table 12Phenethyl alcohol, aldehyde, acid and related acetals and esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

987 Phenethyl alcohol 120b 0.02 6000 0.099 1212 Johannsen and Purchase (1969)1 Phenethyl alcohol988 Phenethyl formate 120b 0.0004 300,000 0.039 3077 Johannsen and Purchase (1969)1 Phenethyl alcohol989 Phenethyl acetate 120b 0.002 60,000 0.041 2927 Johannsen and Purchase (1969)1 Phenethyl alcohol990 Phenethyl propionate 120b 0.00005 2,400,000 0.047 2553 Johannsen and Purchase (1969)1 Phenethyl alcohol991 Phenethyl butyrate 120b 0.0006 200,000 0.034 3529 Johannsen and Purchase (1969)1 Phenethyl alcohol992 Phenethyl isobutyrate 120b 0.001 120,000 0.038 3158 Johannsen and Purchase (1969)1 Phenethyl alcohol993 Phenethyl 2-methylbutyrate 120b 0.000007 17,142,857 0.049 2449 Johannsen and Purchase (1969)1 Phenethyl alcohol994 Phenethyl isovalerate 120b 0.002 60,000 0.014 8571 Johannsen and Purchase (1969)1 Phenethyl alcohol995 Phenethyl hexanoate 120b 0.0002 600,000 0.028 4286 Johannsen and Purchase (1969)1 Phenethyl alcohol996 Phenethyl octanoate 120b 0.0004 300,000 0.028 4286 Johannsen and Purchase (1969)1 Phenethyl alcohol997 Phenethyl tiglate 120b 0.00002 6,000,000 0.042 2857 Johannsen and Purchase (1969)1 Phenethyl alcohol998 Phenethyl senecioate 1.5b 0.00003 50,000 0.0021 714 Posternak et al. (1969)2 Phenethyl senecioate999 Phenethyl phenylacetate 500b 0.001 500,000 0.032 15,625 Hagan et al. (1967)3 Phenethyl phenylacetate1000 Acetaldehyde phenethyl

propyl acetal120b 0.0001 1,200,000 0.052 2308 Johannsen and Purchase (1969)1 Phenethyl alcohol

1001 Acetaldehyde butylphenethyl acetal

120b 2.00 · 10�7 600,000,000 0.0091 13,187 Johannsen and Purchase (1969)1 Phenethyl alcohol

1002 Phenylacetaldehyde 120b 0.0009 133,333 0.011 10,909 Johannsen and Purchase (1969)1 Phenethyl alcohol1003 Phenylacetaldehyde

dimethyl acetal120b 0.0008 150,000 0.052 2308 Johannsen and Purchase (1969)1 Phenethyl alcohol

1004 Phenylacetaldehydeglyceryl acetal

120b 0.00002 6,000,000 0.036 3333 Johannsen and Purchase (1969)1 Phenethyl alcohol

1005 Phenylacetaldehyde2,3-butylene glycol acetal

120b 0.00002 6,000,000 0.023 5217 Johannsen and Purchase (1969)1 Phenethyl alcohol

1006 Phenylacetaldehydedisobutyl acetal

120b 0.0005 240,000 0.035 3429 Johannsen and Purchase (1969)1 Phenethyl alcohol

1007 Phenylacetic acid 120b 0.005 24,000 0.023 5217 Johannsen and Purchase (1969)1 Phenethyl alcohol1008 Methyl phenylacetate 120b 0.0004 300,000 0.21 571 Johannsen and Purchase (1969)1 Phenethyl alcohol1009 Ethyl phenylacetate 120b 0.002 60,000 0.043 2791 Johannsen and Purchase (1969)1 Phenethyl alcohol1010 Propyl phenylacetate 120b 0.000005 24,000,000 0.0068 17,647 Johannsen and Purchase (1969)1 Phenethyl alcohol1011 Isopropyl phenylacetate 120b 0.000001 120,000,000 0.01 12,000 Johannsen and Purchase (1969)1 Phenethyl alcohol1012 Butyl phenylacetate 120b 0.00005 2,400,000 0.029 4138 Johannsen and Purchase (1969)1 Phenethyl alcohol1013 Isobutyl phenylacetate 120b 0.0004 300,000 0.022 5455 Johannsen and Purchase (1969)1 Phenethyl alcohol1014 Isoamyl phenylacetate 120b 0.0006 200,000 0.051 2353 Johannsen and Purchase (1969)1 Phenethyl alcohol1015 Hexyl phenylacetate 120b 0.0001 1,200,000 0.029 4138 Johannsen and Purchase (1969)1 Phenethyl alcohol1016 3-Hexenyl phenylacetate 120b 0.00002 6,000,000 0.019 6316 Johannsen and Purchase (1969)1 Phenethyl alcohol1017 Octyl phenylacetate 120b 1.00 · 10�7 1,200,000,000 0.007 17,143 Johannsen and Purchase (1969)1 Phenethyl alcohol1018 Rhodinyl phenylacetate 120b 2.00 · 10�8 6,000,000,000 0.0095 12,632 Johannsen and Purchase (1969)1 Phenethyl alcohol1019 Linalyl phenylacetate 120b 0.000002 60,000,000 0.05 2400 Johannsen and Purchase (1969)1 Phenethyl alcohol1020 Geranyl phenylacetate 120b 0.00003 4,000,000 0.032 3750 Johannsen and Purchase (1969)1 Phenethyl alcohol1021 Citronellyl phenylacetate 120b 0.00003 4,000,000 0.098 1224 Johannsen and Purchase (1969)1 Phenethyl alcohol1022 Santalyl phenylacetate 120b 0.00002 6,000,000 0.011 10,909 Johannsen and Purchase (1969)1 Phenethyl alcohol

(continued on next page)

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structurally related compounds. Margins of safety for allother members of this group were calculated based onNOELs for structurally related flavouring substances inthis group for which appropriate NOELs were available.Table 13 presents a summary of the comparison of theintake estimates with NOELs for compounds in this groupof flavouring substances.

3.3.4. Sulfur-substituted furan derivatives

3.3.4.1. Parent compound NOELs. All of the compoundsevaluated in this group of flavouring agents by the Com-mittee required toxicity data. Results of the comparisonsof the intake estimates to NOELs for this group of flavour-ing substances are presented in Table 14. Parent NOELswere identified for 2-methyl-3-furanthiol (Oser, 1970b),furfuryl isopropyl sulfide (Posternak et al., 1969), methyl-2-methyl-3-furyl disulfide, (Gallo et al., 1976a), bis(2-methyl-3-furyl) disulfide (Morgareidge and Oser, 1970b),furfuryl mercaptan (Phillips et al., 1977), furfuryl thioace-tate (Posternak et al., 1969), S-2,5-dimethyl-3-thiofuroylfuran (Morgareidge et al., 1974b), 3-[(2-methyl-3-fur-yl)thiol]-4-heptanone (Gallo et al., 1976b), 2-methyl-3-thio-acetoxy-4,5-dihydrofuran (Munday and Gellatly, 1974),bis(2-methyl-3-furyl) tetrasulfide (Morgareidge and Oser,1970c), 2,5-dimethyl-3-furan thioisovalerate (Morgareidgeet al., 1974a), 2,2 0-(thiodimethylene) difuran (Gill andvan Miller, 1987b), 2-methyl-3-, 5- or 6-(furfurylthiol)pyr-azine (Posternak et al., 1975), and ethyl-3-(furfurylthio)propionate (Bio-Research Laboratories, 1980). Consistentwith JECFA�s evaluation of the compounds, the calcula-tion of the margin of safety for 2,2 0-(thiodimethylene) difu-ran (Gill and van Miller, 1987b) was based on a 14-daystudy.


substances. For compounds for which compound-specifictoxicity data were not identified, NOELs determined forstructurally related flavouring substances were utilized. Inkeeping with the evaluation performed by the Committee,the margins of safety were calculated on the basis of theNOELs assigned by the Committee.

3.3.5. Alicyclic ketones, secondary alcohols and related

esters

3.3.5.1. Parent compound NOELs. Although the Commit-tee�s evaluation of the safety of this group of compoundswas not based on toxicity data, suitable parent NOELswere identified for cyclohexanone (Lijinsky and Kovatch,1986), 2-sec-butylcyclohexanone (Hummler, 1969), isopho-rone (Bucher et al., 1986; NTP, 1986), and tetramethyleth-ylcyclohexenone (Posternak et al., 1969) in the JECFAmonograph.

3.3.5.2. NOELs for metabolites and/or structurally relatedsubstances. For cis- and trans-para-1(7),8-menthadien-2-ylacetate margins of safety were calculated based on theNOEL of 375 mg/kg body weight/day for the structurally

Table 13Sulfur-containing heterocyclic compounds—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1030 Thiamine hydrochloride 44b 0.05 880 0.45 98 Oser (1964)1 Thiamine hydrochloride1031 4-Methyl-5-thiazoleethanol 14b 0.006 2333 0.13 108 Oser (1964)2 4-Methyl-5-thiazoleethanol1032 Thiazole 24b 0.000001 24,000,000 0.0031 7742 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1033 2-(1-Methylpropyl)-thiazole 24b 5.00 · 10�7 48,000,000 0.0014 17,143 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1034 2-Isobutylthiazole 24b 0.00005 480,000 0.01 2400 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1035 4,5-Dimethylthiazole 24b 0.000007 3,428,571 0.065 369 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1036 2,4,5-Trimethylthiazole 24b 0.00002 1,200,000 0.0051 4706 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1037 2-Isopropyl-4-methylthiazole 24b 0.0004 60,000 0.00041 58,537 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1038 4-Methyl-5-vinyl thiazole 24b 0.00003 800,000 0.032 750 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1039 2,4-Dimethyl-5-vinylthiazole 24b 1.00 · 10�7 240,000,000 0.012 2000 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1040 Benzothiazole 5.1b 0.00002 255,000 0.0028 1821 Morgareidge (1971a)4 Benzothiazole1041 2-Acetylthiazole 50b 0.0002 250,000 0.00087 57,471 Wheldon et al. (1970a)5 2-Acetylthiazole1042 2-Propionylthiazole 50b 0.000003 16,666,667 0.00016 312,500 Wheldon et al. (1970a)5 2-Acetylthiazole1042 4-Methylthiazole 24b 0.000002 12,000,000 0.0055 4364 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1044 2-Ethyl-4-methylthiazole 24b 0.00007 342,857 0.000025 960,000 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1045 4,5-Dimethyl 2-isobutyl-3-thiazoline 1.2b 0.00007 17,143 0.0063 190 Babish (1978)6 2-(2-Butyl)-4,5-dimethyl-3-thiazoline1046 2- or 4-Isobutyl-(4 or 2),6-

dimethyldihydro-1,3,5-dithiazine11b 0.000002 5,500,000 0.002 5500 Rush (1989a,b)7 2- or 4-Isobutyl-(4 or 2),6-dimethyldihydro-

1,3,5-dithiazine (mixture)1047 2- or 4-Isopropyl-(4 or 2),6-

dimethyldihydro-1,3,5-dithiazine11b 0.000001 11,000,000 0.002 5500 Rush (1989a,b)7 2- or 4-Isopropyl-(4 or 2),6-dimethyldihydro-

1,3,5-dithiazine (mixture)1048 2,4,6-Triisobutyl-5,6-dihydro-

4H-1,3,5-dithiazine11b 0.00004 275,000 0.00083 13,253 Rush (1989a,b)7 2- or 4-Isobutyl-(4 or 2),6-dimethyldihydro-

1,3,5-dithiazine (mixture)1049 2,4,6-Trimethyldihydro-4H-1,3,5-dithiazine 11b 0.00006 183,333 0.037 297 Rush (1989a,b)7 2- or 4-Isobutyl-(4 or 2),6-dimethyldihydro-

1,3,5-dithiazine (mixture)1050 5-Methyl-2-thiophene-carboxyaldehyde 100 0.00002 5,000,000 0.0036 27,778 O�Donoghue (1979)8 Thiophene1051 3-Acetyl-2,5-dimethylthiophene 100 0.0004 250,000 0.01 10,000 O�Donoghue (1979)8 Thiophene1052 2-Thienyl mercaptan 100 5.00 · 10�7 200,000,000 0.0044 22,727 O�Donoghue (1979)8 Thiophene1053 2-Thienyl disulfide 0.29b 0.000001 290,000 0.00012 2417 Morgareidge and Oser (1970a)9 2-Thienyl disulfide1054 4-Methyl-5-thiazoleethanol acetate 14b 0.0002 70,000 0.13 108 Oser (1964)2 4-Methyl-5-thiazoleethanol1055 2,4-Dimethyl-5-acetylthiazole 24b 0.00003 800,000 0.035 686 Shellenberger (1971)3 2,4-Dimethyl-5-acetylthiazole1056 2-Ethoxythiazole 50b 0.000002 25,000,000 0.027 1852 Wheldon et al. (1970a)5 2-Acetylthiazole1057 2-Methyl-5-methoxythiazole 8.6b 2.00 · 10�7 43,000,000 0.021 410 Posternak et al. (1975)10 2-Methyl-5-methoxythiazole1058 4,5-Dimethyl-2-ethyl-3-thiazoline 1.2b 2.00 · 10�7 6,000,000 0.012 100 Babish (1978)6 2-(2-Butyl)-4,5-dimethyl-3-thiazoline1059 2-(2-Butyl)-4,5-dimethyl-3-thiazoline 1.2b 0.00008 15,000 0.0065 185 Babish (1978)6 2-(2-Butyl)-4,5-dimethyl-3-thiazoline

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 90 days, 33 to 44 mg/kg bw/day (Oser, 1964); 2 rat, diet, 90 days, 11 to 14 mg/kg bw/day (Oser, 1964); 3rat, diet, 90 days, 25/24(M/F) mg/kg bw/day (Shellenberger, 1971); 4 rat, diet, 90 days, 5.1 mg/kg bw/day (Morgareidge, 1971a); 5rat, diet, 90 days, 50 mg/kg bw/day (Wheldon et al., 1970a); 6rat, diet, 90 days, 1.2/1.3 (M/F)mg/kg bw/day (Babish, 1978); 7rat, diet, 14 days, 11 mg/kg bw/day (Rush, 1989a,b); 8rat, gavage, up to 19 days, 50, 100, 500, or 1000 mg/kg bw/day (O�Donoghue, 1979); 9rat, diet, 90 days, 0.29 mg/kg bw/day (Morgareidge and Oser, 1970a); 10rat, diet, 90 days, 8.8/8.6 (M/F) mg/kg bw/day (Posternak et al., 1975).



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Table 14Sulfur-substituted furan derivatives—comparison of intake estimates to NOEL

JECFAno.

Flavouring substance NOEL(mg/kg

bw/day)


Intake

(mg/kg

bw/day)

Margin

of safety

Intake

(mg/kg

bw/day)

Margin

of safety

1060 2-Methyl-3-furanthiol 5b 0.00002 250,000 0.00054 9259 Oser (1970b)1 2-Methyl-3-furanthiol

1069 Ethanoic acid, S-(2-methyl-3-furanyl) ester 5b 0.000001 5,000,000 N/A N/A Oser (1970b)1 2-Methyl-3-furanthiol1061 2-Methyl-3-(methylthio)furan 1.3b 0.00002 65,000 0.00017 7647 Posternak et al. (1969)2 Furfuryl isopropyl sulfide

1062 2-Methyl-5-(methylthio)furan 1.3b 0.00002 65,000 0.0036 361 Posternak et al. (1969)2 Furfuryl isopropyl sulfide

1064 Methyl-2-methyl-3-furyl disulfide 1.2b 0.00002 60,000 0.0022 545 Gallo et al. (1976a)3 Methyl-2-methyl-3-furyl disulfide1065 Propyl-2-methyl-3-furyl disulfide 1.2b 0.00001 120,000 0.0022 545 Gallo et al. (1976a)3 Methyl-2-methyl-3-furyl disulfide

1066 Bis(2-methyl-3-furyl) disulfide 0.45b 0.00001 45,000 0.00044 1023 Morgareidge and Oser (1970b)4 Bis(2-methyl-3-furyl) disulfide

1063 2,5-Dimethyl-3-furanthiol 5b 0.00001 500,000 0.0011 4545 Oser (1970b)1 2-Methyl-3-furanthiol1072 Furfuryl mercaptan 3 0.0006 5000 0.014 214 Phillips et al. (1977)5 Furfuryl mercaptan

1074 S-Furfuryl thioacetate 0.81b 0.000008 101,250 0.0034 238 Posternak et al. (1969)6 Furfuryl thioacetate

1076 Furfuryl methyl sulfide 1.3b 0.00002 65,000 0.012 108 Posternak et al. (1969)2 Furfuryl isopropyl sulfide1078 Methyl furfuryl disulfide 1.2b 0.00002 60,000 0.0053 226 Gallo et al. (1976a)3 Methyl-2-methyl-3-furyl disulfide

1079 Furfuryl propyl disulfide 1.2b 0.00005 24,000 0.0025 480 Gallo et al. (1976a)3 Methyl-2-methyl-3-furyl disulfide

1081 2,2 0-(Dithiodimethylene) difuran 3 0.00007 42,857 0.00038 7895 Phillips et al. (1977)5 Furfuryl mercaptan1083 S-Methyl thiofuroate 0.74b 0.000007 105,714 0.0000006 1,233,333 Morgareidge et al. (1974b)7 S-2,5-Dimethyl-3-thiofuroyl furan

1084 4-[(2-Furanmethyl)thio]-2-pentanone 3.8b 0.00001 380,000 0.041 93 Gallo et al. (1976b)8 3-[(2-Methyl-3-furyl)thio]-4-heptanone

1090 2-Methyl-3-tetrahydrofuranthiol 8.3b 0.00007 118,571 0.00083 10,000 Munday and Gellatly (1974)9 2-Methyl-3-thioacetoxy-4,5-dihydrofuran1080 2,2 0-(Thiodimethylene) difuran 10b 0.00002 500,000 0.0085 1176 Gill and van Miller (1987b)10 2,2 0-(Thiodimethylene) difuran

1067 Bis(2,5-dimethyl-3-furyl)disulfide 0.45b 0.00001 45,000 0.00043 1047 Morgareidge and Oser (1970b)4 Bis(2-methyl-3-furyl) disulfide

1068 Bis(2-methyl-3-furyl) tetrasulfide 0.56b 0.00001 56,000 0.00047 1191 Morgareidge and Oser (1970c)11 Bis(2-methyl-3-furyl) tetrasulfide1070 2,5-Dimethyl-3-furan thioisovalerate 0.73b 0.00001 73,000 0.00027 2704 Morgareidge et al. (1974a)12 2,5-Dimethyl-3-furan thioisovalerate

1071 S-2,5-Dimethyl-3-thiofuroyl furan 0.74b 2.00 · 10�7 3,700,000 0.00085 871 Morgareidge et al. (1974b)7 S-2,5-Dimethyl-3-thiofuroyl furan

1073 S-Furfuryl thioformate 0.81b 0.00003 27,000 0.003 270 Posternak et al. (1969)6 Furfuryl thioacetate1075 S-Furfuryl thiopropionate 0.81b 2.00 · 10�7 4,050,000 0.0061 133 Posternak et al. (1969)6 Furfuryl thioacetate

1077 Furfuryl isopropyl sulfide 1.3b 0.000002 650,000 0.0019 684 Posternak et al. (1969)2 Furfuryl isopropyl sulfide

1082 2-Methyl-3-, 5- or 6-(furfurylthio)pyrazine 1.6b 0.00001 160,000 0.0028 571 Posternak et al. (1975)13 2-Methyl-3-, 5- or 6-(furfurylthio)pyrazine

1085 3-[(2-Methyl-3-furyl)thio]-4-heptanone 3.8b 0.00001 380,000 0.0045 844 Gallo et al. (1976b)8 3-[(2-Methyl-3-furyl)thio]-4-heptanone

1086 2,6-Dimethyl-3-[(2-methyl-3-furyl)thio]-

4-heptanone

3.8b 0.00001 380,000 0.0045 844 Gallo et al. (1976b)8 3-[(2-Methyl-3-furyl)thio]-

4-heptanone1087 4-[(2-Methyl-3-furyl)thio]-5-nonanone 3.8b 0.00001 380,000 0.0045 844 Gallo et al. (1976b)8 3-[(2-Methyl-3-furyl)thio]-4-heptanone

1088 Ethyl 3-(furfurylthio) propionate 17b 0.000003 5,666,667 0.0042 4048 Bio-Research Laboratories (1980)14 Ethyl 3-(furfurylthio) propionate

1089 2-Methyl-3-thioacetoxy-4,5-dihydrofuran 8.3b 0.00001 830,000 0.0053 1566 Munday and Gellatly (1974)9 2-Methyl-3-thioacetoxy-4,5-dihydrofuran

1091 cis- and trans-2,5-Dimethyltetrahydrofuran-3-thiol 8.3b 0.00002 415,000 0.0018 4611 Munday and Gellatly (1974)9 2-Methyl-3-thioacetoxy-4,

5-dihydrofuran1092 cis-and trans-2,5-Dimethyltetrahydro-

3-furyl thioacetate

8.3b 0.00003 276,667 0.015 553 Munday and Gellatly (1974)9 2-Methyl-3-thioacetoxy-4,5-dihydrofuran

N/A = Not available.Species, route of exposure, study duration, dose levels tested: 1rat, diet, 90 days, 5 mg/kg bw/day (Oser, 1970b); 2rat, diet, 90 days, 1.3 mg/kg bw/day (Posternak et al., 1969); 3rat, diet, 90 days, 1.2 mg/kg bw/day (Gallo et al., 1976a); 4rat, diet, 90 days, 0.45 mg/kg bw/day (Morgareidge and Oser, 1970b); 5rat, gavage, 13 weeks, 1, 3, or 30 mg/kg bw/day (Phillips et al., 1977); 6rat, diet, 90 days, 0.83/0.81 (M/F) mg/kg bw/day (Posternak et al., 1969); 7rat, diet, 90 days, 0.74 mg/kg bw/day (Morgareidge et al., 1974b); 8rat, diet, 90 days, 3.8 mg/kg bw/day (Gallo et al., 1976b); 9rat, diet, 1 year, 1.4 (16weeks only), 2.8 (16 weeks only), 5.6 (16 weeks only), or 8.3 mg/kg bw/day (Munday and Gellatly, 1974); 10rat, diet, 14 days, 10 mg/kg bw/day (Gill and van Miller, 1987b); 11rat, diet, 90 days, 0.56 mg/kg bw/day (Morgareidge and Oser, 1970c); 12rat, diet, 90 days, 0.73 mg/kg bw/day (Morgareidge et al., 1974a); 13rat, diet, 90 days, 1.7/1.6 (M/F) mg/kg bw/day (Posternak et al., 1975); 14 rat, diet, 5.8or 17 mg/kg bw/day (Bio-Research Laboratories, 1980).



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80

9


related compound menthol (NCI, 1979) as selected in theformer study by Munro and Kennepohl (2001).

Although a single-dose level, 90-day study was identifiedfor 2-hexylidenecyclopentanone (Posternak et al., 1969),the multiple-dose level study identified for the structurallyrelated compound 2-sec-butylcyclohexanone was consi-dered to be more appropriate for the calculation of themargin of safety. The NOELs for cyclohexanone, 2-sec-butylcyclohexanone, and isophorone were considered tobe appropriate for the calculation of the margins of safetyfor several other structurally related compounds. A sum-mary of the results of the comparison of the intake esti-mates with NOELs is presented in Table 15.

3.3.6. Aliphatic secondary alcohols, ketones and relatedesters

3.3.6.1. Parent compound NOELs. As in the case of theprevious group, none of the flavouring agents in thisgroup required toxicity data; however, appropriate NOELswere available for 5-methyl-5-hexen-2-one (Gill and vanMiller, 1987c), 2,6,10-trimethyl-2,6,10-pentadecatrien-14-one (DeGroot et al., 1974), and (E,R)-3,7-dimethyl-1,5,7-octatrien-3-ol (Wnorowski, 1997), 4-hexen-3-one (Shel-lenberger, 1970a,b), 2-octen-4-one (Cox et al., 1974a),1-octen-3-one (Cox et al., 1974b), and 1-octen-3-ol (Poster-nak, 1964) in the accompanying JECFA report.

3.3.6.2. NOELs for metabolites and/or structurally relatedsubstances. The esters 2-pentyl butyrate and 2-pentyl ace-tate are expected to hydrolyze to 2-pentanol, which hasbeen previously evaluated by the Committee. In the studyby Munro and Kennepohl (2001) the margin of safety forthe alcohol was calculated using a NOEL for 2-heptanone(Gaunt et al., 1972b). In keeping with the previous paper,margins of safety for the 2-pentanol esters were calculatedbased on the NOEL for 2-heptanone. The NOEL for2-heptanone also was considered to be appropriate forthe calculation of the margin of safety for (±)-heptan-2-yl butyrate, which is expected to hydrolyze to 2-heptanol,a compound also previously evaluated by JECFA. In thestudy conducted by Munro and Kennepohl (2001) the mar-gin of safety for 2-heptanol was calculated based on theNOEL for 2-heptanone. Similarly, since the ester (±)-hep-tan-3-yl acetate is expected to hydrolyze to 3-heptanol forwhich 3-heptanone was selected as the NOEL basis inMunro and Kennepohl (2001), in keeping with the previousstudy, the margin of safety for the ester was calculated onthe basis of the NOEL for 3-heptanone (O�Donoghue et al.,1984). The ester (±)-nonan-3-yl acetate is expected to behydrolyzed to 3-nonanol. Although 3-nonanol has notbeen previously evaluated by JECFA, the Committee hasevaluated a structurally similar compound, 3-octanol.The NOEL for hexyl alcohol was determined to be anappropriate NOEL basis for 3-octanol by Munro and Ken-nepohl (2001). Therefore, in keeping with the previousstudy, 230 mg/kg body weight/day for hexyl alcohol was

determined to be an appropriate NOEL basis for (±)-nonan-3-yl acetate.

Margins of safety for all other flavouring substances inthis group were calculated based on NOELs available forother structurally related compounds in this group andare presented in Table 16.


61st meeting in 2003

3.4.1. Alicyclic, alicyclic-fused and aromatic-fused ring

lactones

3.4.1.1. Parent compound NOELs. Several compounds inthis group of flavouring agents required toxicity datafor the evaluation of their safety, including dihydromint-lactone (Cormack et al., 2000), 3-propylidenephthalide(Posternak et al., 1969), and 6-methylcoumarin (Haganet al., 1967). The NOELs selected by the Committee forthe evaluation of these compounds were maintained forthe calculation of the margins of safety in the presentstudy.

Several short- and long-term studies were identified fordihydrocoumarin and 6-methylcoumarin. In a 2-yearmouse study conducted with dihydrocoumarin, a NOELcould not be established in females due to increased inci-dence of hepatocellular neoplasms at the lowest dose level(200 mg/kg body weight; 5 days per week) evaluated;however, the occurrence of the liver tumours in micewas considered by the Committee as not relevant to thesafety evaluation of dihydrocoumarin in humans, inwhich low levels of intake are expected from use ofdihydrocoumarin as a flavouring agent (JECFA, 2004).Furthermore, neither a rat nor a dog study, which wereboth similar in duration, confirmed these effects. There-fore, the NOEL selected for the calculation of the marginof safety was based on the 2-year rat study in which noadverse effects were observed at dose levels of up to300 mg dihydrocoumarin/kg body weight/day adminis-tered via gavage (NTP, 1993b). Moreover, absence ofany adverse effects in the 2-year-long dog study in whichanimals received 150 mg dihydrocoumarin/kg bodyweight/day in the diet (Hagan et al., 1967) further confirmthe safety of dihydrocoumarin. Likewise, 2-year studieswere performed in both rats and dogs (Hagan et al.,1967) with 6-methylcoumarin. The multiple dose levelrat study demonstrating a NOEL of 175 mg/kg bodyweight/day was determined to be more appropriate forthe calculation of the margin of safety, rather than thesingle-dose level dog study, in which 6-methylcoumarinwas provided at a dose level of 50 mg/kg body weight/day.

A suitable NOEL also was provided for dehydroment-hofurolactone (Voss, 1985) in the JECFA report, eventhough a NOEL was not required for the safety evaluationof this compound by JECFA. Although only a 14-daystudy was available for the evaluation of the marginof safety for sclareolide (Terrill, 1990), the NOEL is

Table 15Alicyclic ketones, secondary alcohols and related esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1093 Cyclohexyl acetate 650b 0.0002 3,250,000 0.29 2241 Lijinsky and Kovatch (1986)1 Cyclohexanone1094 Cyclohexyl butyrate 650b 0.000002 325,000,000 0.078 8333 Lijinsky and Kovatch (1986)1 Cyclohexanone1095 Cyclohexyl formate 650b 0.000003 216,666,667 0.081 8025 Lijinsky and Kovatch (1986)1 Cyclohexanone1096 Cyclohexyl isovalerate 650b 0.000005 130,000,000 0.075 8667 Lijinsky and Kovatch (1986)1 Cyclohexanone1097 Cyclohexyl propionate 650b 8.00 · 10�7 812,500,000 0.062 10,484 Lijinsky and Kovatch (1986)1 Cyclohexanone1098 cis- and trans-para-1(7),8-

Menthadien-2-yl acetate375b 0.00001 37,500,000 0.017 22,059 NCI (1979)2 Menthol

1099 3,5,5-Trimethylcyclohexanol 650b 0.000002 325,000,000 0.0017 382,353 Lijinsky and Kovatch (1986)1 Cyclohexanone1100 Cyclohexanone 650b 0.000002 325,000,000 0.02 32,500 Lijinsky and Kovatch (1986)1 Cyclohexanone1101 Cyclopentanone 370 3.00 · 10�7 1,233,333,333 0.0075 49,333 Hummler (1969)3 2-sec-Butylcyclohexanone1102 2-Methylcyclohexanone 650b 0.000002 325,000,000 0.036 18,056 Lijinsky and Kovatch (1986)1 Cyclohexanone1103 3-Methylcyclohexanone 650b 0.000002 325,000,000 0.036 18,056 Lijinsky and Kovatch (1986)1 Cyclohexanone1104 4-Methylcyclohexanone 650b 0.000002 325,000,000 0.036 18,056 Lijinsky and Kovatch (1986)1 Cyclohexanone1105 1-Methyl-1-cyclopenten-3-one 370 0.000001 370,000,000 0.0092 40,217 Hummler (1969)3 2-sec-Butylcyclohexanone1106 2-Hexylidenecyclopentanone 370 0.000005 74,000,000 0.082 4512 Hummler (1969)3 2-sec-Butylcyclohexanone1107 3-Methyl-2-cyclohexen-1-one 250 0.000002 125,000,000 0.00047 531,915 Bucher et al. (1986); NTP (1986)4 Isophorone1108 2,2,6-Trimethylcyclohexanone 650b 0.00004 16,250,000 0.00088 738,636 Lijinsky and Kovatch (1986)1 Cyclohexanone1109 2-sec-Butylcyclohexanone 370 0.0001 3,700,000 0.091 4066 Hummler (1969)3 2-sec-Butylcyclohexanone1110 4-Isopropyl-2-cyclohexenone 250 2.00 · 10�8 12,500,000,000 0.0005 500,000 Bucher et al. (1986); NTP (1986)4 Isophorone1111 Tetramethylethylcyclohexenone

(mixture of isomers)40b 0.0002 200,000 0.0092 4348 Posternak et al. (1969)5 Tetramethylethylcyclohexenone

(mixture of isomers)1112 Isophorone 250 0.00008 3125,000 0.054 4630 Bucher et al. (1986); NTP (1986)4 Isophorone1113 3-Methyl-5-propyl-2-cyclohexen-1-one 250 0.00007 3,571,429 0.029 8621 Bucher et al. (1986); NTP (1986)4 Isophorone1114 3-Methyl-2-(2-pentenyl)-2-cyclopenten-1-one 370 0.0003 1,233,333 0.016 23,125 Hummler (1969)3 2-sec-Butylcyclohexanone1115 Isojasmone 370 0.000007 52,857,143 0.01 37,000 Hummler (1969)3 2-sec-Butylcyclohexanone1116 (E)-2-(2-Octenyl)cyclopentanone 370 0.0001 3,700,000 0.081 4568 Hummler (1969)3 2-sec-Butylcyclohexanone1117 2-(3,7-Dimethyl-2,6-octadienyl)

cyclopentanone370 0.0001 3,700,000 0.081 4568 Hummler (1969)3 2-sec-Butylcyclohexanone

Species, route of exposure, study duration, dose levels tested: 1rat, drinking water, 730 days, 330 or 650 mg/kg bw/day (Lijinsky and Kovatch, 1986); 2rat, diet, 103 weeks, 187.5 or 375 mg/kg bw/day(NCI, 1979); 3rat, diet, 91 days, 160, 370, or 900 mg/kg bw/day (Hummler, 1969); 4mouse, gavage, 730 days, 250 or 500 mg/kg bw/day (Bucher et al., 1986; NTP, 1986); 5rat, diet, 90 days, 40/48 (M/F)mg/kg bw/day (Posternak et al., 1969).



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Table 16Aliphatic secondary alcohols, ketones and related esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1118 3-Decanone 10b 0.00007 142,857 0.033 303 Gill and van Miller (1987c)1 5-Methyl-5-hexen-2-one1119 5-Methyl-5-hexen-2-one 10b 0.000005 2,000,000 0.0023 4348 Gill and van Miller (1987c)1 5-Methyl-5-hexen-2-one1120 6-Methyl-5-hepten-2-one 10b 0.002 5000 0.0091 1099 Gill and van Miller (1987c)1 5-Methyl-5-hexen-2-one1121 3,4,5,6-Tetra-hydropseudoionone 3.5b 2.00 · 10�7 17,500,000 0.0042 833 DeGroot et al. (1974)2 2,6,10-Trimethyl-2,6,10-pentadecatrien-14-one1122 6,10-Dimethyl-5,9-undecadien-2-one 3.5b 0.0008 4375 0.024 146 DeGroot et al. (1974)2 2,6,10-Trimethyl-2,6,10-pentadecatrien-14-one1123 2,6,10-Trimethyl-2,6,10-pentadecatrien-14-one 3.5b 0.000002 1,750,000 0.0034 1029 DeGroot et al. (1974)2 2,6,10-Trimethyl-2,6,10-pentadecatrien-14-one1124 3-Penten-2-one 6.6b 0.000005 1,320,000 0.018 367 Shellenberger (1970a,b)3 4-Hexen-3-one1125 4-Hexen-3-one 6.6b 0.0002 33,000 0.0079 835 Shellenberger (1970a,b)3 4-Hexen-3-one1126 2-Hepten-4-one 6.6b 2.00 · 10�7 33,000,000 0.009 733 Shellenberger (1970a,b)3 4-Hexen-3-one1127 3-Hepten-2-one 6.6b 0.000003 2,200,000 0.0089 742 Shellenberger (1970a,b)3 4-Hexen-3-one1128 3-Octen-2-one 6.7b 0.00002 335,000 0.0086 779 Cox et al. (1974a)4 2-Octen-4-one1129 2-Octen-4-one 6.7b 0.00005 134,000 0.0038 1763 Cox et al. (1974a)4 2-Octen-4-one1130 3-Decen-2-one 6.7b 2.00 · 10�7 33,500,000 0.029 231 Cox et al. (1974a)4 2-Octen-4-one1131 4-Methyl-3-penten-2-one 6.6b 0.000007 942,857 0.0061 1082 Shellenberger (1970a,b)3 4-Hexen-3-one1132 5-Methyl-3-hexen-2-one 6.6b 0.000002 3,300,000 0.019 347 Shellenberger (1970a,b)3 4-Hexen-3-one1133 5-Methyl-2-hepten-4-one 6.6b 0.0001 66,000 0.029 228 Shellenberger (1970a,b)3 4-Hexen-3-one1134 6-Methyl-3,5-heptadien-2-one 6.6b 0.0002 33,000 0.013 508 Shellenberger (1970a,b)3 4-Hexen-3-one1135 (E)-7-Methyl-3-octen-2-one 6.7b 0.00003 223,333 0.0025 2680 Cox et al. (1974a)4 2-Octen-4-one1136 3-Nonen-2-one 6.7b 0.0002 33,500 0.0038 1763 Cox et al. (1974a)4 2-Octen-4-one1137 (E) & (Z)-4,8-Dimethyl-3,7-nonadien-2-one 6.7b 0.0001 67,000 0.15 45 Cox et al. (1974a)4 2-Octen-4-one1138 (E)-6-Methyl-3-hepten-2-one 6.7b 0.00007 95,714 0.01 670 Cox et al. (1974a)4 2-Octen-4-one1139 (E,E)-3,5-Octadien-2-one 6.7b 0.00007 95,714 0.015 447 Cox et al. (1974a)4 2-Octen-4-one1140 3-Octen-2-ol 6.7b 0.00002 335,000 0.00034 19,706 Cox et al. (1974a)4 2-Octen-4-one1141 (E)-2-Octen-4-ol 6.7b 0.00002 335,000 0.044 152 Cox et al. (1974a)4 2-Octen-4-one1142 2-Pentyl butyrate 20 0.00001 2,000,000 0.017 1176 Gaunt et al. (1972b)5 2-Heptanone1143 (±)-Heptan-3-yl acetate 1000 0.00007 14,285,714 0.033 30,303 O�Donoghue et al. (1984)6 3-Heptanone1144 (±)-Heptan-2-yl butyrate 20 0.00007 285,714 0.018 1111 Gaunt et al. (1972b)5 2-Heptanone1145 (±)-Nonan-3-yl acetate 230b 0.00007 3,285,714 0.038 6053 Eibert (1992)7 Hexyl alcohol1146 2-Pentyl acetate 20 0.00005 400,000 0.11 182 Gaunt et al. (1972b)5 2-Heptanone1147 1-Penten-3-one 6.7b 0.000005 1,340,000 3.33 · 10�5 201,201 Cox et al. (1974b)4 1-Octen-3-one1148 1-Octen-3-one 6.7b 0.00002 335,000 0.0052 1288 Cox et al. (1974b)4 1-Octen-3-one1149 2-Pentyl-1-buten-3-one 6.7b 0.000003 2,233,333 6.67 · 10�6 1,004,498 Cox et al. (1974b)4 1-Octen-3-one1150 1-Penten-3-ol 12b 0.00003 400,000 0.018 667 Posternak (1964)8 1-Octen-3-ol1151 1-Hexen-3-ol 12b 0.00003 400,000 5.33 · 10�5 225,141 Posternak (1964)8 1-Octen-3-ol1152 1-Octen-3-ol 12b 0.005 2400 0.034 353 Posternak (1964)8 1-Octen-3-ol1153 1-Decen-3-ol 12b 0.000002 6,000,000 0.005 2400 Posternak (1964)8 1-Octen-3-ol1154 (E,R)-3,7-Dimethyl-1,5,7-octatrien-3-ol 10b 0.0001 100,000 0.0013 7692 Wnorowski (1997)9 (E,R)-3,7-Dimethyl-1,5,7-octatrien-3-ol1155 6-Undecanone 10b 0.00007 142,857 0.031 323 Gill and van Miller (1987c)1 5-Methyl-5-hexen-2-one1156 2-Methylheptan-3-one 10b 0.00007 142,857 0.047 213 Gill and van Miller (1987c)1 5-Methyl-5-hexen-2-one

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 14 days, 10 mg/kg bw/day (Gill and van Miller, 1987c); 2rat, gavage, 14 days, 0.35 or 3.5 mg/kg bw/day (DeGroot et al., 1974);3rat, diet, 90 days, 6.7/6.6 (M/F) mg/kg bw/day (Shellenberger, 1970a,b); 4rat, diet, 90 days, 6.7 mg/kg bw/day (Cox et al., 1974a,b); 5rat, gavage, 13 weeks, 20, 100, or 500 mg/kg bw/day (Gaunt et al.,1972b); 6rat, gavage, 14 weeks, 250, 500, 1000, 2000, or 4000 mg/kg bw (5 days per week) (O�Donoghue et al., 1984); 7dog, diet, 13 weeks, 0.5 or 1% (�230 to 695 mg/kg bw/day) (Eibert, 1992); 8rat,diet, 90 days, 12/14 mg/kg bw/day (Posternak, 1964); 9rat, gavage, 14 days, 10 mg/kg bw/day (Wnorowski, 1997).



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supported by the NOEL established for the structurallyrelated compound dihydromintlactone (Cormack et al.,2000).


substances. A group of structurally related lactones waspreviously evaluated by the Committee in 1997 andincluded in the study comparing daily intakes of flavouringsubstances to NOELs by Munro and Kennepohl (2001). Astudy conducted by Bar and Griepentrog (1967) with therelated lactones c-nonalactone and c-undecalactone servedas the basis for the ADI set by JECFA for these com-pounds in 1967. Accordingly, the NOEL of 250 mg/kgbody weight/day identified for c-nonalactone and c-undec-alactone (Bar and Griepentrog, 1967) was used as theNOEL basis for the calculation of the margins of safetyfor a number of structurally related lactones in this groupof flavouring agents for which parent NOELs were notavailable.

For all compounds in this group, which were evaluatedby JECFA based on the NOEL established for 3-propylide-nephthalide, the margins of safety also were calculatedusing the NOEL for 3-propylidenephthalide. NOELs forthe remaining compounds were selected from NOELsavailable for other compounds evaluated in this group offlavouring agents, which were structurally similar or wereexpected to be subject to a similar metabolic fate. Table17 presents a summary of the comparison of the intakeestimates with NOELs for compounds in this group offlavouring substances.

3.4.2. Aliphatic, alicyclic, linear a,b-unsaturated di- and

trienals and related alcohols, acids and esters

3.4.2.1. Parent compound NOELs. In evaluating the safetyof trans,trans-2,4-hexadienal, 2-trans,4-trans-decadienal,and several structurally related substances in this groupof flavouring agents, the Committee required toxicity data.In keeping with JECFA�s evaluation, the NOELs identifiedby the Committee also were selected for the calculation ofthe margins of safety in this study. Several additional suit-able parent NOELs were included in the JECFA mono-graph for certain members of this group of flavouringagents. For 2-trans-6-cis-dodecadienal and 2-trans-4-cis-7-cis-tridecatrienal the respective NOELs were based on arat study in which the compounds were administered as amixture in the diet (Edwards, 1973). For (E,E)-2,4-hexadi-enoic acid a number of studies were identified which dem-onstrated no adverse effects. Ultimately, the NOEL for thecalculation of the margin of safety was based on the resultsof the longest-term study (Gaunt et al., 1975).


substances. In a study conducted by Edwards (1973), 2-trans-6-cis-dodecadienal and 2-trans-4-cis-7-cis-tridecatrie-nal were provided to rats as a mixture. Based on the resultsof this study, the more conservative NOEL for 2-trans-6-cis-dodecadienal was selected for calculating the margin

of safety for several structurally related compounds. Asnoted above, margins of safety for substances related totrans,trans-2,4-hexadienal and 2-trans,4-trans-decadienalwere calculated based on the respective NOELs selectedfor these compounds at the time of JECFA�s evaluation.Margins of safety for all other compounds were based onthe most appropriate NOEL for structurally similar com-pounds in this group of flavouring agents. The results ofthe comparison of the intake estimates with the NOELsare presented in Table 18.

3.4.3. Aliphatic branched-chain saturated and unsaturated

alcohols, aldehydes, acids and related esters

3.4.3.1. Parent compound NOELs. A group ADI of 0.5 mg/kg body weight/day was established for citral equivalentsby the Committee in 1979 and subsequently maintained atthe 61st meeting; however, at the 61st meeting more recentlonger-term NTP mouse and rat studies were reviewed,which were supportive of higher NOELs than the oneselected for the determination of the ADI. AlthoughJECFA based the evaluation of the safety of citral on alower NOEL established under the conditions of the NTPmouse study in which equivocal evidence of carcinogenicitywas observed in females, the margin of safety was calculatedusing the NOEL of 100 mg/kg body weight/day derived onthe basis of the rat study (NTP, 2003).

The representative NOEL selected for dl-citronellol wasbased on the results of a dietary rat study in which dl-citro-nellol was administered as part of a mixture consisting ofcitronellol and linalool in equal amounts (Oser, 1958); how-ever, in another longer-term study in which rats received amixture of geranyl acetate and citronellyl acetate, a higherNOEL of 290 mg/kg body weight/day was identified forcitronellyl acetate, which is expected to hydrolyze to citro-nellol (approximately 229 mg/kg body weight/day citronel-lol equivalents) (NTP, 1987), thus confirming the NOEL ofthe Oser (1958) study. Likewise, a study was identified inwhich the safety of a geraniol extract containing 3,7-dimethyl-2,6-octadienol (geraniol) and 3,7-dimethyl-1,6-octadienol was investigated, demonstrating no adverseeffects at 50 mg/kg body weight/day (Hagan et al., 1967).Although this study was selected as the NOEL basis forthe calculation of the margin of safety for geraniol, no toxi-cologically significant adverse effects were reported in thestudy in which a mixture of geranyl acetate (ester of gera-niol) and citronellyl acetate was administered to rats, result-ing in a dose level of 710 mg/kg body weight/day of geranylacetate (approximately 558 mg/kg body weight/day ofgeraniol equivalents) (NTP, 1987).


substances. The calculation of the margin of safety for12-methyltridecanal, a compound structurally similar tooctanoic acid, was based on the NOEL for hexyl alcohol(Eibert, 1992), which served as the NOEL basis for the cal-culation of the margin of safety for octanoic acid in theMunro and Kennepohl (2001) study.

Table 17Alicyclic, alicyclic-fused and aromatic-fused ring lactones—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1157 4-Hydroxy-4-methyl-5-hexenoic acid c-lactone 250b 0.00005 5,000,000 0.47 532 Bar and Griepentrog (1967)1 c-Nonalactone/c-undecalactone1158 (±)3-Methyl-c-decalactone 250b 0.00008 3,125,000 0.0045 55,556 Bar and Griepentrog (1967)1 c-Nonalactone/c-undecalactone1159 4-Hydroxy-4-methyl-7-cis-decenoic acid c-lactone 250b 0.0002 1,250,000 0.036 6944 Bar and Griepentrog (1967)1 c-Nonalactone/c-undecalactone1160 Tuberose lactone 250b 0.0002 1,250,000 0.062 4032 Bar and Griepentrog (1967)1 c-Nonalactone/c-undecalactone1161 Dihydromintlactone 15.5 0.0002 77,500 0.0052 2981 Cormack et al. (2000)2 Dihydromintlactone1162 Mintlactone 15.5 0.0002 77,500 0.0013 11,923 Cormack et al. (2000)2 Dihydromintlactone1163 Dehydromenthofurolactone 1 0.0002 5000 0.0013 769 Voss (1985)3 Dehydromenthofurolactone1164 (±)(2,6,6-Trimethyl-

2-hydroxycyclohexylidene) acetic acid c-lactone15.5 0.00002 775,000 3.33 · 10�7 46,546,547 Cormack et al. (2000)2 Dihydromintlactone

1165 Sclareolide 7.86b 0.0001 78,600 0.016 491 Terrill (1990)4 Sclareolide1166 Octahydrocoumarin 300 0.000001 300,000,000 0.039 7692 NTP (1993b)5 Dihydrocoumarin1167 2-(4-Methyl-2-hydroxyphenyl)propionic acid c-lactone 5.42b 0.00003 180,667 0.0087 623 Posternak et al. (1969)6 3-Propylidenephthalide1168 3-Propylidenephthalide 5.42b 0.0009 6022 0.0057 951 Posternak et al. (1969)6 3-Propylidenephthalide1169 3-n-Butylphthalide 5.42b 0.00001 542,000 0.00048 11,292 Posternak et al. (1969)6 3-Propylidenephthalide1170 3-Butylidenephthalide 5.42b 0.0002 27,100 0.02 271 Posternak et al. (1969)6 3-Propylidenephthalide1171 Dihydrocoumarin 300 0.02 15,000 0.093 3226 NTP (1993b)5 Dihydrocoumarin1172 6-Methylcoumarin 175 0.005 35,000 0.034 5147 Hagan et al. (1967)7 6-Methylcoumarin

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 2 years, 50 or 250 mg/kg bw/day (Bar and Griepentrog, 1967); 2rat, diet, 28 days, 5.5, 15.5, or 27.8 mg/kg bw/day (Cormacket al., 2000); 3rat, diet, 90 days, 1, 10, or 100 mg/kg bw/day (Voss, 1985); 4rat, diet, 14 days, 7.86/7.94 (M/F) mg/kg bw/day (Terrill, 1990); 5rat, gavage, 721 days, 75, 150, 300, 600, or 1200 mg/kg bw/day (NTP, 1993b); 6rat, diet, 90 days, 5.42/6.55 (M/F) mg/kg bw/day (Posternak et al., 1969); 7rat, diet, 730 days, 25, 50, 175, 375, or 750 mg/kg bw/day (Hagan et al., 1967).



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Table 18Aliphatic, alicyclic, linear a, b-unsaturated di- and trienals and related alcohols, acids and esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1173 2,4-Pentadienal 15 0.000003 5,000,000 0.021 714 NTP (2001)1 trans, trans-2,4-Hexadienal1174 (E,E)-2,4-Hexadien-1-ol 15 0.000007 2,142,857 0.0037 4054 NTP (2001)1 trans, trans-2,4-Hexadienal1175 trans,trans-2,4-Hexadienal 15 0.00002 750,000 0.0072 2083 NTP (2001)1 trans, trans-2,4-Hexadienal1176 (E,E)-2,4-Hexadienoic acid 750 0.0001 7,500,000 0.03 25,000 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1177 Methyl sorbate 750 0.000002 375,000,000 0.0058 129,310 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1178 Ethyl sorbate 750 0.001 750,000 0.029 25,862 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1179 2,4-Heptadienal 15 0.0004 37,500 0.0049 3061 NTP (2001)1 trans, trans-2,4-Hexadienal1180 (E,E)-2,4-Octadien-1-ol 15 0.0003 50,000 0.017 882 NTP (2001)1 trans,trans-2,4-Hexadienal1181 trans,trans-2,4-Octadienal 15 0.00001 1,500,000 0.0097 1546 NTP (2001)1 trans,trans-2,4-Hexadienal1182 2-trans, 6-trans-Octadienal 2b 0.000002 1,000,000 0.0027 741 Edwards (1973)3 2-trans-6-cis-Dodecadienal1183 2,4-Nonadien-1-ol 34b 0.0004 85,000 0.022 1545 Damske et al. (1980)4 2-trans,4-trans-Decadienal1184 2,6-Nonadien-1-ol 2b 0.00003 66,667 0.0013 1538 Edwards (1973)3 2-trans-6-cis-Dodecadienal1185 2,4-Nonadienal 34b 0.00003 1,133,333 0.012 2833 Damske et al. (1980)4 2-trans,4-trans-Decadienal1186 Nona-2-trans-6-cis-dienal 2b 0.0004 5000 0.00015 13,333 Edwards (1973)3 2-trans-6-cis-Dodecadienal1187 2-trans-6-trans-Nonadienal 2b 1.00 · 10�7 20,000,000 0.00015 13,333 Edwards (1973)3 2-trans-6-cis-Dodecadienal1188 (E,Z)-2,6-Nonadien-1-ol acetate 2b 0.0003 6667 0.0012 1667 Edwards (1973)3 2-trans-6-cis-Dodecadienal1189 (E,E)-2,4-Decadien-1-ol 34b 0.0004 85,000 0.017 2000 Damske et al. (1980)4 2-trans,4-trans-Decadienal1190 2-trans,4-trans-Decadien-1-ol 34b 0.001 34,000 0.017 2000 Damske et al. (1980)4 2-trans,4-trans-Decadienal1191 Methyl (E)-2-(Z)-4-decadienoate 750 0.00002 37,500,000 0.0055 136,364 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1192 Ethyl trans-2-cis-4-decadienoate 750 0.0006 1,250,000 0.042 17,857 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1193 Ethyl 2,4,7-decatrienoate 750 0.000007 107,142,857 0.000015 50,000,000 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1194 Propyl 2,4-decadienoate 750 0.00002 37,500,000 0.0052 144,231 Gaunt et al. (1975)2 (E,E)-2,4-Hexadienoic acid1195 2,4-Undecadienal 34b 0.00007 485,714 0.0053 6415 Damske et al. (1980)4 2-trans,4-trans-Decadienal1196 trans,trans-2,4-Dodecadienal 34b 0.00001 3,400,000 0.0018 18,889 Damske et al. (1980)4 2-trans,4-trans-Decadienal1197 2-trans-6-cis-Dodecadienal 2b 0.00001 200,000 0.00013 15,385 Edwards (1973)3 2-trans-6-cis-Dodecadienal1198 2-trans-4-cis-7-cis-Tridecatrienal 33b 0.000005 6,600,000 0.0013 25,385 Edwards (1973)5 2-trans-4-cis-7-cis-Tridecatrienal

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 98 days, 7.5, 15, 30, 60, or 120 mg/kg bw/day (NTP, 2001); 2rat, diet, 730 days, 750 or 5000 mg/kg bw/day (Gaunt et al., 1975);3rat, diet, 28 days, 0.2, 0.4, 1, 2, 4, 10, or 20 ppm (2.06 mg/kg bw/day) (Edwards, 1973); 4rat, diet, 90 days, 3.4, 11, or 34 mg/kg bw/day (Damske et al., 1980); 5rat, diet, 28 days, 3.2, 6.4, 16, 32, 64, 160,or 320 ppm (33 mg/kg bw/day) (Edwards, 1973).



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Several flavouring substances in this group were deter-mined to be structurally similar to isovaleric acid, whichwas evaluated by JECFA in 1997 (JECFA, 1998). Inkeeping with the study conducted by Munro and Kenne-pohl (2001) in which a NOEL for isoamyl alcohol (Carpa-nini et al., 1973) was determined to be most suitable forcalculating the margin of safety for isovaleric acid, themargins of safety for compounds related to isovaleric acidalso were based on the NOEL for isoamyl alcohol. Allother compounds in this group of flavouring substanceswere determined by the study authors to be structurallyrelated to citral, dl-citronellol, or geraniol and, thus, therespective NOELs were used for the calculation of themargins of safety. The calculated margins of safety forthis group of flavouring substances are presented in Table19.

3.4.4. Aliphatic and aromatic ethers

3.4.4.1. Parent compound NOELs. In this group of flavour-ing substances, appropriate NOELs were available foreucalyptol (Roe et al., 1979), tetrahydro-4-methyl-2-(2-methylpropen-1-yl)pyran (Posternak et al., 1969), b-naph-thyl methyl ether (Oser et al., 1965), para-methylanisole(Brunsborg et al., 1994), dibenzyl ether (Burdock andFord, 1992), meta-dimethoxybenzene (Bar and Griepen-trog, 1967), diphenyl ether (Pecchiani and Saffiotti, 1957),para-dimethoxybenzene (Altmann et al., 1985), carvacrylethyl ether (Gill and van Miller, 1987d), cycloionone(Wnorowski, 1998), and 1,2-dimethoxybenzene (Trimmeret al., 1992) in the JECFA monograph. The NOELs usedto calculate the margins of safety for eucalyptol and diben-zyl ether for which according to the procedure for the eval-uation of flavouring substances toxicity data were required,were consistent with those selected by JECFA. Althoughthe NOELs selected for carvacryl ethyl ether and 1,2-dimethoxybenzene were based on the results of 14-daystudies (Gill and van Miller, 1987d; Trimmer et al.,1992), in both cases the NOELs are supported by a higherNOEL reported for the structurally related compoundmeta-dimethoxybenzene (Bar and Griepentrog, 1967).


substances. Since aliphatic ethers are expected to be subjectto O-dealkylation resulting in the formation of correspond-ing alcohols and aldehydes, margins of safety for sec-butylethyl ether and 1-ethoxy-3-methyl-2-butene were calculatedbased on the NOEL for acetaldehyde (Til et al., 1988) (seeSection 3.2.6).

The NOELs for anisole and ortho-methylanisole for thecalculation of the margins of safety were based on the rep-resentative NOEL for the structurally related compound,eugenol (NTP, 1983) (see Section 3.1.3). Likewise, theNOEL established for para-cresol (EPA, 1988b) (see Sec-tion 3.1.3) was considered to be appropriate for the calcu-lation of the margins of safety for the structurally relatedcompounds benzyl ethyl ether, benzyl butyl ether, andmethyl phenethyl ether.

Although occurrences of osteoporosis in studies con-ducted with para-propylanisole precluded establishing aNOEL on the basis of studies conducted with the com-pound itself at dose levels ranging between 100 and1000 mg/kg body weight/day (Hagan et al., 1967), theCommittee based their evaluation on the results of along-term study conducted with the structurally relatedcompound trans-anethol, in which no toxicologically sig-nificant adverse effects were observed at a dose level of300 mg/kg body weight/day (Minnema, 1997). Therefore,in keeping with the evaluation conducted by JECFA, theNOEL of 300 mg/kg body weight/day established fortrans-anethol was selected as the NOEL basis for para-propylanisole.

The margins of safety for all other compounds werebased on NOELs available for other structurally similarflavouring substances included in this group. Table 20 pre-sents a summary of the comparison of the intake estimateswith the selected NOELs.

3.4.5. Hydroxypropenylbenzenes

3.4.5.1. Parent compound NOELs. JECFA�s evaluation ofall members in this group of flavouring agents proceededvia the A-side of the Procedure and none of the compoundsrequired any toxicity data; however, 14-week dietarymouse and rat studies have been performed with isoeuge-nol (NTP, 2002), and were reviewed in the JECFA report.Although in the rat study minimal to mild olfactory epithe-lial degeneration was reported at every dose level of isoeu-genol administered, these non-neoplastic lesions wereconsidered by the NTP study authors as not life-threaten-ing. Therefore, based on the absence of any other toxico-logically significant adverse effects at dose levels of upto 150 mg isoeugenol/kg body weight/day, a NOEL of150 mg/kg body weight/day was selected for isoeugenol.Moreover, in mice the NOEL was determined to be300 mg/kg body weight/day. Appropriate NOELs alsowere identified for propenylguaethol (Terrill, 1991) andfor isoeugenyl benzyl ether (Boe et al., 1989).


substances. Although a 90-day study was identified for iso-eugenyl methyl ether, this was a single-dose level study(Osborne, 1981). Therefore in contrast to the evaluationconducted by JECFA, the NOEL established for isoeuge-nol, on the basis of the multiple-dose level NTP study,was considered to be more appropriate for the calculationof the margin of safety of isoeugenyl methyl ether, which isexpected to undergo O-demethylation to isoeugenol. Ashorter term 28-day, multiple-dose level study performedwith isoeugenyl methyl ether, demonstrated a NOEL of100 mg/kg body weight/day, with adverse effects observedonly at the next higher dose level of 300 mg/kg bodyweight/day. The NOEL selected for isoeugenol also wasconsidered to be appropriate for the isoeugenol esters,and for isoeugenyl ethyl ether and 4-propenyl-2,6-dimeth-oxyphenol. For this group of flavouring agents the results

Table 19Aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acids and related esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1199 (±)2-Methyl-1-butanol 1000b 0.0006 1,666,667 0.0068 147,059 Carpanini et al. (1973)1 Isoamyl alcohol1200 3-Methyl-2-buten-1-ol 100 0.00009 1,111,111 0.002 50,000 NTP (2003)2 Citral1201 2-Methyl-2-butenal 1000b 0.00001 100,000,000 0.038 26,316 Carpanini et al. (1973)1 Isoamyl alcohol1202 3-Methyl-2-butenal 1000b 0.00006 16,666,667 0.0053 188,679 Carpanini et al. (1973)1 Isoamyl alcohol1203 Ammonium isovalerate 1000b 0.0003 3,333,333 0.11 9091 Carpanini et al. (1973)1 Isoamyl alcohol1204 3-Methylcrotonic acid 1000b 0.002 500,000 0.0074 135,135 Carpanini et al. (1973)1 Isoamyl alcohol1205 trans-2-Methyl-2-butenoic acid 1000b 0.00008 12,500,000 0.07 14,286 Carpanini et al. (1973)1 Isoamyl alcohol1206 Isobutyl 2-butenoate 1000b 0.0008 1,250,000 0.023 43,478 Carpanini et al. (1973)1 Isoamyl alcohol1207 2-Methylallyl butyrate 1000b 0.000003 333,333,333 0.0049 204,082 Carpanini et al. (1973)1 Isoamyl alcohol1208 4-Methyl-2-pentenal 100 0.000005 20,000,000 0.0051 19,608 NTP (2003)2 Citral1209 2-Methyl-2-pentenal 100 0.00007 1,428,571 0.037 2703 NTP (2003)2 Citral1210 2-Methyl-2-pentenoic acid 100 0.0007 142,857 0.037 2703 NTP (2003)2 Citral1211 2,4-Dimethyl-2-pentenoic acid 100 0.000002 50,000,000 0.037 2703 NTP (2003)2 Citral1212 2-Methylheptanoic acid 100 0.0003 333,333 0.0052 19,231 NTP (2003)2 Citral1213 Isobutyl angelate 1000b 0.000002 500,000,000 0.017 58,824 Carpanini et al. (1973)1 Isoamyl alcohol1214 2-Butyl-2-butenal 100 2.00 · 10�7 500,000,000 0.0072 13,889 NTP (2003)2 Citral1215 2-Isopropyl-5-methyl-2-hexenal 100 0.000005 20,000,000 0.0086 11,628 NTP (2003)2 Citral1216 2-Ethyl-2-heptenal 100 0.000002 50,000,000 0.064 1563 NTP (2003)2 Citral1217 2-Methyl-2-octenal 100 0.0001 1,000,000 0.00083 120,482 NTP (2003)2 Citral1218 4-Ethyloctanoic acid 100 0.00007 1,428,571 0.0015 66,667 NTP (2003)2 Citral1219 dl-Citronellol 51b 0.006 8500 0.019 2684 Oser (1958)3 dl-Citronellol1220 Citronellal 51b 0.02 2550 0.02 2550 Oser (1958)3 dl-Citronellol1221 3,7-Dimethyl-6-octenoic acid 51b 0.00005 1,020,000 0.004 12,750 Oser (1958)3 dl-Citronellol1222 Rhodinol 50b 0.0009 55,556 0.02 2500 Hagan et al. (1967)4 Geraniol1223 Geraniol 50b 0.01 5000 0.057 877 Hagan et al. (1967)4 Geraniol1224 Nerol 50b 0.005 10,000 0.052 962 Hagan et al. (1967)4 Geraniol1225 Citral 100 0.1 1000 0.42 238 NTP (2003)2 Citral1226 8-Ocimenyl acetate 50b 0.0001 500,000 0.0083 6024 Hagan et al. (1967)4 Geraniol1227 2,6-Dimethyl-10-methylene-2,6,11-dodecatrienal 50b 0.00008 625,000 0.066 758 Hagan et al. (1967)4 Geraniol1228 3, 7, 11-Trimethyl-2,6,10-dodecatrienal 50b 0.000003 16,666,667 0.0058 8621 Hagan et al. (1967)4 Geraniol1229 12-Methyltridecanal 230b 0.000008 28,750,000 0.089 2584 Eibert (1992)5 Hexyl alcohol1230 Farnesol 50b 0.0002 250,000 0.011 4545 Hagan et al. (1967)4 Geraniol

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 17 weeks, 150, 500, or 1000 mg/kg bw/day (Carpanini et al., 1973); 2rat, diet, 104 to 105 weeks, 0, 50, 100, or 210 mg/kg bw/day(NTP, 2003); 3rat, diet, 12 weeks, 51/56 (M/F) mg/kg bw/day (Oser, 1958); 4rat, diet, 27–28 weeks, 50 mg/kg bw/day (Hagan et al., 1967); 5dog, diet, 13 weeks, 0.5 or 1% (equivalent to �230 to 695 mg/kg bw/day) (Eibert, 1992).



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Table 20Aliphatic and aromatic ethers—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1231 sec-Butyl ethyl ether 675b 0.0001 6,750,000 0.0029 232,759 Til et al. (1988)1 Acetaldehyde1232 1-Ethoxy-3-methyl-2-butene 675b 0.00003 22,500,000 0.0026 259,615 Til et al. (1988)1 Acetaldehyde1233 1,4-Cineole 32b 0.002 16,000 0.036 889 Roe et al. (1979)2 Eucalyptol1234 Eucalyptol 32b 0.03 1067 0.022 1455 Roe et al. (1979)2 Eucalyptol1235 Nerol oxide 2.5b 0.00002 125,000 0.0006 4167 Posternak et al. (1969)3 Tetrahydro-4-methyl-2-(2-methylpropen-

1-yl)pyran1236 2,2,6-Trimethyl-6-vinyltetrahydropyran 2.5b 0.0001 25,000 0.0007 3571 Posternak et al. (1969)3 Tetrahydro-4-methyl-2-(2-methylpropen-

1-yl)pyran1237 Tetrahydro-4-methyl-2-(2-methylpropen-

1-yl)pyran2.5b 0.00007 35,714 0.0077 325 Posternak et al. (1969)3 Tetrahydro-4-methyl-2-(2-methylpropen-

1 -yl)pyran1238 Theaspirane 32b 0.00003 1,066,667 0.0013 24,615 Roe et al. (1979)2 Eucalyptol1239 Cycloionone 120 0.00003 4,000,000 0.025 4800 Wnorowski (1998)4 Cycloionone1240 1,5,5,9-Tetramethyl-13-oxatricyclo

[8.3.0.0(4,9)]tridecane32b 0.00002 1,600,000 0.000024 1,333,333 Roe et al. (1979)2 Eucalyptol

1241 Anisole 250 5.00 · 10�7 500,000,000 0.13 1923 NTP (1983)5 Eugenol1242 ortho-Methylanisole 250 0.00005 5,000,000 0.026 9615 NTP (1983)5 Eugenol1243 para-Methylanisole 40 0.0002 200,000 0.029 1379 Brunsborg et al. (1994)6 para-Methylanisole1244 para-Propylanisole 300 0.002 150,000 0.24 1250 Minnema (1997)7 trans-Anethol1245 2,4-Dimethylanisole 22b 0.000003 7,333,333 0.00033 66,667 Gill and van Miller (1987d)8 Carvacryl ethyl ether1246 1-Methyl-3-methoxy-4-isopropylbenzene 22b 0.00003 733,333 0.012 1833 Gill and van Miller (1987d)8 Carvacryl ethyl ether1247 Carvacryl ethyl ether 22b 0.000002 11,000,000 0.022 1000 Gill and van Miller (1987d)8 Carvacryl ethyl ether1248 1,2-Dimethoxybenzene 10b 0.0003 33,333 0.0012 8333 Trimmer et al. (1992)9 1,2-Dimethoxybenzene1249 meta-Dimethoxybenzene 250b 0.00008 3,125,000 0.034 7353 Bar and Griepentrog (1967)10 meta-Dimethoxybenzene1250 para-Dimethoxybenzene 1000b 0.0003 3,333,333 0.18 5556 Altmann et al. (1985)11 para-Dimethoxybenzene1251 3,4-Dimethoxy-1-vinylbenzene 10b 2.00 · 10�7 50,000,000 0.0049 2041 Trimmer et al. (1992)9 1,2-Dimethoxybenzene1252 Benzyl ethyl ether 50 0.00003 1,666,667 0.021 2381 EPA (1988b)12 para-Cresol1253 Benzyl butyl ether 50 3.00 · 10�7 166,666,667 0.026 1923 EPA (1988b)12 para-Cresol1254 Methyl phenethyl ether 50 0.0005 100,000 0.034 1471 EPA (1988b)12 para-Cresol1255 Diphenyl ether 530b 0.0002 2,650,000 0.0016 331,250 Pecchiani and Saffiotti (1957)13 Diphenyl ether1256 Dibenzyl ether 196 0.004 49,000 0.32 613 Burdock and Ford (1992)14 Dibenzyl ether1257 b-Naphthyl methyl ether 5.1b 2.00 · 10�7 25,500,000 0.0027 1889 Oser et al. (1965)15 b-Naphthyl methyl ether1258 b-Naphthyl ethyl ether 5.1b 0.00007 72,857 0.043 119 Oser et al. (1965)15 b-Naphthyl methyl ether1259 b-Naphthyl isobutyl ether 5.1b 0.00003 170,000 0.021 243 Oser et al. (1965)15 b-Naphthyl methyl ether

Species, route of exposure, study duration, dose levels tested: 1rat, drinking water, 4 weeks, 25, 125, or 675 mg/kg bw/day (Til et al., 1988); 2mouse, gavage, 560 days, 8 or 32 mg/kg bw/day (Roe et al.,1979); 3rat, diet, 90 days, 2.5/2.8 (M/F) mg/kg bw/day (Posternak et al., 1969); 4rat, gavage, 28 days, 30, 120, 400, or 1000 mg/kg bw/day (Wnorowski, 1998); 5rat, diet, 103 weeks, 250/550 or 500/1150(M/F) mg/kg bw/day (NTP, 1983); 6rat, gavage, 28 days, 40, 120, or 240 mg/kg bw/day (Brunsborg et al., 1994); 7rat, diet, 90 days, 150, 300, 600, or 900 mg/kg bw/day (Minnema, 1997); 8rat, diet, 14days, 22 mg/kg bw/day (Gill and van Miller, 1987d); 9rat, diet, 14 days, 10 mg/kg bw/day (Trimmer et al., 1992); 10rat, diet, 730 days, 50 or 250 mg/kg bw/day (Bar and Griepentrog, 1967); 11rat, diet,28 or 56 days, 1000 mg/kg bw/day (Altmann et al., 1985); 12rat, gavage, 13 weeks, 50, 180, or 600 mg/kg bw/day (EPA, 1988b); 13rat, diet, 13 months, 396 or 530 mg/kg bw/day (Pecchiani and Saffiotti,1957); 14rat, diet, 91 days, 62, 196, or 620 mg/kg bw/day (Burdock and Ford, 1992); 15rat, diet, 90 days, 5.1/5.7 (M/F) mg/kg bw/day (Oser et al., 1965).



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Table 21Hydroxypropenylbenzenes—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1260 Isoeugenol 150 0.002 75,000 0.04 3750 NTP (2002)1 Isoeugenol1261 Isoeugenyl formate 150 0.000003 50,000,000 0.025 6000 NTP (2002)1 Isoeugenol1262 Isoeugenyl acetate 150 0.0002 750,000 0.043 3488 NTP (2002)1 Isoeugenol1263 Isoeugenyl phenylacetate 150 0.000005 30,000,000 0.0079 18,987 NTP (2002)1 Isoeugenol1264 Propenylguaethol 250 0.006 41,667 0.024 10,417 Terrill (1991)2 Propenylguaethol1265 4-Propenyl-2,6-dimethoxyphenol 150 0.00003 5,000,000 0.00055 272,727 NTP (2002)1 Isoeugenol1266 Isoeugenyl methyl ether 150 0.002 75,000 0.12 1250 NTP (2002)1 Isoeugenol1267 Isoeugenyl ethyl ether 150 2.00 · 10�7 750,000,000 0.08 1875 NTP (2002)1 Isoeugenol1268 Isoeugenyl benzyl ether 60 0.00002 3,000,000 0.034 1765 Boe et al. (1989)3 Isoeugenyl benzyl

ether

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 98 days, 37.5, 75, 150, 300, or 600 mg/kg bw/day (NTP, 2002); 2rat, gavage, 28days, 250, 1250, or 2500 mg/kg bw/day (Terrill, 1991); 3rat, gavage, 28 days, 60, 120, or 240 mg/kg bw/day (Boe et al., 1989).

a Highest intake estimate was selected from European or US per capita intake data.


of the comparison of the intake estimates with the NOELsare presented in Table 21.

3.4.6. Addendum to the safety evaluation of linear and

branched-chain aliphatic unsaturated, unconjugated

alcohols, aldehydes, acids, and related estersIn 1999, the Committee evaluated a total of 42 flavour-

ing agents belonging to this congeneric group of flavouringsubstances. As an extension to the former evaluation, anadditional 20 structurally related compounds were evalu-ated in 2003. As per the Procedure for the evaluationof flavouring agents, none of the compounds required toxi-cological data for the evaluation. Thus, the margins ofsafety were calculated based on NOELs for structurallyrelated analogues.

The margin of safety for the ester isoprenyl acetate wascalculated using the NOEL selected for isoamyl alcohol byMunro and Kennepohl (2001), which is structurally relatedto the alcohol component of the ester.

The NOEL established for geraniol (Hagan et al., 1967)(see Section 3.4.2.2) was considered to be appropriate forthe calculation of the margins of safety for the structurallyrelated compounds (Z,Z)-3,6-nonadien-1-ol, and (E)-3-(Z)-6-nonadien-1-ol and its ester (E)-3-(Z)-6-nonadien-1-ol acetate.

The calculation of the margins of safety for 9-decenal,and 4-decenoic acid and its ester cis-4-decenyl acetate wasconducted using the NOEL established for 10-undecenoicacid (Newell et al., 1949), which was selected as the NOELbasis for the structurally related compounds 9-decenoicacid and 4-decenal in the study by Munro and Kennepohl(2001). All remaining compounds were either structurallyrelated to cis-3-hexen-1-ol or metabolized to substancesevaluated by the Committee in 1999, for which marginsof safety calculated by Munro and Kennepohl (2001) alsowere based on the NOEL for cis-3-hexen-1-ol. Accord-ingly, the NOEL selected for cis-3-hexen-1-ol served as

the basis for the calculation of the margins of safety forthese related compounds. Table 22 provides a summaryof the margins of safety calculated for the compounds inthis group of flavouring agents.

3.4.7. Addendum to the safety evaluation of simplealiphatic and aromatic sulfides and thiols

3.4.7.1. Parent compound NOELs. Based on the procedurefor the safety evaluation of flavouring agents, JECFArequired toxicity data for every compound evaluated in thiscongeneric group; however, a toxicity study was identi-fied only for spiro(2,4-dithia-1-methyl-8-oxabicyclo(3.3.0)-octane-3,30-(10-oxa-20-methyl)cyclopentane, based on whicha NOEL of 25 mg/kg body weight/day was established(Wheldon et al., 1970b).


substances. In keeping with JECFA�s evaluation, themargins of safety for all remaining members of this groupof flavouring agents were based on NOELs for previouslyJECFA-evaluated, structurally related compounds, whichthe Committee determined as suitable surrogates for theevaluation of the safety of these substances. Study detailsand the results of the comparison of the estimated intakeswith the NOELs are summarized in Table 23.


63rd meeting in 2004

3.5.1. Pyridine, pyrrole and quinoline derivatives3.5.1.1. Parent compound NOELs. A NOEL was establishedfor indole, based on a study in which adverse effects were lim-ited to incidences of moderate, reversible anaemia (Kaiser,1953). Additionally, suitable NOELs also were identifiedfor 6-methylquinoline (Posternak et al., 1969), methyl 2-pyrrolyl ketone (Posternak et al., 1975), N-furfurylpyrrole(Morgareidge, 1971c), and 2-pyridinemethanethiol (Poster-

Table 22Linear and branched-chain aliphatic unsaturated, unconjugated alcohols, aldehydes, acids, and related esters; additional compounds—comparison ofintake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1269 Isoprenyl acetate 1000b 0.0002 5,000,000 0.031 32,258 Carpanini et al. (1973)1 Isoamyl alcohol1270 4-Pentenyl acetate 130b 0.00007 1,857,143 0.078 1667 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1271 3-Hexenal 130b 0.0009 144,444 0.013 10,000 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1272 3-Hexenyl formate 130b 0.0003 433,333 0.0037 35,135 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1273 Ethyl 5-hexenoate 130b 0.00007 1,857,143 0.02 6500 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1274 cis-3-Hexenyl propionate 130b 0.0003 433,333 0.043 3023 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1275 cis-3-Hexenyl isobutyrate 130b 0.0003 433,333 0.049 2653 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1276 (Z)-3-Hexenyl (E)-2-butanoate 130b 0.000003 43,333,333 0.014 9286 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1277 cis-3-Hexenyl tiglate 130b 0.001 130,000 0.047 2766 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1278 cis-3-Hexenyl valerate 130b 0.0002 650,000 0.044 2955 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1279 3-Hexenyl 2-hexenoate 130b 0.000002 65,000,000 0.1 1300 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1280 (Z)-4-Hepten-1-ol 130b 0.00003 4,333,333 0.02 6500 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1281 Ethyl cis-4-heptenoate 130b 0.00007 1,857,143 0.058 2241 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1282 (Z)-5-Octenyl propionate 130b 0.00007 1,857,143 0.017 7647 Gaunt et al. (1969)2 cis-3-Hexen-1-ol1283 (Z,Z)-3,6-Nonadien-1-ol 50b 0.00002 2,500,000 0.0015 33,333 Hagan et al. (1967)3 Geraniol1284 (E)-3-(Z)-6-Nonadien-1-ol 50b 0.00002 2,500,000 0.0015 33,333 Hagan et al. (1967)3 Geraniol1285 (E)-3-(Z)-6-Nonadien-1

-ol acetate50b 0.0003 166,667 0.0015 33,333 Hagan et al. (1967)3 Geraniol

1286 9-Decenal 2500b 0.00001 250,000,000 1.67 · 10�5 149,700,599 Newell et al. (1949)4 10-Undecenoicacid

1287 4-Decenoic acid 2500b 0.00003 83,333,333 0.0098 255,102 Newell et al. (1949)4 10-Undecenoicacid

1288 cis-4-Decenyl acetate 2500b 0.00003 83,333,333 0.017 147,059 Newell et al. (1949)4 10-Undecenoicacid

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 17 weeks, 150, 500, or 1000 mg/kg bw/day (Carpanini et al., 1973); 2rat,drinking water, 98 days, 130/170 (M/F) mg/kg bw/day (Gaunt et al., 1969); 3rat, diet, 27–28 weeks, 50 mg/kg bw/day (Hagan et al., 1967); 4rat, diet, 8weeks, 500, 1000, or 2500 mg/kg bw/day (Newell et al., 1949).




nak et al., 1969), with the latter two compounds being theonly members of this group requiring toxicity data for eval-uation of their safety by JECFA.

Although a higher NOEL of 37 mg/kg body weight/daywas available for 2-acetylpyridine (Til and van der Meulen,1971), a more conservative NOEL of 3.1 mg/kg bodyweight/day (Posternak et al., 1975) was selected as the basisfor the calculation of the margin of safety.


substances. The margins of safety for all of the remainingcompounds evaluated in this group of flavouring agentswere calculated based on NOELs identified for compoundswith a related metabolic fate or structural similarity. Theresults of the comparison of the intake estimates andNOELs for this group of flavouring agents are summarizedin Table 24.

3.5.2. Aliphatic and alicyclic hydrocarbons

3.5.2.1. Parent compound NOELs. In this group of flavour-ing agents, the safety evaluation of a few of the compoundsby JECFA required toxicity data. Among these, the evalu-ation of myrcene by the Committee was based on a NOEL

of 6250 mg/kg body weight/day (NTP, 2004b,c). With theexception of female mice, kidney effects in male and femalerats, and liver hypertrophy in male mice were observed atthis dose level following administration of myrcene viagavage for a period of 13 weeks. In keeping with theevaluation of myrcene by the Committee, the NOEL of6250 mg/kg body weight/day was used for the calculationof the margins of safety for myrcene.

Several short- and long-term studies were conductedwith d-limonene, which also were reviewed by the Commit-tee in their evaluation of this flavouring agent. Althoughnephropathy was observed in male rats receiving d-limo-nene via gavage for a period of 103 weeks at all dose levelsevaluated (NTP, 1990), the increase in the incidence ofrenal tubular tumours in male rats was determined to bea a2u-globulin-associated response and as such not relevantto the evaluation of the safety of d-limonene in humans.For all other toxicologically significant endpoints, NOELsof 150 (the highest dose level tested) and 300 mg/kg bodyweight/day were determined for males and females, respec-tively. The higher NOEL of 300 mg/kg body weight/daywas utilized to calculate the margin of safety for d-limo-nene in this study. The NOEL also is supported by the

Table 23Simple aliphatic and aromatic sulfides and thiols; additional compounds—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Margin of safety

1289 erythro- and threo-Mercapto-2-methylbutan-1-ol 1.9b 0.00003 63,333 0.0005 3800 Cox et al. (1974c)1 2-Mercapto-3-butanol1290 (±)2-Mercapto-2-methylpentanol 1.9b 0.00007 27,143 3.33 · 10�5 57,057 Cox et al. (1974c)1 2-Mercapto-3-butanol1291 3-Mercapto-2-methylpentan-1-ol 1.9b 0.00002 95,000 1.67 · 10�5 113,772 Cox et al. (1974c)1 2-Mercapto-3-butanol1292 3-Mercapto-2-methylpentanal 1.9b 0.00007 27,143 0.00017 11,176 Cox et al. (1974c)1 2-Mercapto-3-butanol1293 4-Mercapto-4-methyl-2-pentanone 1.9b 3.00 · 10�7 6,333,333 0.014 136 Morgareidge (1971b)2 3-Mercapto-2-pentanone1294 (±)Ethyl-3-mercaptobutyrate 1.9b 0.00007 27,143 0.0025 760 Cox et al. (1974c)1 2-Mercapto-3-butanol1295 Ethyl 4-(acetylthio)butyrate 6.5b 0.00007 92,857 0.024 271 Shellenberger (1970c)3 Ethylthioacetate1296 spiro(2,4-Dithia-1-methyl-8-oxabicyclo

(3.3.0)octane-3,3 0-(1 0-oxa-20-methyl)cyclopentane25 0.00003 833,333 0.00067 37,313 Wheldon et al. (1970b)4 spiro(2,4-Dithia-1-methyl-

8-oxabicyclo(3.3.0)octane-3,3 0-(1 0-oxa-20-methyl)cyclopentane

1297 2-(Methylthio)ethanol 1.4b 0.00002 70,000 0.035 40 Cox et al. (1979)5 2-(Methylthiomethyl)-3-phenylpropenal

1298 Ethyl 5-(methylthio)valerate 1.4b 0.00003 46,667 0.0055 255 Cox et al. (1979)5 2-(Methylthiomethyl)-3-phenylpropenal

1299 2,3,5-Trithiahexane 0.3b 7.00 · 10�7 428571 0.0063 48 Mondino (1981)6 3-Methyl-1,2,4-trithiane1300 Diisopropyl trisulfide 4.8b 1.00 · 10�7 48,000,000 0.018 267 Morgareidge and Oser (1970d)7 Dipropyltrisulfide

Species route of exposure, study duration, dose levels tested: 1rat, oral, 92 days, 1.9 mg/kg bw/day (Cox et al., 1974c); 2rat, oral, 92 days, 1.9 mg/kg bw/day (Morgareidge, 1971b); 3rat, oral, 13 weeks,6.5 mg/kg bw/day (Shellenberger, 1970c); 4rat, diet, 90 days, 25, 250, or up to 1000 mg/kg bw/day (Wheldon et al., 1970b); 5rat, oral, 92 days, 1.4 mg/kg bw/day (Cox et al., 1979); 6rat, oral, 13 weeks,0.3 mg/kg bw/day (Mondino, 1981); 7rat, oral, 92 days, 4.8 mg/kg bw/day (Morgareidge and Oser, 1970d).



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Table 24Pyridine, pyrrole and quinoline derivatives—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1301 Indole 100b 0.0005 200,000 0.0022 45,455 Kaiser (1953)1 Indole1302 6-Methylquinoline 2.21b 0.00007 31,571 0.006 368 Posternak et al. (1969)2 6-Methylquinoline1303 Isoquinoline 2.21b 0.000001 2,210,000 0.003 737 Posternak et al. (1969)2 6-Methylquinoline1304 Skatole 100b 0.00005 2,000,000 0.0025 40,000 Kaiser (1953)1 Indole1305 1-Ethyl-2-acetylpyrrole 86b 2.00 · 10�7 430,000,000 0.017 5059 Posternak et al. (1975)3 Methyl 2-pyrrolyl

ketone1306 1-Methyl-2-acetylpyrrole 86b 0.00002 4,300,000 0.025 3440 Posternak et al. (1975)3 Methyl 2-pyrrolyl

ketone1307 Methyl 2-pyrrolyl ketone 86b 0.00007 1,228,571 0.069 1246 Posternak et al. (1975)3 Methyl 2-pyrrolyl

ketone1308 2-Pyridinemethanethiol 3.42b 1.00 · 10�7 34,200,000 0.0052 658 Posternak et al. (1975)4 2-Pyridinemethanethiol1309 2-Acetylpyridine 3.1b 0.001 3100 0.022 141 Posternak et al. (1975)5 2-Acetylpyridine1310 N-Furfurylpyrrole 12.21b 0.000002 6,105,000 0.014 872 Morgareidge (1971c)6 N-Furfurylpyrrole1311 2-(2-Methylpropyl)pyridine 3.1b 0.00002 155,000 8.33 · 10�5 37,215 Posternak et al. (1975)5 2-Acetylpyridine1312 3-(2-Methylpropyl)pyridine 3.1b 0.000001 3,100,000 0.0028 1107 Posternak et al. (1975)5 2-Acetylpyridine1313 2-Pentlpyridine 3.1b 0.000001 3,100,000 0.0023 1348 Posternak et al. (1975)5 2-Acetylpyridine1314 Pyrrole 86b 0.000002 43,000,000 0.014 6143 Posternak et al. (1975)3 Methyl 2-pyrrolyl

ketone1315 3-Ethylpyridine 3.1b 0.0002 15,500 0.00017 18,235 Posternak et al. (1975)5 2-Acetylpyridine1316 3-Acetylpyridine 3.1b 0.0004 7750 0.0072 431 Posternak et al. (1975)5 2-Acetylpyridine1317 2,6-Dimethylpyridine 3.1b 0.000005 620,000 0.0052 596 Posternak et al. (1975)5 2-Acetylpyridine1318 5-Ethyl-2-methylpyridine 3.1b 0.000002 1,550,000 0.00083 3735 Posternak et al. (1975)5 2-Acetylpyridine1319 2-Propionylpyrrole 86b 0.00003 2,866,667 0.00017 505,882 Posternak et al. (1975)3 Methyl 2-pyrrolyl

ketone1320 Methyl nicotinate 3.1b 0.00001 310,000 0.022 141 Posternak et al. (1975)5 2-Acetylpyridine1321 2-(3-Phenylpropyl)pyridine 3.1b 0.00003 103,333 0.011 282 Posternak et al. (1975)5 2-Acetylpyridine1322 2-Propylpyridine 3.1b 0.00002 155,000 0.0025 1240 Posternak et al. (1975)5 2-Acetylpyridine

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 590 days, 100 mg/kg bw/day (Kaiser, 1953); 2rat, diet, 90 days, 2.21/2.67 (M/F)mg/kg bw/day (Posternak et al., 1969); 3rat, diet, 91 days, 87/86 (M/F) mg/kg bw/day (Posternak et al., 1975); 4rat, diet, 90 days, 3.43/3.42 (M/F) mg/kg bw/day (Posternak et al., 1969); 5rat, diet, 91 days, 3.1 mg/kg bw/day (Posternak et al., 1975); 6rat, diet, 90 days, 12.21 mg/kg bw/day (Morgareidge,1971c).




results of a 6-month gavage study conducted in dogs inwhich no adverse effects were reported at 100 mg/kgbody weight/day (Webb et al., 1990), which was chosenas the basis for the NOEL used by JECFA for the evalua-tion of d-limonene. Additionally, a NOEL suitable forthe calculation of the margin of safety also was identifiedfor 1,3,5-undecatriene (Shapiro, 1988) in the JECFAreport.

The evaluation of camphene by the Committee pro-ceeded via the A-side of the Procedure and no toxicologicalstudies evaluating the potential toxicity of camphene werereviewed at the meeting; however, during the completionof this study, a study report was identified for camphenein which a NOEL of 250 mg/kg body weight/day wasreported in female rats based on the results of a 28-daystudy (Hoechst, 1991). Sex-specific kidney effects wereobserved in camphene-treated male rats, but as suggestedby the study authors, these were considered to be consistentwith a2u-globulin deposition and thus not relevant to theevaluation of camphene safety in humans.


substances. Although JECFA based the evaluation of b-pinene on the results of a short-term 14-day single-doselevel study (Shapiro, 1988), the NOEL for d-limonenewas considered to be a more suitable basis for the calcula-tion of the margins of safety for b-pinene and its structur-ally related compounds (i.e., a-pinene and d-3-carene) inthis study.

Margins of safety for all other flavouring substances inthis group were calculated based on NOELs selected forthe structurally related compounds, myrcene or d-limone.For a summary of the results of the comparison of esti-mated intakes with NOELs for all compounds in this groupof flavouring agents refer to Table 25.

3.5.3. Aromatic hydrocarbons

3.5.3.1. Parent compound NOELs. Several studies wereincluded in the JECFA monograph for biphenyl; however,the representative NOEL of 25 mg/kg body weight/daywas based on the results of a 2-year multiple-dose level

Table 25Aliphatic and alicyclic hydrocarbons—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1341 1,3,5-Undecatriene 2b 0.000003 666,667 0.00017 11765 Shapiro (1988)1 1,3,5-Undecatriene1327 Myrcene 6250 0.1 2500 0.057 4386 NTP (2004b,c)2 Myrcene1338 3,7-Dimethyl-1,3,6-octatriene 6250 0.001 250,000 0.024 10417 NTP (2004b,c)2 Myrcene1343 Farnesene (a and b) 6250 0.0007 357,143 0.15 1667 NTP (2004b,c)2 Myrcene1344 1-Methyl-1,3-cyclohexadiene 300 0.005 60,000 0.013 23,077 NTP (1990)3 d-Limonene1326 d-Limonene 300 0.7 429 1.93 155 NTP (1990)3 d-Limonene1331 Terpinolene 300 0.01 30,000 0.077 3896 NTP (1990)3 d-Limonene1339 para-Mentha-1,3-diene 300 0.002 150,000 0.063 4762 NTP (1990)3 d-Limonene1340 para-Mentha-l,4-diene 300 0.02 15,000 0.052 5769 NTP (1990)3 d-Limonene1328 a-Phellandrene 300 0.007 42,857 0.56 536 NTP (1990)3 d-Limonene1336 Bisabolene 300 0.0002 1,500,000 0.003 100,000 NTP (1990)3 d-Limonene1342 d-3-Carene 300 0.0007 428,571 0.13 2308 NTP (1990)3 d-Limonene1329 a-Pinene 300 0.04 7500 0.13 2308 NTP (1990)3 d-Limonene1330 b-Pinene 300 0.03 10,000 0.11 2727 NTP (1990)3 d-Limonene1323 Camphene 250b 0.0005 500,000 0.11 2273 Hoechst (1991)4 Camphene1346 Cadinene 300 8.00 · 10�7 375,000,000 N/A N/A NTP (1990)3 d-Limonene1337 Valencene 300 0.001 300,000 0.0052 57692 NTP (1990)3 d-Limonene1324 b-Caryophyllene 300 0.008 37,500 0.17 1765 NTP (1990)3 d-Limonene1347 Guaiene 300 0.00005 6,000,000 N/A N/A NTP (1990)3 d-Limonene1345 b-Bourbonene 300 0.000003 100,000,000 N/A N/A NTP (1990)3 d-Limonene

N/A = Not available.Species, route of exposure, study duration, dose levels tested: 1rat, diet, 14 days, 2 mg/kg bw/day (Shapiro, 1988); 2rat/mouse, gavage, 13 weeks, 250, 500,1000, 2000, or 4000 mg/kg bw/day (NTP, 2004b,c); 3rat, gavage, 103 weeks, 75/300 or 150/600 (M/F) mg/kg bw/day (NTP, 1990); 4rat, oral, 28 days,250 mg/kg bw/day (female NOEL) (Hoechst, 1991).




dietary rat study (Umeda et al., 2002). Suitable NOELs forthe calculation of margins of safety also were identified for4-methylbiphenyl (Posternak et al., 1975) and para,a-dim-ethylstyrene (Posternak et al., 1969) in the JECFA report.


substances. Since JECFA�s evaluation of this group of fla-vouring agents, an additional 6-month, multiple dose levelstudy (Wolf et al., 1956) was identified for a structurallyrelated substance, cumene, which has not been previouslyevaluated by JECFA, but for which a NOEL of 154 mg/kg body weight/day was determined. Hence, the NOELfor cumene was considered to be appropriate for the calcu-lation of the margin of safety for para-cymene in the pres-ent study.

The margin of safety for 1-methylnaphthalene, the onlyremaining flavouring substance in this group for which aNOEL was not available, was calculated using the NOELidentified for the structurally similar compound 4-meth-ylbiphenyl. The results of the comparison of the estimatedintakes with NOELs for this group of flavouring agents arepresented in Table 26.

3.5.4. Aliphatic, linear a,b-unsaturated aldehydes, acidsand related alcohols, acetals and esters

3.5.4.1. Parent compound NOELs. Even though the evalua-tion of all compounds in this group by the Committee pro-

ceeded in the absence of toxicity data, toxicity studies wereavailable in the JECFA report for ethyl acrylate and 2-hex-enal. For ethyl acrylate several studies were reviewed.Although a NOEL could not be established for ethyl acry-late on the basis of mouse and rat long-term NTP gavagestudies in which toxicologically significant effects werereported at the lowest dose level of 100 mg/kg bodyweight/day, a NOEL of 75 mg/kg body weight/day wasdetermined for ethyl acrylate on the basis of a 730-day oraltoxicity dog study (Borzelleca et al., 1964). Furthermore, inanother study, higher NOELs of 170 and 120 mg/kg bodyweight/day were observed in male and female rats, respec-tively, administered ethyl acrylate in drinking water (Borz-elleca et al., 1964).

For 2-hexenal, a NOEL of 80 mg/kg body weight/daywas established based on the results of a dietary rat study(Gaunt et al., 1971a).


substances. Margins of safety for trans-2-hexenoic acid, thealcohols 2-hexen-1-ol and (Z)-2-hexen-1-ol and theirrelated esters, as well as for the structurally related com-pounds trans-2-heptenal and the acid, (E)-2-heptenoic acid,were calculated based on the NOEL for 2-hexenal. Marginsof safety for the remaining compounds evaluated in thisgroup of flavouring agents were calculated on the basisof the NOELs selected by Munro and Kennepohl (2001)

Table 26Aromatic hydrocarbons—comparison of intake estimates to NOEL

JECFA no. Flavouring substance NOEL(mg/kgbw/day)


Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1325 para-Cymene 154 0.02 7700 0.081 1901 Wolf et al. (1956)1 Cumene1333 para,a-Dimethylstyrene 0.6b 0.0004 1500 0.0057 105 Posternak et al. (1969)2 para,a-Dimethylstyrene1332 Biphenyl 25 0.00001 2,500,000 0.0029 8621 Umeda et al. (2002)3 Biphenyl1334 4-Methylbiphenyl 9b 0.000001 9,000,000 0.011 818 Posternak et al. (1975)4 4-Methylbiphenyl1335 1-Methylnaphthalene 9b 0.00002 450,000 0.0011 8182 Posternak et al. (1975)4 4-Methylbiphenyl

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 6 months, 154, 462, or 769 mg/kg bw/day (Wolf et al., 1956); 2rat, diet, 13weeks, 0.6 mg/kg bw/day (Posternak et al., 1969); 3rat, diet, 105 weeks, 25, 75, or 225 mg/kg bw/day (Umeda et al., 2002); 4rat, diet, 90 days, 9 mg/kg bw/day (Posternak et al., 1975).




for the structurally related compounds 10-undecenoic acid(Newell et al., 1949) and cis-3-hexen-1-ol (Gaunt et al.,1969).

Table 27 presents the calculated margins of safety for allcompounds in this group of flavouring agents.

3.5.5. Monocyclic and bicyclic secondary alcohols, ketones

and related esters3.5.5.1. Parent compound NOELs. In this group of flavour-ing substance, appropriate NOELs were available forisobornyl acetate (Gaunt et al., 1971b), 3-methyl-1-cyclo-pentadecanone (You et al., 1997), and nootkatone (Joneset al., 2004); however, neither these nor any other membersof this group were evaluated by the Committee based ontoxicity data. Additionally, several short-term (14–91day) studies also were identified for 3-l-menthoxypro-pane-1,2-diol. The most conservative NOEL of 30 mg/kg body weight/day was selected for the calculation of themargin of safety for the diol based on the results of a 91-day-long rat study (Wolf, 1992). For d-camphor, a 56-day oral toxicity study was conducted with Sage oil withan estimated d-camphor content of 30% (Skramlik, 1959),which served as the NOEL basis for the calculation ofthe margin of safety.


substances. Although studies were identified for borneol,these were short-term studies performed only at single-doselevels, at which, in some cases, adverse effects werereported. Therefore, the NOEL for the ester isobornylacetate (Gaunt et al., 1971b), which is expected to hydro-lyze to the alcohol, was selected as a more appropriateNOEL basis for borneol. The NOEL for isobornyl acetatealso was considered to be appropriate for the calculation ofthe margins of safety for the structurally related compoundisoborneol, and related esters.

No animal toxicity studies were available for methyljasmonate; however, a NOEL was available for the struc-turally related compound isophorone (Bucher et al., 1986;NTP, 1986) (see Section 3.3.5), which was considered to

be appropriate for the calculation of the margin of safetyfor methyl jasmonate.

The NOEL of 375 mg/kg body weight/day for menthol(NCI, 1979) as selected by Munro and Kennepohl (2001)also was considered to be appropriate for the calculationof the margins of safety for several structurally related com-pounds in this group for which NOELs were not available.Likewise, the respective NOELs determined as appropriatefor the calculation of the margins of safety for a- and b-ionone (Ford et al., 1983) in the study by Munro and Ken-nepohl (2001), were selected as representative NOELs forthe a- and b-ionone-related ester compounds. The marginof safety for 3-methyl-2-(n-pentanyl)-2-cyclopenten-1-onewas calculated on the basis of the NOEL selected for thestructurally related compound 3-ethyl-2-hydroxy-cyclopen-tene-1-one (King et al., 1979) by Munro and Kennepohl(2001). Margins of safety for the alcohols 2(10)-pinen-3-oland verbenol were calculated using the NOEL establishedfor the structurally related terpene hydrocarbon d-limonene(NTP, 1990; see Section 3.5.2). The NOEL for d-camphoralso was considered to be an appropriate NOEL basis fora number of structurally related compounds in this groupof flavouring agents. The margins of safety for the remain-ing compounds in this group were calculated based on theNOELs selected for nootkatone and 3-methyl-1-cyclopen-tadecanone. The results for this group of flavouring sub-stances of the comparison of the intake estimates withNOELs are presented in Table 28.

3.5.6. Tetrahydrofuran and furanone derivatives

3.5.6.1. Parent compound NOELs. NOELs determined to beappropriate for the calculation of the margins of safety wereavailable for tetrahydrofurfuryl alcohol (Arts and Lina,2003), 4-hydroxy-2,5-dimethyl-3(2H)-furanone (Kelly andBolte, 2003), 2-(3-phenylpropyl)tetrahydrofuran (Posternaket al., 1969), 2-hexyl-4-acetoxytetrahydrofuran (Rabino-wicz, 1963), 2-methyltetrahydrofuran-3-one (Shellenberger,1970d), 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone (Coxand Re, 1978), and 4-acetoxy-2,5-dimethyl-3(2H)furanone(Drummond, 1993) in this congeneric group of flavouring

Table 27Aliphatic, linear a,b-unsaturated aldehydes, acids and related alcohols, acetals and esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1348 Butyl 2-decenoate 2500b 0.000005 500,000,000 0.21 11,905 Newell et al. (1949)1 10-Undecenoic acid1349 2-Decenal 2500b 0.0001 25,000,000 0.085 29,412 Newell et al. (1949)1 10-Undecenoic acid1350 2-Dodecenal 2500b 0.0003 8,333,333 0.013 192,308 Newell et al. (1949)1 10-Undecenoic acid1351 Ethyl acrylate 75b 0.00003 2,500,000 0.043 1744 Borzelleca et al. (1964)2 Ethyl acrylate1352 Ethyl 2-nonynoate 2500b 0.00002 125,000,000 0.0046 543,478 Newell et al. (1949)1 10-Undecenoic acid1353 2-Hexenal 80 0.01 8000 0.027 2963 Gaunt et al. (1971a)3 2-Hexenal1354 2-Hexen-1-ol 80 0.007 11,429 0.077 1039 Gaunt et al. (1971a)3 2-Hexenal1355 (E)-2-Hexen-1-yl acetate 80 0.003 26,667 0.025 3200 Gaunt et al. (1971a)3 2-Hexenal1356 Methyl 2-nonynoate 2500b 0.0004 6,250,000 0.0091 274,725 Newell et al. (1949)1 10-Undecenoic acid1357 Methyl 2-octynoate 130b 0.0006 216,667 0.025 5200 Gaunt et al. (1969)4 cis-3-Hexen-1-ol1358 Methyl 2-undecynoate 2500b 7.00 · 10�7 3,571,428,571 0.07 35,714 Newell et al. (1949)1 10-Undecenoic acid1359 2-Tridecenal 2500b 0.00001 250,000,000 0.0037 675,676 Newell et al. (1949)1 10-Undecenoic acid1360 trans-2-Heptenal 80 0.0005 160,000 0.0059 13,559 Gaunt et al. (1971a)3 2-Hexenal1361 trans-2-Hexenoic acid 80 0.0006 133,333 0.045 1778 Gaunt et al. (1971a)3 2-Hexenal1362 2-Nonenal 2500b 0.00003 83,333,333 0.011 227,273 Newell et al. (1949)1 10-Undecenoic acid1363 2-Octenal 130b 0.00007 1,857,143 0.01 13,000 Gaunt et al. (1969)4 cis-3-Hexen-1-ol1364 2-Pentenal 130b 0.00002 6,500,000 0.022 5909 Gaunt et al. (1969)4 cis-3-Hexen-1-ol1365 trans-2-Nonen-1-ol 2500b 0.000002 1,250,000,000 0.00065 3,846,154 Newell et al. (1949)1 10-Undecenoic acid1366 2-Undecenal 2500b 0.000007 357,142,857 8.33 · 10�5 30,012,005 Newell et al. (1949)1 10-Undecenoic acid1367 trans-2-Octen-

1-yl acetate130b 0.00001 13,000,000 8.33 · 10�5 1,560,624 Gaunt et al. (1969)4 cis-3-Hexen-1-ol

1368 trans-1-Octen-1-yl butanoate

130b 0.00001 13,000,000 3.33 · 10�5 3,903,904 Gaunt et al. (1969)4 cis-3-Hexen-1-ol

1369 cis-2-Nonen-1-ol 2500b 0.00003 83,333,333 6.67 · 10�5 37,481,259 Newell et al. (1949)1 10-Undecenoic acid1370 (E)-2-Octen-1-ol 130b 0.000003 43,333,333 0.00017 764,706 Gaunt et al. (1969)4 cis-3-Hexen-1-ol1371 (E)-2-Butenoic acid 2500b 0.0001 25,000,000 0.019 131,579 Newell et al. (1949)1 10-Undecenoic acid1372 (E)-2-Decenoic acid 2500b 0.00007 35,714,286 0.016 156,250 Newell et al. (1949)1 10-Undecenoic acid1373 (E)-2-Heptenoic acid 80 0.00007 1,142,857 0.0047 17,021 Gaunt et al. (1971a)3 2-Hexenal1374 (Z)-2-Hexen-1-ol 80 0.0002 400,000 0.077 1039 Gaunt et al. (1971a)3 2-Hexenal1375 trans-2-Hexenyl butyrate 80 0.00007 1,142,857 0.036 2222 Gaunt et al. (1971a)3 2-Hexenal1376 (E)-2-Hexenyl formate 80 0.0001 800,000 0.025 3200 Gaunt et al. (1971a)3 2-Hexenal1377 trans-2-Hexenyl

isovalerate80 0.00007 1,142,857 0.025 3200 Gaunt et al. (1971a)3 2-Hexenal

1378 trans-2-Hexenylpropionate

80 0.00007 1,142,857 0.025 3200 Gaunt et al. (1971a)3 2-Hexenal

1379 trans-2-Hexenylpentanoate

80 0.00007 1,142,857 0.025 3200 Gaunt et al. (1971a)3 2-Hexenal

1380 (E)-2-Nonenoic acid 2500b 0.00005 50,000,000 0.0088 284,091 Newell et al. (1949)1 10-Undecenoic acid1381 (E)-2-Hexenyl hexanoate 130b 0.000002 65,000,000 0.00083 156,627 Gaunt et al. (1969)4 cis-3-Hexen-1-ol1382 (Z)-3- and (E)-2-

Hexenyl propionate130b 0.00001 13,000,000 0.12 1083 Gaunt et al. (1969)4 cis-3-Hexen-1-ol

1383 (E)-2-Hexenaldiethyl acetal

80 0.000005 16,000,000 0.0017 47,059 Gaunt et al. (1971a)3 2-Hexenal

1384 2-Undecen-1-ol 2500b 0.000008 312,500,000 0.0012 2,083,333 Newell et al. (1949)1 10-Undecenoic acid

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 8 weeks, 500, 1000, or 2500 mg/kg bw/day (Newell et al., 1949); 2dog, capules, 2years, 0.75, 7.5, or 75 mg/kg bw/day (Borzelleca et al., 1964); 3rat, gavage, 91 days, 13, 32, 80, or 200 mg/kg bw/day (Gaunt et al., 1971a); 4rat, drinkingwater, 98 days, 130/170 (M/F) mg/kg bw/day (Gaunt et al., 1969).




substances. The NOEL used to calculate the margin of safetyfor 4-hydroxy-2,5-dimethyl-3(2H)-furanone (Kelly andBolte, 2003), the only compound in this group requiring tox-icity data for JECFA�s evaluation, also was selected as thebasis for the safety evaluation by the Committee. In the caseof 4-hydroxy-5-methyl-3(2H)-furanone the NOEL wasestablished based on the results of a dietary rat study in

which the compound was provided as part of a mixture offlavouring substances (Munday and Kirkby, 1973).


substances. The NOEL determined for linalyl cinnamate(Hagan et al., 1967) (see Section 3.1.1) was consideredappropriate as a NOEL basis for the structurally related

Table 28Monocyclic and bicyclic secondary alcohols, ketones and related esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1385 Borneol 15 0.003 5000 0.017 882 Gaunt et al. (1971b)1 Isobornyl acetate1386 Isoborneol 15 0.0004 37,500 0.052 288 Gaunt et al. (1971b)1 Isobornyl acetate1387 Bornyl acetate 15 0.0004 37,500 0.021 714 Gaunt et al. (1971b)1 Isobornyl acetate1388 Isobornyl acetate 15 0.02 750 0.026 577 Gaunt et al. (1971b)1 Isobornyl acetate1389 Bornyl formate 15 0.00002 750,000 0.019 789 Gaunt et al. (1971b)1 Isobornyl acetate1390 Isobornyl formate 15 0.00001 1,500,000 0.012 1250 Gaunt et al. (1971b)1 Isobornyl acetate1391 Isobornyl propionate 15 0.00005 300,000 0.0035 4286 Gaunt et al. (1971b)1 Isobornyl acetate1392 Bornyl valerate 15 0.00008 187,500 0.025 600 Gaunt et al. (1971b)1 Isobornyl acetate1393 endo-Bornyl isovalerate 15 0.000008 1,875,000 0.016 938 Gaunt et al. (1971b)1 Isobornyl acetate1394 Isobornyl isovalerate 15 0.000001 15,000,000 0.01 1500 Gaunt et al. (1971b)1 Isobornyl acetate1395 d-Camphor 75 0.007 10,714 0.045 1667 Skramlik (1959)2 d-Camphor1396 d-Fenchone 75 0.0001 750,000 0.028 2679 Skramlik (1959)2 d-Camphor1397 Fenchyl alcohol 75 0.001 75,000 0.0089 8427 Skramlik (1959)2 d-Camphor1398 Nootkatone 10b 0.003 3333 0.026 385 Jones et al. (2004)3 Nootkatone1399 1,3,3-Trimethyl-

2-norbonanyl acetate75 0.00005 1,500,000 0.00073 102,740 Skramlik (1959)2 d-Camphor

1400 Methyl jasmonate 250 0.0005 500,000 0.0011 227,273 Bucher et al. (1986);NTP (1986)4

Isophorone

1401 Cycloheptadeca-9-en-1-one 20b 0.000005 4,000,000 7.33 · 10�5 272,851 You et al. (1997)5 3-Methyl-1-cyclopentadecanone

1402 3-Methyl-1-cyclopentadecanone

20b 0.000007 2,857,143 7.83 · 10�5 255,428 You et al. (1997)5 3-Methyl-1-cyclopentadecanone

1403 2(10)-Pinen-3-ol 300 2.00 · 10�7 1,500,000,000 0.0048 62,500 NTP (1990)6 d-Limonene1404 Verbenol 300 0.000005 60,000,000 0.0048 62,500 NTP (1990)6 d-Limonene1405 7-Methyl-4,4a,5,6-tetrahydro-

2(3H)-naphthalenone10b 7.00 · 10�7 14,285,714 0.00067 14,925 Jones et al. (2004)3 Nootkatone

1406 3-Methyl-2-(n-pentanyl)-2-cyc1openten-1-one

400b 0.000007 57,142,857 0.0035 114,286 King et al. (1979)7 3-Ethyl-2-hydroxy-2-cyc1openten-1-one

1407 Dihydronootkatone 10b 0.00002 500,000 0.0067 1493 Jones et al. (2004)3 Nootkatone1408 3-l-Menthoxypropane-1,2-diol 30 0.01 3000 0.88 34 Wolf (1992)8 3-l-Menthoxy-

propane-1,2-diol1409 b-Ionyl acetate 10 0.0002 50,000 0.00067 14,925 Ford et al. (1983)9 b-Ionone1410 a-Isomethyllionyl acetate 10 0.0002 50,000 0.00067 14,925 Ford et al. (1983)9 a-Ionone1411 3-(l-Menthoxy)-2-

methylpropane-1,2-diol30 0.001 30,000 1.43 21 Wolf (1992)8 3-l-Menthoxy-

propane-1,2-diol1412 Bornyl butyrate 15 0.0002 75,000 0.0073 2055 Gaunt et al. (1971b)1 Isobornyl acetate1413 d,l-Mentho1-(±)-propylene

glycol carbonate375b 0.002 187,500 0.97 387 NCI (1979)10 Menthol

1414 l-Monomenthyl glutarate 375b 0.002 187,500 0.15 2500 NCI (1979)10 Menthol1415 l-Menthyl methyl ether 375b 0.0009 416,667 0.15 2500 NCI (1979)10 Menthol1416 para-Menthane-3,8-dio1 375b 0.0003 1,250,000 0.047 7979 NCI (1979)10 Menthol

Species, route of exposure, study duration, dose levels tested: 1rat, gavage, 91 days, 15, 90, or 270 mg/kg bw/day (Gaunt et al., 1971b); 2rat, oral, 8 weeks,250(75), 500(150), 1000(300), or 1200(360) mg/kg bw/day sage oil (30% camphor) (Skramlik, 1959); 3rat, gavage, 28 days, 10 mg/kg bw/day (Jones et al.,2004); 4mouse, gavage, 730 days, 250 or 500 mg/kg bw/day (Bucher et al., 1986; NTP, 1986); 5dog, oral, 4 weeks, 0.2, 2.0, or 20 mg/kg bw/day (Youet al., 1997); 6rat, gavage, 103 weeks, 75/300, or 150/600 (M/F) mg/kg bw/day (NTP, 1990); 7rat, diet, 91 days, 100, 200, or 400 mg/kg bw/day (King et al.,1979); 8rat, diet, 91 days, 30, 200, or 1000 mg/kg bw/day (Wolf, 1992); 9rat, diet, 90 days, 10 or 100 mg/kg bw/day (Ford et al., 1983); 10rat, diet, 103weeks, 187.5 or 375 mg/kg bw/day (NCI, 1979).




compound linalool oxide. For esters of tetrahydrofurfurylalcohol, margins of safety were calculated based on theNOEL established for the alcohol. For all remainingcompounds, margins of safety were calculated based onNOELs available for structurally related compounds inthis group of flavouring agents. The results of the compar-ison of the intake estimates with the selected NOELs areprovided in Table 29.

3.5.7. Phenyl-substituted aliphatic alcohols and related

aldehydes and esters

3.5.7.1. Parent compound NOELs. Although none of theevaluations of any of the compounds in this group offlavouring agents required toxicity data, suitable NOELswere presented in the JECFA monograph for 2-phenylpro-pionaldehyde (Pelling et al., 1976) and b-methylphenethylalcohol (Gaunt et al., 1982).

Table 29Tetrahydrofuran and furanone derivatives—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1440 2-Hexyl-4-acetoxytetrahydrofuran 4.5b 0.00001 450,000 0.001 4500 Rabinowicz (1963)1 2-Hexyl-4-acetoxytetrahydrofuran1441 2-(3-Phenylpropyl)tetrahydrofuran 43b 0.00001 4,300,000 0.0025 17,200 Posternak et al. (1969)2 2-(3-Phenylpropyl)tetrahydrofuran1442 Tetrahydrofurfuryl acetate 60 0.0001 600,000 0.022 2727 Arts and Lina (2003)3 Tetrahydrofurfuryl alcohol1443 Tetrahydrofurfuryl alcohol 60 0.0006 100,000 0.0036 16,667 Arts and Lina (2003)3 Tetrahydrofurfuryl alcohol1444 Tetrahydrofurfuryl butyrate 60 0.000003 20,000,000 0.037 1622 Arts and Lina (2003)3 Tetrahydrofurfuryl alcohol1445 Tertahydrofurfuryl propionate 60 0.00008 750,000 0.015 4000 Arts and Lina (2003)3 Tetrahydrofurfuryl alcohol1446 4-Hydroxy-2,5-dimethyl-3(2H)-furanone 200 0.09 2222 0.062 3226 Kelly and Bolte (2003)4 4-Hydroxy-2,5-dimethyl-3(2H)-furanone1447 Tetrahydrofurfuryl cinnamate 60 2.00 · 10�7 300,000,000 0.015 4000 Arts and Lina (2003)3 Tetrahydrofurfuryl alcohol1448 2-Methyltetrahydrofuran-3-one 91b 0.0004 227,500 0.013 7000 Shellenberger (1970d)5 2-Methyltetrahydrofuran-3-one1449 2-Ethyl-4-hydroxy-5-methyl-3(2H)-furanone 1.43b 0.004 358 0.0055 260 Cox and Re (1978)6 2-Ethyl-4-hydroxy-5-methyl-3(2H)-furanone1450 4-Hydroxy-5-methyl-3(2H)-furanone 146b 0.0009 162,222 0.025 5840 Munday and Kirkby (1973)7 4-Hydroxy-5-methyl-3(2H)-furanone1451 2,5-Dimethyl-4-methoxy-3(2H)-furanone 146b 0.0002 730,000 0.013 11,231 Munday and Kirkby (1973)7 4-Hydroxy-5-methyl-3(2H)-furanone1452 2,2-Dimethyl-5-(1-methylpropen-

1-yl)tetrahydrofuran43b 0.0002 215,000 0.00009 477,778 Posternak et al. (1969)2 2-(3-Phenylpropyl)tetrahydrofuran

1453 2,5-Diethyltetrahydrofuran 43b 0.000002 21,500,000 0.012 3583 Posternak et al. (1969)2 2-(3-Phenylpropyl)tetrahydrofuran1454 Linalool oxide 500a 0.001 500,000 0.018 27,778 Hagan et al. (1967)8 Linalyl cinnamate1455 5-Isopropenyl-2-methyl-2-vinyltetrahydrofuran 43b 0.00002 2,150,000 0.00006 716,667 Posternak et al. (1969)2 2-(3-Phenylpropyl)tetrahydrofuran1456 4-Acetoxy-2,5-dimethyl-3(2H)furanone 18b 0.0001 180,000 0.016 1125 Drummond (1993)9 4-Acetoxy-2,5-dimethyl-3(2H)furanone1457 (±)-2-(5-Methyl-5-vinyltetrahydrofuran-2-

yl) propionaldehyde43b 0.00002 2,150,000 0.031 1387 Posternak et al. (1969)2 2-(3-Phenylpropyl)tetrahydrofuran

Species, route of exposure, study duration, dose levels tested: 1rat, diet, 90 days, 4.5/5.3 (M/F) mg/kg bw/day (Rabinowicz, 1963); 2rat, diet, 90 days, 43/49 (M/F) mg/kg bw/day (Posternak et al., 1969);3rat, diet, 28 days, 60, 600, or 3000 mg/kg bw/day (Arts and Lina, 2003); 4rat, diet, 730 days, 100, 200, or 400 mg/kg bw/day (Kelly and Bolte, 2003); 5rat, diet, 91 days, 92/91 (M/F) mg/kg bw/day(Shellenberger, 1970d); 6rat, diet, 93 days, 1.43 mg/kg bw/day (Cox and Re, 1978); 7rat, diet, 365 days, 146 mg/kg bw/day (Munday and Kirkby, 1973); 8rat, diet, 17 weeks, 50, 120, or 500 mg/kg bw/day(Hagan et al., 1967); 9rat, diet, 14 days, 18 mg/kg bw/day (Drummond, 1993).



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substances. For 5-methyl-2-phenyl-2-hexenal and 4-methyl-2-phenyl-2-pentenal the NOEL for the structurallyrelated compound 2-hexenal (Gaunt et al., 1971a) (seeSection 3.5.4) was considered to be appropriate as theNOEL basis for the calculation of their respective marginsof safety. For 2-phenylpropionaldehyde dimethyl acetal,2-(para-tolyl)propionaldehyde, 3-methyl-2-phenylbutyral-dehyde, 2-phenyl-2-butenal, and 2-phenyl-4-pentenal,margins of safety were calculated based on the NOELdetermined for the structurally related compound, 2-phe-nylpropionaldehyde. For all other compounds including2-methyl-3-tolylpropionaldehyde (ortho, meta, and para)and 2-methyl-4-phenylbutyraldehyde for which onlyshort-term single-dose level 90-day studies were available,the margins of safety were based on the NOEL for thestructurally related compound phenethyl alcohol basedon the results of a longer-term (i.e., 54 week) single-doselevel study (see Section 3.2.2). Table 30 provides a sum-mary of the margins of safety calculated for this groupof flavouring agents.

4. Discussion

Between 2000 and 2004, a total of 822 flavouring agentsbelonging to one of 30 congeneric groups were consideredat the annual JECFA meetings. Due to uncertainty regard-ing the use of 13 of these substances as flavouring agents,only 809 substances were actually evaluated by JECFA.These 809 substances were considered by JECFA not topresent a safety concern at the reported intake levels result-ing from their use as flavouring agents. Based on the �Pro-cedure for the Safety Evaluation of Flavouring Agents�adopted by JECFA (1998), toxicity data were requiredfor a relatively small portion of the flavouring agents.The majority of the evaluations proceeded on the basis ofmetabolism to innocuous substances and thus relied onthe threshold of toxicological concern level determinedfor each structural class of flavouring agent to assess thesafety of the flavouring agent at the reported intake levels.To determine whether this procedure correctly detects thepotential for a safety concern, the present study was under-taken as an extension of a previous study conducted byMunro and Kennepohl (2001), in which NOELs wereselected for the first 592 flavouring agents evaluated byJECFA and compared to the estimated daily per capitaintakes for these agents. The present study also includeda comparison of the margins of safety calculated basedon estimated intake values derived using the MSDIapproach (i.e., per capita intake values), with margins ofsafety calculated on the basis of PADI values. As notedin Table 31, PADI values were calculated for a total of805 flavouring substances. For the 4 flavouring substancescadinene, guaiene, b-bourbonene, and ethanoic acid, S-(2-methyl-3-furanyl) ester, PADIs were not calculated; how-ever, MSDI values were reported to be in the range of0.0000008–0.00005 mg/kg body weight/day indicating that

these four flavouring agents are very low-poundagesubstances.

Traditionally, a safety factor of 100, comprising a 10-fold factor accounting for interspecies variability andanother 10-fold factor representative of the range in thesensitivity within the human population, is considered topresent an adequate margin of safety and therefore supportthe safety of a chemical (WHO, 1987). Table 31 presentsthe ranges of the margins of safety based on the MSDIand PADI estimates of intake for the flavouring agents,and the cumulative percent of the flavouring agents fallinginto each range. For a few compounds the calculation ofthe margin of safety was based on a NOEL derived onthe basis of only a 14-day toxicity study; however, in mostcases the margins of safety for these compounds were atleast 1000. For three substances (i.e., 2,4,6-trimethyldihy-dro-4H-1,3,5-dithiazine, 6,10-dimethyl-5,9-undecadien-2-one, and sclareolide) the margins of safety as calculatedbased on 14-day study NOELs were below 1000, butgreater than 100. In all three cases the NOELs were derivedfrom a study in which no adverse effects were observed atthe highest dose level tested. Consequently, the marginsof safety calculated using these NOELs are considered tobe the minimum values available for these flavouringsubstances.

Based on the highest MSDI value available for eachcompound, a margin of safety of less than 100 existed foronly one of the 809 evaluated flavouring agents (i.e., methylsalicylate). For the remainder of the flavouring substances,a margin of safety of greater than 100 was calculated.Moreover, 99% of the flavouring agents considered had amargin of safety of greater than 1000. Based on the mostrecent US annual production volume of methyl salicylateand on the assumption that only 10% of the populationare �eaters� of the flavouring agent, the margin of safetyfor methyl salicylate was below 100; however, as notedby JECFA, a margin of safety of greater than 100 wasobtained when the intake estimate was based on the mea-sured portion of �eaters� of methyl salicylate, which actuallycomprise approximately 50% of the US population(JECFA, 2002). Moreover, all of the nine flavouringsubstances for which margins of safety in the range of101–1000 were determined [i.e., cinnamaldehyde, benzalde-hyde, vanillin, ethyl vanillin, thiamine hydrochloride,citral, d-limonene, isobornyl acetate, and 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone], are expected to be effi-ciently metabolized to innocuous products, thus furtherensuring that their use as flavouring substances is notexpected to be a safety concern. Generally, these resultsobtained following calculation of the margins of safetyon the basis of MSDI values closely parallel those reportedin the former study in which 98% of the first 592 JECFA-evaluated flavouring agents had a margin of safety ofgreater than 1000 and only a single compound was identi-fied with a margin of safety below 100.

The margins of safety were recalculated using PADI val-ues as the basis for the intake estimates, which approximate

Table 30Phenyl-substituted aliphatic alcohols and related aldehydes and esters—comparison of intake estimates to NOEL

JECFAno.



Intake(mg/kgbw/day)

Marginof safety

Intake(mg/kgbw/day)

Marginof safety

1458 Ethyl 4-phenylbutyrate 120b 2.00 · 10�7 600,000,000 0.022 5455 Johannsen and Purchase (1969)1 Phenethyl alcohol1459 b-Menthylphenethyl alcohol 10 0.000002 5,000,000 0.0005 20,000 Gaunt et al. (1982)2 b-Methylphenethyl alcohol1460 2-Methyl-4-phenyl-2-butyl acetate 120b 0.000007 17,142,857 0.00083 144,578 Johannsen and Purchase (1969)1 Phenethyl alcohol1461 2-Methyl-4-phenyl-2-butyl isobutyrate 120b 0.00003 4,000,000 0.32 375 Johannsen and Purchase (1969)1 Phenethyl alcohol1462 2-Methyl-4-phenylbutyraldehyde 120b 0.000007 17,142,857 0.04 3000 Johannsen and Purchase (1969)1 Phenethyl alcohol1463 3-Methyl-2-phenylbutyraldehyde 10 0.000001 10,000,000 0.033 303 Pelling et al. (1976)3 2-Phenylpropionaldehyde1464 Methyl 4-phenylbutyrate 120b 2.00 · 10�7 600,000,000 0.049 2449 Johannsen and Purchase (1969)1 Phenethyl alcohol1465 2-Methyl-3-(p-isopropylphenyl)

propionaldehyde120b 0.006 20,000 0.034 3529 Johannsen and Purchase (1969)1 Phenethyl alcohol

1466 2-Methyl-3-tolylpropionaldehyde(ortho, meta, and para)

120b 0.0004 300,000 0.011 10,909 Johannsen and Purchase (1969)1 Phenethyl alcohol

1467 2-Phenylpropionaldehyde 10 0.002 5000 0.015 667 Pelling et al. (1976)3 2-Phenylpropionaldehyde1468 2-Phenylpropionaldehyde

dimethyl acetal10 0.00008 125,000 0.095 105 Pelling et al. (1976)3 2-Phenylpropionaldehyde

1469 2-Phenylpropyl butyrate 120b 0.000008 15,000,000 0.061 1967 Johannsen and Purchase (1969)1 Phenethyl alcohol1470 2-Phenylpropyl isobutyrate 120b 0.00003 4,000,000 0.056 2143 Johannsen and Purchase (1969)1 Phenethyl alcohol1471 2-(para-Tolyl)propionaldehyde 10 7.00 · 10�7 14,285,714 0.005 2000 Pelling et al. (1976)3 2-Phenylpropionaldehyde1472 5-Methyl-2-phenyl-2-hexenal 80 0.0003 266,667 0.03 2667 Gaunt et al. (1971a)4 2-Hexenal1473 4-Methyl-2-phenyl-2-pentenal 80 0.00008 1,000,000 0.022 3636 Gaunt et al. (1971a)4 2-Hexenal1474 2-Phenyl-2-butenal 10 0.00003 333,333 0.026 385 Pelling et al. (1976)3 2-Phenylpropionaldehyde1475 Ethyl 2-ethyl-3-phenylpropanoate 120b 0.00002 6,000,000 0.0086 13,953 Johannsen and Purchase (1969)1 Phenethyl alcohol1476 2-Phenyl-4-pentenal 10 7.00 · 10�7 14,285,714 0.0016 6250 Pelling et al. (1976)3 2-Phenylpropionaldehyde1477 2-Methyl-4-phenyl-2-butanol 120b 0.00007 1,714,286 0.049 2449 Johannsen and Purchase (1969)1 Phenethyl alcohol1478 2-Oxo-3-phenylpropionic acid

and 2-Oxo-3-phenylpropionic acid sodium salt120b 0.000002 60,000,000 0.0028 42,857 Johannsen and Purchase (1969)1 Phenethyl alcohol

Species, route of exposure, study duration, dose levels tested: 1rat, drinking water, 56 weeks, 120 mg/kg bw/day (Johannsen and Purchase, 1969); 2rat, diet, 91 days, 10, 40, or 160 mg/kg bw/day (Gauntet al., 1982); 3rat, gavage, 105 days, 10, 50, or 500 mg/kg bw/day (Pelling et al., 1976); 4rat, gavage, 91 days, 13, 32, 80, or 200 mg/kg bw/day (Gaunt et al., 1971a).



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Table 31Margin of safety ranges for JECFA-evaluated flavouring substances based on the MSDI and PADI methods of estimating intake of flavouring substances

Margin of safety MSDI PADI

No. of flavouring substances Cumulative percent (%) No. of flavouring substances Cumulative percent (%)

100,000,001+ 84 10 2 0.210,000,001–100,000,000 121 25 4 0.71,000,001–10,000,000 200 50 18 3100,001–1,000,000 216 77 67 1110,001–100,000 125 92 186 341001–10,000 52 99 343 77101–1000 9a 99.9 169 9811–100 1b 100 13c 99.6Less than 11 0 – 3d 100Total 808e 805f

a Includes cinnamaldehyde, benzaldehyde, vanillin, ethyl vanillin, thiamine hydrochloride, citral, d-limonene, isobornyl acetate, and 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone.

b Methyl salicylate.c Includes 3,4-xylenol, para-vinylphenol, methyl salicylate, thiamine hydrochloride, 4,5-dimethyl-2-ethyl-3-thiazoline, 4-[(2-furanmethyl)thio]-2-penta-

none, 2-(methylthio)ethanol, 2,3,5-trithiahexane, 3-l-menthoxypropane-1,2-diol, 3-l-(menthoxy)-2-methylpropane-1,2-diol, 4-phenyl-2-butyl acetate, (E) &(Z)-4,8-dimethyl-3,7-nonadien-2-one, and 2,3,6-trimethylphenol.

d Includes para-ethylphenol, 2,5-xylenol, and 2,6-xylenol.e One flavouring substances (i.e., acetaldehyde ethyl cis-3-hexenyl acetal) was reported in the poundage surveys to have no exposure and the evaluation

of 13 substances was deferred (808 + 1 + 13 = 822).f PADI values were not calculated for 4 flavouring substances and the evaluation of 13 substances was deferred (805 + 4 + 13 = 822).


intake values obtained using the mTAMDI approachapplied by the European Food Safety Authority in theirevaluation of flavouring substances (EFSA, 2004). By vir-tue of the differences in the methodology used to obtainthe respective intake values (MSDI versus PADI), PADIvalues are typically higher than the corresponding MSDIvalues. Using the same NOEL values as those used to cal-culate the margins of safety based on the MSDI estimates,a total of 16 (2% of the total) compounds were identifiedwith margins of safety of less than 100 when intake esti-mates were based on PADI values. Accordingly, furtheranalysis of these substances is warranted.

Of these 16 compounds with margins of safety below100, six compounds (i.e., para-ethylphenol, 2,5-xylenol,2,6-xylenol, 3,4-xylenol, para-vinylphenol, and 2,3,6-trim-ethylphenol) were considered by JECFA to be structuralclass I substances, for which a threshold of toxicologicalconcern level of 1.8 mg/day has been established (Munroet al., 1996). Moreover, these compounds can be predictedto be metabolized to innocuous products. Since the PADIvalues for these 6 compounds fall below the threshold ofconcern and they are metabolized to innocuous substances,these compounds would not be expected to be of a safetyconcern based on the �Procedure for the Safety Evaluationof Flavouring Agents�. Thus, based on the calculation ofthe margins of safety using PADI values available for805 of the flavouring agents, a total of 10 compounds(1%) [i.e., methyl salicylate, 2-(methylthio)ethanol, 2,3,5-trithiahexane, 3-l-menthoxypropane-1,2-diol, 3-l-(menth-oxy)-2-methylpropane-1,2-diol, 4-phenyl-2-butyl acetate,thiamine hydrochloride, 4,5-dimethyl-2-ethyl-3-thiazoline,4-[(2-furanmethyl)thio]-pentanone, and (E)- & (Z)-4,8-dimethyl-3,7-nonadien-2-one] had margins of safety of less

than 100 and for which, according to the �Procedure for theSafety Evaluation of Flavouring Agents�, additional datawould be required to complete the safety evaluation. Forsix of these substances [i.e., methyl salicylate, 3-l-menth-oxypropane-1,2-diol, 3-l-(menthoxy)-2-methylpropane-1,2-diol, 4-phenyl-2-butyl acetate, thiamine hydrochloride,and (E)- & (Z)-4,8-dimethyl-3,7-nonadien-2-one] JECFAconcluded that they would be metabolized to innocuousproducts; however, according to the �Procedure� all 10flavouring agents would require further toxicologicalevaluation.

It should be noted that based on the conservativeassumptions made in the calculation of PADI values, inmany instances large over-estimates of the actual dailyintakes resulting from the use of these substances as fla-vouring agents are expected. For example, for two of thecompounds with margins of safety below 100, 3-l-menth-oxypropane-1,2-diol and 3-l-(menthoxy)-2-methylpro-pane-1,2-diol, PADI values of 52.7 and 85.4 mg/day werereported, respectively, which are approximately 100- to1000-fold greater than the corresponding MSDI values(i.e., 0.6 and 0.06 mg/day, respectively). Moreover, thePADI values were based on the assumption that these com-pounds are added to two highly consumed foods (i.e., pud-dings and soft drinks) in order to provide a mint flavourand would entirely replace all other menthol and pepper-mint flavours in all foods contained in the correspondingfood categories. It is highly unlikely, given the current pro-duction volumes of other mint flavourings (e.g.,>2,000,000 kg/yr for peppermint oil in the US), that 3-l-menthoxypropane-1, 2-diol and 3-l-(menthoxy)-2-methyl-propane-1,2-diol would become the sole source of mintflavour.


Overall, this comparison of the estimated daily intakesof flavouring agents with NOEL values from animal stud-ies, together with the previous comparison conducted byMunro and Kennepohl (2001), have consistently demon-strated that the majority of the flavouring agents have highmargins of safety and therefore limited toxicological poten-tial. Moreover, in the event that the intake levels as used inthe evaluations conducted by JECFA were underestimated,it is evident from the calculation of the margins of safetyusing PADI values, which are typically several fold greaterthan the corresponding MSDI values, that for all but a fewof the flavouring substances an adequate margin of safetyexists. Following re-calculation of the margins of safetyusing PADI values for 805 of the compounds, 98%possessed margins of safety of greater than 100. Therefore,although the �Procedure for the Safety Evaluation ofFlavouring Agents� does not in every instance requiretoxicological data, but rather relies primarily on struc-ture–activity relationships to assess safety, this study con-firms that on the basis of a more traditional toxicologicalprocess of evaluating chemical safety, the procedurecorrectly evaluated the substances as not presenting a con-cern for safety at current estimates of intake.

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Comparison of Estimated Daily Intakes of Flavouring Substances With No-observed-effect Levels