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        INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

        WORLD HEALTH ORGANIZATION



        SAFETY EVALUATION OF CERTAIN
        FOOD ADDITIVES AND CONTAMINANTS



        WHO FOOD ADDITIVES SERIES 40





        Prepared by:
          The forty-ninth meeting of the Joint FAO/WHO Expert
          Committee on Food Additives (JECFA)



        World Health Organization, Geneva 1998



    ESTERS OF ALIPHATIC ACYCLIC PRIMARY ALCOHOLS WITH ALIPHATIC LINEAR
    SATURATED CARBOXYLIC ACIDS

    First draft prepared by
    Dr J. Gry,
    Institute of Toxicology, National Food Agency of Denmark
    Ministry of Food, Agriculture and Fisheries
    Soborg, Denmark

        1.  Evaluation
            1.1 Introduction
            1.2 Estimated daily  per capita intake
            1.3 Absorption, metabolism and elimination
            1.4 Application of the Procedure for the Safety Evaluation of
                Flavouring Agents
            1.5 Consideration of combined intakes
            1.6 Conclusions
        2.  Relevant background information
            2.1 Explanation
            2.2 Intake data
            2.3 Biological data
                2.3.1   Absorption and metabolism
                2.3.2   Toxicological studies
                    2.3.2.1 Acute toxicity
                    2.3.2.2 Short-term toxicity
                    2.3.2.3 Long-term toxicity
                    2.3.2.4 Genotoxicity
                    2.3.2.5 Reproductive toxicity
                    2.3.2.6 Developmental toxicity
        3.  References

    1.  EVALUATION

    1.1  Introduction

        The Committee evaluated a group of esters of 67 aliphatic linear
    and branched-chain saturated and monounsaturated primary alcohols and
    aliphatic linear saturated carboxylic acids using the Procedure for
    the Safety Evaluation of Flavouring Agents (the "Procedure") (see
    Figure 1 and Table 1).

        One member of the group, butyl acetate, was previously evaluated
    at the eleventh meeting, when the Committee was unable to establish an
    ADI due to a lack of data (Annex 1, reference 14).



        Table 1.  Summary of results of safety evaluations on esters of aliphatic acyclic primary alcohols and aliphatic linear saturated
              carboxylic acids

    Step 1:   2-Ethylbutyl acetate is in structural Class II, the human intake threshold of which is 540 g per day. All of the other
              substances in the group are in structural Class I, the human intake threshold of which is 1800 g per day.
    Step 2:   cis-3-/trans-2-hexenyl propionate is postponed.  All of the other substances in this group are metabolized to innocuous
              products.

                                                                                                                                        
    No.     Substance              Step A3                        Step A4                      Comments                Conclusion based
                                   Does intake exceed the         Endogenous or                                        on current levels
                                   human intake threshold?1       metabolized to                                       of intake
                                   Intake estimates               endogenous
                                   (g/person per day)            substances?
                                                                                                                                        

    0117    Propyl formate                   No                                                                        No safety concern
                                   USA: 0.38   Europe: 5.0
    0118    Butyl formate                    No                                                                        No safety concern
                                   USA: 0.17   Europe: 21
    0119    n-Amyl formate                   No                                                                        No safety concern
                                   USA:  110   Europe:  29
    0120    Hexyl formate                    No                                                                        No safety concern
                                   USA:  8.0   Europe:  8.7
    0121    Heptyl formate                   No                                                                        No safety concern
                                   USA:  0.10  Europe:  0.00
    0122    Octyl formate                    No                                                                        No safety concern
                                   USA:  0.95  Europe:  0.14
    0123    cis-3-Hexenyl formate            No                                                                        No safety concern
                                   USA:  1.7   Europe:  43
    0124    Isobutyl formate                 No                                                                        No safety concern
                                   USA:  1.5   Europe:  4.7
    0125    Methyl acetate                   No                                                                        No safety concern
                                   USA:  110   Europe:  460
    0126    Propyl acetate                   No                                                                        No safety concern
                                   USA:  440   Europe:  180
    0127    Butyl acetate                    No                                                                        No safety concern
                                   USA:  170   Europe:  1200
                                                                                                                                        

    Table 1.  Continued...

                                                                                                                                        
    No.     Substance              Step A3                        Step A4                      Comments                Conclusion based
                                   Does intake exceed the         Endogenous or                                        on current levels
                                   human intake threshold?1       metabolized to                                       of intake
                                   Intake estimates               endogenous
                                   (g/person per day)            substances?
                                                                                                                                        

    0128    Hexyl acetate                   Yes                        Yes         Hexanoic acid, the metabolite       No safety concern
                                   USA:  160   Europe:  3200                       of the component hexyl alcohol,
                                                                                   and acetic acid are endogenous
    0129    Heptyl acetate                   No                                                                        No safety concern
                                   USA:  2.3   Europe:  56
    0130    Octyl acetate                    No                                                                        No safety concern
                                   USA:  9.5   Europe:  83
    0131    Nonyl acetate                    No                                                                        No safety concern
                                   USA:  2.5   Europe:  6.6
    0132    Decyl acetate                    No                                                                        No safety concern
                                   USA:  21    Europe:  7.3
    0133    Lauryl acetate                   No                                                                        No safety concern
                                   USA:  0.57  Europe:  9.3
    0134    cis-3-Hexenyl acetate            No                                                                        No safety concern
                                   USA:  57    Europe:  640
    0135    trans-3-Heptenyl
            acetate                          No                                                                        No safety concern
                                   USA:  0.76  Europe:  0.24
    0136    10-Undecen-1-yl
            acetate                          No                                                                        No safety concern
                                   USA:  0.10  Europe:  0.83
    0137    Isobutyl acetate                 No                                                                        No safety concern
                                   USA:  1300  Europe:  1200
    0138    2-Methylbutyl acetate            No                                                                        No safety concern
                                   USA:  360   Europe:  130
    0140    2-Ethylbutyl acetate             No                                                                        No safety concern
                                   USA:  0.17  Europe:  4.0
    0141    Methyl propionate                No                                                                        No safety concern
                                   USA:  30    Europe:  9.3
                                                                                                                                        

    Table 1.  Continued...

                                                                                                                                        
    No.     Substance              Step A3                        Step A4                      Comments                Conclusion based
                                   Does intake exceed the         Endogenous or                                        on current levels
                                   human intake threshold?1       metabolized to                                       of intake
                                   Intake estimates               endogenous
                                   (g/person per day)            substances?
                                                                                                                                        

    0142    Propyl propionate                No                                                                        No safety concern
                                   USA:  44    Europe:  9.6
    0143    Butyl propionate                 No                                                                        No safety concern
                                   USA:  1.1   Europe:  10
    0144    Hexyl propionate                 No                                                                        No safety concern
                                   USA:  3.0   Europe:  5.7
    0145    Octyl propionate                 No                                                                        No safety concern
                                   USA:  0.02  Europe:  0.00
    0146    Decyl propionate                 No                                                                        No safety concern
                                   USA:  0.95  Europe:  0.00
    0147    cis-3- & trans-2-
            Hexenyl propionate                                                     Postponed, pending consideration
                                   USA:  430   Europe:  0.00                       on alpha, beta-unsaturated
                                                                                   carbonyl compounds2
    0148    Isobutyl propionate              No                                                                        No safety concern
                                   USA:  6.5   Europe:  12
    0149    Methyl butyrate                  No                                                                        No safety concern
                                   USA:  44    Europe:  220
    0150    Propyl butyrate                  No                                                                        No safety concern
                                   USA:  38    Europe:  75
    0151    Butyl butyrate                   No                                                                        No safety concern
                                   USA:  63    Europe:  390
    0152    n-Amyl butyrate                  No                                                                        No safety concern
                                   USA:  200   Europe:  450
    0153    Hexyl butyrate                   No                                                                        No safety concern
                                   USA:  27    Europe:  110
    0154    Heptyl butyrate                  No                                                                        No safety concern
                                   USA:  3.8   Europe:  6.0
    0155    Octyl butyrate                   No                                                                        No safety concern
                                   USA:  0.38  Europe:  16
                                                                                                                                        

    Table 1.  Continued...

                                                                                                                                        
    No.     Substance              Step A3                        Step A4                      Comments                Conclusion based
                                   Does intake exceed the         Endogenous or                                        on current levels
                                   human intake threshold?1       metabolized to                                       of intake
                                   Intake estimates               endogenous
                                   (g/person per day)            substances?
                                                                                                                                        

    0156    Decyl butyrate                   No                                                                        No safety concern
                                   USA:  0.08  Europe:  0.00
    0157    cis-3-Hexenyl butyrate           No                                                                        No safety concern
                                   USA:  4.8   Europe:  160
    0158    Isobutyl butyrate                No                                                                        No safety concern
                                   USA:  7.4   Europe:  47
    0159    Methyl valerate                  No                                                                        No safety concern
                                   USA:  11    Europe:  30
    0160    Butyl valerate                   No                                                                        No safety concern
                                   USA:  0.10  Europe:  3.7
    0161    Propyl hexanoate                 No                                                                        No safety concern
                                   USA:  0.17  Europe:  14
    0162    Butyl hexanoate                  No                                                                        No safety concern
                                   USA:  1.9   Europe:  15
    0163    n-Amyl hexanoate       No                                                                                  No safety concern
                                   USA:  8.8   Europe:  8.7
    0164    Hexyl hexanoate                  No                                                                        No safety concern
                                   USA:  13    Europe:  150
    0165    cis-3-Hexenyl
            hexanoate                        No                                                                        No safety concern
                                   USA:  1.3   Europe:  42
    0166    Isobutyl hexanoate               No                                                                        No safety concern
                                   USA:  1.7   Europe:  6.1
    0167    Methyl heptanoate                No                                                                        No safety concern
                                   USA:  0.10  Europe:  5.7
    0168    Propyl heptanoate                No                                                                        No safety concern
                                   USA:  0.38  Europe:  0.14
    0169    Butyl heptanoate                 No                                                                        No safety concern
                                   USA:  4.4   Europe:  0.00
                                                                                                                                        

    Table 1.  Continued...

                                                                                                                                        
    No.     Substance              Step A3                        Step A4                      Comments                Conclusion based
                                   Does intake exceed the         Endogenous or                                        on current levels
                                   human intake threshold?1       metabolized to                                       of intake
                                   Intake estimates               endogenous
                                   (g/person per day)            substances?
                                                                                                                                        

    0170    n-Amyl heptanoate                No                                                                        No safety concern
                                   USA:  0.02  Europe:  0.61
    0171    Octyl heptanoate                 No                                                                        No safety concern
                                   USA:  0.38  Europe:  0.21
    0172    Isobutyl heptanoate              No                                                                        No safety concern
                                   USA:  1.9   Europe:  0.01
    0173    Methyl octanoate                 No                                                                        No safety concern
                                   USA:  0.17  Europe:  9.7
    0174    n-Amyl octanoate                 No                                                                        No safety concern
                                   USA:  1.9   Europe:  3.4
    0175    Hexyl octanoate                  No                                                                        No safety concern
                                   USA:  0.95  Europe:  1.3
    0176    Heptyl octanoate                 No                                                                        No safety concern
                                   USA:  0.95  Europe:  0.71
    0177    Octyl octanoate                  No                                                                        No safety concern
                                   USA:  2.3   Europe:  0.03
    0178    Nonyl octanoate                  No                                                                        No safety concern
                                   USA:  0.95  Europe:  0.14
    0179    Methyl nonanoate                 No                                                                        No safety concern
                                   USA:  2.3   Europe:  0.86
    0180    Methyl laurate                   No                                                                        No safety concern
                                   USA:  0.76  Europe:  5.1
    0181    Butyl laurate                    No                                                                        No safety concern
                                   USA:  0.10  Europe:  0.00
    0182    Isoamyl laurate                  No                                                                        No safety concern
                                   USA:  0.57  Europe:  0.14
    0183    Methyl myristate                 No                                                                        No safety concern
                                   USA:  46    Europe:  62
    0184    Butyl stearate                   No                                                                        No safety concern
                                   USA:  5.5   Europe:  5.1
                                                                                                                                        
    Table 1.  Continued...

    1  The human intake threshold for Class I is 1800 g per day; 540 g per day for Class II; and 90 g per day for Class III
    2  One of the predicted main metabolites of trans-2-hexenyl propionate is trans-2-hexenol which would be oxidized to the 
    alpha,-unsaturated substance, trans-2-hexenal

    

    1.2  Estimated daily  per capita intake

        The total annual volume of the 67 esters in this group is
    approximately 19 tonnes in the USA and 65 tonnes in Europe. In the USA
    more than 70% of the total annual volume is accounted for by five
    substances, amyl butyrate,  cis-3- &  trans-2-hexenyl propionate,
    and the acetate esters of propyl alcohol, isobutyl alcohol and
    2-methylbutyl alcohol. In Europe, more than 75% of the total annual
    volume is accounted for by seven substances, butyl butyrate, amyl
    butyrate and the acetate esters of methyl alcohol, butyl alcohol,
    hexyl alcohol,  cis-3-hexenol and isobutyl alcohol. Based on the
    reported annual volumes in the USA and Europe, the total estimated
    daily  per capita intakeof the 67 esters of aliphatic acyclic primary
    alcohols and aliphatic linear saturated carboxylic acids used as
    flavouring agents is 3.8 mg  per capita per day in the USA and 9.2 mg
     per capita per day in Europe. The use of 7 of the esters (heptyl
    formate, octyl propionate, decyl propionate, decyl butyrate, butyl
    heptanoate, butyl dodecanoate,  cis-3- &  trans-2-hexenyl
    propionate) has been reported in the USA but not in Europe.

        Esters of aliphatic acyclic primary alcohols and aliphatic linear
    saturated carboxylic acids are principal components of alcoholic
    beverages and a wide variety of fruits. Quantitative data on the
    natural occurrence in food have been reported for 37 substances in the
    group. In the USA, it is indicated that intake of these substances
    from natural sources exceeds intake from their use as flavouring
    agents.

    1.3  Absorption, metabolism and elimination

        In general, aliphatic linear and branched-chain esters of
    aliphatic linear saturated carboxylic acids are anticipated to be
    hydrolysed to their component alcohols and carboxylic acids. The
    metabolism of the saturated acids and alcohols is considered in the
    introduction to this chapter on flavouring agents.

        The three monounsaturated alcohols in this group of esters are all
    anticipated to be oxidized via their corresponding aldehydes to their
    carboxylic acids, which are then metabolized in the fatty acid -
    oxidation and other well-known metabolic pathways.

    1.4  Application of the Procedure for the Safety
    Evaluation of Flavouring Agents

        The stepwise evaluations of the 67 esters of aliphatic acyclic
    primary alcohols and linear saturated aliphatic carboxylic acids used
    as flavouring substances are summarized in Table 1.

        Step 1. The assignment of the structural class is the first step
    in the sequence. All but one of the 67 esters of aliphatic acyclic
    primary alcohols and linear saturated aliphatic carboxylic acids were
    classified in structural Class I. 2-Ethylbutyl acetate contains a
    sterically hindered functional group and therefore is in Class II.

        Step 2. At this step evaluation of one substance,  cis-3- and
     trans-2-hexenyl propionate, was postponed, pending consideration of
    alpha,-unsaturated carbonyl compounds.

        The available data indicate that the esters in this group would be
    hydrolysed in humans to their component alcohols and carboxylic acids.
    The aliphatic acyclic primary alcohols are oxidized to their
    corresponding carboxylic acids, which are either conjugated and
    excreted in the urine, or undergo -oxidation and cleavage. The
    aliphatic linear saturated carboxylic acids are endogenous in humans.
    At current levels of  per capita intake these esters would not be
    expected to saturate the metabolic pathways. Therefore, the response
    to Step 2 for each of the remaining 66 esters of aliphatic acyclic
    primary alcohols and aliphatic linear saturated carboxylic acids is
    "yes".

        Step A3. The human intake threshold for structural Class I is 1800
    g/person per day. Sixty-four (64) of the 65 Class I esters in this
    group have USA and European daily  per capita intake levels  less
    than 1800 g/person per day (see Table 1). Only hexyl acetate has an
    intake greater than 1800 g/person per day. 2-Ethylbutyl acetate is a
    Class II substance for which intake levels in the USA and Europe are
    below the intake threshold of 540 g/person per day.

        Step A4. This step must be considered only for hexyl acetate, the
    only substance in this group with an estimated intake level that
    exceeds the Class I threshold. The component hexyl alcohol is oxidized
    to hexanoic acid which is endogenous as an intermediary metabolite in
    the fatty acid pathway and acetate is a component of the tricarboxylic
    acid cycle. In the opinion of the Committee the endogenous levels of
    these two metabolites would not give rise to perturbations outside the
    physiological range. Therefore, hexyl acetate was also determined to
    be of no safety concern based on its structural class and known
    metabolism.

        Based on results of the safety evaluation sequence, 66 esters of
    aliphatic acyclic primary alcohols and aliphatic linear saturated
    carboxylic acids evaluated do not pose a safety concern when used at
    current levels of intake as flavouring agents. One substance,  cis-3-
    &  trans-2-hexenyl propionate was postponed, pending consideration on
    alpha,-unsaturated carbonyl compounds.

    1.5  Consideration of combined intakes

        In the unlikely event that all foods containing all the 66 esters
    evaluated were consumed simultaneously the estimated daily  per 
     capita intake in the USA and Europe would exceed the human intake
    threshold for substances in class I. All the flavouring agents in this
    group of esters are expected to be metabolized via well known
    biochemical pathways to innocuous metabolic and/or endogenous
    substances and in the opinion of the Committee the endogenous levels
    of these metabolites would not give rise to perturbations outside the

    physiological range. Accordingly, even a combined theoretical intake
    would be of no safety concern.

    1.6  Conclusions

        The Committee concluded that the substances in this group would
    not present safety concerns at the current levels of intake.

        No toxicity data were required for the application of the
    Procedure for this group of esters. The Committee noted that the
    available toxicity data were consistent with the results of the safety
    evaluation using the Procedure.

    2.  RELEVANT BACKGROUND INFORMATION

    2.1  Explanation

        Ten linear saturated primary alcohols in a homologous series from
    C1 to C12 are components of 51 esters in this group of 67 esters
    (see Table 2). Seven esters contain four different aliphatic linear
    unsaturated primary alcohols, five of which include 
     cis-3-hexen-1-ol. The remaining nine esters contain four different
    saturated branched-chain primary alcohols, six of which include
    isobutyl alcohol. Twelve aliphatic linear saturated carboxylic acids
    in a homologous series from C1 to C18 are acid components of the 67
    esters. There is a significant amount of structural uniformity among
    the alcohol and carboxylic acid components of the 67 esters.

        In the USA, the esters of aliphatic acyclic primary alcohols and
    aliphatic linear saturated carboxylic acids are generally used as
    flavouring substances up to average maximum levels of 200 mg/kg.
    Higher levels of use (up to 3000 mg/kg) are permitted in food
    categories such as chewing gum and hard candy. In Europe the upper use
    levels for these flavouring substances are generally 1 to 30 mg/kg
    foods and in special food categories like candy and alcoholic
    beverages up to 300 mg/kg foods (CE, 1992; SCF, 1995).

    2.2  Intake data

        The annual volumes of the 67 esters of this group in Europe (IOFI,
    1995) and in the USA (NAS, 1987) are given in Table 2.

    Table 2.  Most recent reported annual usage in Europe and USA

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    Propyl formate
    USA                   2.0                    0.38     0.01
    Europe                35                     5.0      0.08

    Butyl formate
    USA                   0.9                    0.17     0.00
    Europe                150                    21       0.34

    n-Amyl formate
    USA                   570                    110      1.8
    Europe                200                    29       0.48

    Hexyl formate
    USA                   42                     8.0      0.13
    Europe                61                     8.7      0.15

    Heptyl formate
    USA                   0.5                    0.10     0.00
    Europe                0.0                    0.00     0.00

    Octyl formate
    USA                   5.0                    0.95     0.02
    Europe                1.0                    0.14     0.00

    cis-3-Hexenyl formate
    USA                   9.0                    1.7      0.03
    Europe                300                    43       0.71

    Isobutyl formate
    USA                   8.0                    1.5      0.03
    Europe                33                     4.7      0.08

    Methyl acetate
    USA                   600                    110      1.9
    Europe                3300                   460      7.7

    Propyl acetate
    USA                   2300                   440      7.4
    Europe                1300                   180      3.1

    Butyl acetate
    USA                   870                    170      2.8
    Europe                8400                   1200     20

    Table 2.  Continued...

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    Hexyl acetate
    USA                   840                    160      2.7
    Europe                23000                  3200     54

    Heptyl acetate
    USA                   12                     2.3      0.04
    Europe                390                    56       0.93

    Octyl acetate
    USA                   50                     9.5      0.16
    Europe                590                    83       1.4

    Nonyl acetate
    USA                   13                     2.5      0.04
    Europe                46                     6.6      0.11

    Decyl acetate
    USA                   110                    21       0.35
    Europe                51                     7.3      0.12

    Lauryl acetate
    USA                   3.0                    0.57     0.01
    Europe                65                     9.3      0.15

    cis-3-Hexenyl acetate
    USA                   300                    57       0.95
    Europe                4500                   640      11

    trans-3-Heptenyl
    acetate
    USA                   4.0                    0.76     0.01
    Europe                1.7                    0.24     0.00

    10-Undecen-1-yl
    acetate
    USA                   0.5                    0.10     0.00
    Europe                5.8                    0.83     0.01

    Isobutyl acetate
    USA                   6600                   1300     21
    Europe                8100                   1200     19

    2-Methylbutyl acetate
    USA                   1900                   360      6.0
    Europe                900                    130      2.1

    Table 2.  Continued...

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    2-Ethylbutyl acetate
    USA                   0.9                    0.17     0.00
    Europe                28                     4.0      0.07

    Methyl propionate
    USA                   160                    30       0.51
    Europe                65                     9.3      0.15

    Propyl propionate
    USA                   230                    44       0.73
    Europe                67                     9.6      0.16

    Butyl propionate
    USA                   6.0                    1.1      0.02
    Europe                72                     10       0.17

    Hexyl propionate
    USA                   16                     3.0      0.05
    Europe                40                     5.7      0.10

    Octyl propionate
    USA                   0.1                    0.02     0.00
    Europe                0.0                    0.00     0.00

    Decyl propionate
    USA                   5.0                    0.95     0.02
    Europe                0.0                    0.00     0.00

    cis-3- & trans-2-
    Hexenyl propionate
    USA                   2300                   430      7.2
    Europe                0.0                    0.00     0.00

    Isobutyl propionate
    USA                   34                     6.5      0.11
    Europe                86                     12       0.20

    Methyl butyrate
    USA                   230                    44       0.73
    Europe                1500                   220      3.6

    Propyl butyrate
    USA                   200                    38       0.63
    Europe                520                    75       1.2

    Table 2.  Continued...

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    Butyl butyrate
    USA                   330                    63       1.1
    Europe                2700                   390      6.5

    n-Amyl butyrate
    USA                   1000                   200      3.3
    Europe                3100                   450      7.5

    Hexyl butyrate
    USA                   140                    27       0.44
    Europe                750                    110      1.8

    Heptyl butyrate
    USA                   20                     3.8      0.06
    Europe                42                     6.0      0.10

    Octyl butyrate
    USA                   2.0                    0.38     0.01
    Europe                112                    16       0.27

    Decyl butyrate
    USA                   0.4                    0.08     0.00
    Europe                0.0                    0.00     0.00

    cis-3-Hexenyl
    butyrate
    USA                   25                     4.8      0.08
    Europe                1100                   160      2.7

    Isobutyl butyrate
    USA                   39                     7.4      0.12
    Europe                330                    47       0.78

    Methyl valerate
    USA                   60                     11       0.19
    Europe                210                    30       0.50

    Butyl valerate
    USA                   0.5                    0.10     0.00
    Europe                26                     3.7      0.06

    Propyl hexanoate
    USA                   0.9                    0.17     0.00
    Europe                96                     14       0.23

    Table 2.  Continued...

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    Butyl hexanoate
    USA                   10                     1.9      0.03
    Europe                100                    15       0.24

    n-Amyl hexanoate
    USA                   46                     8.8      0.15
    Europe                61                     8.7      0.15

    Hexyl hexanoate
    USA                   70                     13       0.22
    Europe                1000                   150      2.4

    cis-3-Hexenyl
    hexanoate
    USA                   7.0                    1.3      0.02
    Europe                290                    42       0.69

    Isobutyl hexanoate
    USA                   9.0                    1.7      0.03
    Europe                43                     6.1      0.10

    Methyl heptanoate
    USA                   0.5                    0.10     0.00
    Europe                40                     5.7      0.10

    Propyl heptanoate
    USA                   2.0                    0.38     0.01
    Europe                1.0                    0.14     0.00

    Butyl heptanoate
    USA                   23                     4.4      0.07
    Europe                0.0                    0.00     0.00

    n-Amyl heptanoate
    USA                   0.1                    0.02     0.00
    Europe                4.3                    0.61     0.01


    Octyl heptanoate
    USA                   2.0                    0.38     0.01
    Europe                1.5                    0.21     0.00

    Isobutyl heptanoate
    USA                   10                     1.9      0.03
    Europe                0.1                    0.01     0.0002

    Table 2.  Continued...

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    Methyl octanoate
    USA                   0.9                    0.17     0.003
    Europe                68                     9.7      0.16

    n-Amyl octanoate
    USA                   10                     1.9      0.03
    Europe                24                     3.4      0.06

    Hexyl octanoate
    USA                   5.0                    0.95     0.02
    Europe                9.0                    1.3      0.02

    Heptyl octanoate
    USA                   5.0                    0.95     0.02
    Europe                5.0                    0.71     0.01

    Octyl octanoate
    USA                   12                     2.3      0.04
    Europe                0.2                    0.03     0.00

    Nonyl octanoate
    USA                   5.0                    0.95     0.02
    Europe                1.0                    0.14     0.00

    Methyl nonanoate
    USA                   12                     2.3      0.04
    Europe                6.0                    0.86     0.01

    Methyl laurate
    USA                   4.0                    0.76     0.01
    Europe                36                     5.1      0.09

    Butyl laurate
    USA                   0.5                    0.10     0.00
    Europe                0.0                    0.00     0.00

    Isoamyl laurate
    USA                   3.0                    0.57     0.01
    Europe                1.0                    0.14     0.00

    Methyl myristate
    USA                   240                    46       0.76
    Europe                440                    62       1.0

    Table 2.  Continued...

                                                                        
    Substance                 Most recent          Per capita intake2
                          annual volume1 (kg)    g/day   g/kg bw per day
                                                                        

    Butyl stearate
    USA                   29                     5.5      0.09
    Europe                36                     5.1      0.09

    Total
    USA                   20000                  3800     63
    Europe                65000                  9200     150
                                                                     

    1 USA: National Academy of Science (NAS, 1987) Evaluating the safety
    of food chemicals. Washington DC. Respondants to the annual NAS survey
    were requested to report annual poundages of < 1.0 lbs to two digits
    past the decimal point. Europe: International Organization of the
    Flavor Industry (IOFI; 1995) European inquiry on volume of use.
    Private communication to FEMA.

    2 Intake calculated as follows: [[(annual volume, kg) x (1 x 109
    g/kg)]/[population x 0.6 x 365 days]], where population (10%, "eaters
    only") = 24 x 106 for the USA and 32 x 106 for Europe; 0.6 represents
    the assumption that only 60% of the flavor volume was reported in the
    survey (NAS, 1987; IOFI, 1995). Intake (g/kg bw/d) calculated as
    follows: [(g/d)/body weight], where body weight = 60 kg. Slight
    variations may occur from rounding off.

    2.3  Biological data

    2.3.1  Absorption and metabolism

        Generally, linear and branched-chain alkyl esters are hydrolysed
    to their component alcohols and carboxylic acids in the intestinal
    tract, blood and most tissues throughout the body, as described in the
    introduction to this chapter on flavouring agents. For this group of
    esters this is further supported by a series of  in vitro hydrolysis
    studies on butyl acetate and structurally related esters as reported
    in Table 3.

        Following hydrolysis the component alcohols and carboxylic acids
    are metabolized as considered above (section 1.3) and in the
    introduction to this chapter on flavouring agents.



        Table 3.  Hydrolysis data for esters of aliphatic acyclic primary alcohols with aliphatic linear saturated carboxylic acids

                                                                                                                                        
    Ester                 Artificial         Artificial           Rat liver        Rat small              % Hydrolysis     % Hydrolysis
                          gastric juice1     pancreatic           preparation1     intestinal             after 2 hours    after 4 hours
                          t0.5 (min)         juice1 t0.5 (min)    t0.5 (sec)       mucosa1 t0.5 (sec)
                                                                                                                                        

    Butyl acetate         318                66.0                 491              108                    232, 723         412, 923
    Ethyl acetate8        not reported       not reported         not reported     not reported           1004             not reported
    Ethyl butyrate8       490                5.67                 not reported     not reported           152, 1005        not reported
    Ethyl hexanoate8      293                3.47                 0.1              0.5                    not reported     not reported
    Ethyl heptanoate8     770                9.78                 0.2              0.6                    102, 1003        192
    Ethyl nonanoate8      177                5.92                 not reported     not reported           372, 1005        612
    Ethyl laurate8        640                6.10                 not reported     not reported           122, 1005        232
    Ethyl decanoate8      not reported       not reported         not reported     not reported           806,7            not reported
    Isopropyl butyrate8   not reported       not reported         not reported     not reported           404,6            not reported
    Isoamyl acetate8      not reported       not reported         not reported     not reported           206, 1004        not reported
    Isoamyl butyrate8     660                11.3                 0.5              0.1                    122, 1003        222
    Isoamyl hexanoate8    146                37.8                 not reported     not reported           not reported     not reported
    Allyl hexanoate       1120               1.98                 4.0              0.1                    1007             not reported
    Citronellyl acetate   not reported       not reported         not reported     not reported           1007             not reported
                                                                                                                                        

    1 Longland et al., 1977
    2 In artificial gastric juice. Gangolli & Shilling, 1968
    3 In artificial pancreatic juice. Gangolli & Shilling, 1968
    4 In whole homogenate of pig jejunum. Grundschober, 1977
    5 In artificial pancreatic juice after only 1 hour. Gangolli & Shilling, 1968
    6 By pancreatin. Leegwater & van Straten, 1974
    7 By pancreatin. Grundschober, 1977
    8 Structurally related ester
    

    2.3.2  Toxicological studies

    2.3.2.1  Acute toxicity

        Oral acute toxicity studies have been reported for 51 of the 67
    esters of aliphatic acyclic primary alcohols and aliphatic linear
    saturated carboxylic acids. The very low oral acute toxicity of this
    group of esters is demonstrated by oral LD50 values greater than 1850
    mg/kg bw (e.g., Smyth  et al., 1954).

    2.3.2.2  Short-term toxicity

        Results of short-term toxicity studies for 6 of the 67 esters and
    for some structurally related esters and selected hydrolysis products
    are summarized in Table 4. Available short-term toxicity studies on
    the esters and on some of their component alcohols are described in
    more detail below.

     a) Methyl octanoate

        Methyl octanoate was diluted in cotton-seed oil and incorporated
    into the diet of groups of 15 male and 15 female FDRL rats for 90
    days. The dosage levels were 3.2 and 3.6 mg/kg bw per day for males
    and females, respectively. Observations included food consumption,
    body weight, haematology, blood chemical determinations, liver and
    kidney weights and histological examination. No treatment-related
    adverse effects were reported (Oser et al., 1965).

     b) Methyl butyrate, octanoate and dodecanoate

        In a limited 12-week study with only one dose level, groups of up
    to 10 male and up to 10 female USC strain-rats were given a daily oral
    dose of 100 mg methyl butyrate, methyl octanoate, methyl dodecanoate
    or the structurally-related esters methyl hexanoate, methyl decanoate
    and methyl tetradecanoate as part of a fat-free diet. The study was
    designed to evaluate the influence of aliphatic esters on endogenous
    levels of lipids and cholesterol in rats maintained on fat-free diets.
    A statistically significant decrease in weight gain occurred in males
    treated with methyl octanoate. A statistically significant increase
    was observed in the liver cholesterol level of males given methyl
    laurate, but was not accompanied by an increase in total plasma
    cholesterol when compared with controls. No microscopic examination
    was reported (Alfin-Slater  et al., 1965).

     c) Amyl butyrate, and structurally-related ethyl esters

        Groups of 10 male and 10 female Osborne-Mendel rats were
    maintained on diets containing either amyl butyrate or the
    structurally related esters ethyl formate or ethyl pentanoate at
    concentrations of 1000, 2500 or 10 000 mg/kg (equivalent to 50, 250 or
    500 mg/kg bw per day) for 16-17 weeks. Additionally,



        Table 4.  Short-term toxicity studies for esters of aliphatic acyclic primary alcohols with aliphatic linear saturated
    carboxylic acids and structurally-related substances

                                                                                                                            
    Substance                Species, sex      Route       Time        NOEL1                  Reference
                                                           (days)      (mg/kg bw per day)
                                                                                                                            
    Ethyl formate            Rat, m & f        Oral        119         >500                   Hagan et al., 1967
    Ethyl acetate2           Rat, m & f        Oral        371-392     >43                    Johannsen & Purchase, 1969
    Butyl acetate            Rat               Oral        180         >0.5                   Petrovskaya & Bul'bin, 1969
    Octyl acetate            Rat, m & f        Gavage      91 weeks    >10004                 Daughtrey et al., 1989a
    Methyl butyrate          Rat, m & f        Oral        84          >3003,5                Alfin-Slater et al., 1965
    Amyl butyrate            Rat               Oral        112         >500                   Hagan et al., 1967
    Ethyl pentanoate2        Rat, m & f        Oral        119         >500                   Hagan et al., 1967
    Methyl hexanoate2        Rat, m & f        Oral        84          >3003,5                Alfin-Slater et al., 1965
    Ethyl heptanoate2        Rat, m & f        Oral        90          >500                   Hagan et al., 1967
    Methyl octanoate         Rat, m & f        Oral        84          >300                   Alfin-Slater et al., 1965
    Methyl octanoate         Rat, m & f        Oral        90          >3.63                  Oser et al., 1965
    Ethyl nonanoate2         Rat, m & f        Oral        112         >500                   Hagan et al., 1967
    Ethyl nonanoate2         Rat, m & f        Oral        112         >10003                 FDA, 1954
    Methyl decanoate2        Rat, m & f        Oral        84          >3003,5                Alfin-Slater et al., 1965
    Methyl laurate           Rat, m & f        Oral        84          >3003,5                Alfin-Slater et al., 1965
    Methyl myristate2        Rat, m & f        Oral        84          >300                   Alfin-Slater et al., 1965
    Isobutyl isobutyrate2    Rats, m & f       Gavage      126         >1000                  Drake et al., 1978
    3-Methylbutyl alcohol2   Rat, m & f        Gavage      119          >1000                 Carpanini et al., 1973
    2-Methyl-1-propanol2     Rat, m & f        Oral        90          >1450                  BASF, 1992
    Hexyl alcohol2           Rat, m & f        Oral        90          5776                   Eibert, 1992
    cis-3-Hexenol2           Rat, m & f        Oral        98          120-150                Gaunt et al., 1969
                                                                                                                            
    1 A NOEL reported in this table as "greater than" (>) indicates that no adverse effects were observed at the highest dose
    level in the study, and therefore an actual NOEL was not obtained.
    2 A structurally related substance to the group
    3 Only one dose level
    4 Increased liver weights in high-dose (1000 mg/kg bw) and intermediate-dose (500 mg/kg bw) groups and mild nephropathy
    in the high-dose males were judged by the authors to be of minimal toxicological significance.
    5 No histopathology reported
    6 No statistical analysis of data
    7 Only 2 males and 2 females per dose.
    

    ethyl heptanoate was tested at concentrations of 1000 and 10 000 mg/kg
    diet for 13 weeks, and ethyl nonanoate was tested for 16 weeks at 10
    000 mg/kg diet in groups of 5 males and 5 females. There were no
    effects on growth or haematology in any of the groups, and no
    macroscopic abnormalities at any dose level. Microscopic examination
    was performed on tissues from the 10 000 mg/kg groups which revealed
    no changes (Hagan et al., 1967).

     d) Butyl acetate

        Butyl acetate was orally administered to 40 white rats at dose
    levels of 0, 0.005, 0.05 and 0.5 mg/kg bw per day for six months.
    Animals in the control group, and eight animals in the high-dose group
    underwent pathomorphological examination at the end of the study. No
    changes in the internal organs of the animals were reported
    (Petrovskaya & Bul'bin, 1969).

     e) Octyl acetate

        Groups of 20 male and 20 female Sprague-Dawley rats received
    undiluted octyl acetate by gavage at doses of 100, 500 or 1000 mg/kg
    bw per day, 5 days per week, for 13 weeks. Control rats received
    distilled water at a dose of 1000 mg/kg bw per day. After 45 days of
    dosing, five animals per group were sacrificed and necropsied. There
    were no statistically significant differences in mean haematology
    values between the test and control animals. Serum chemistry values
    showed no evidence of any treatment-related effects. Gross necropsy
    showed no indication of any significant treatment-related effects.

        After 13 weeks, the remaining animals were sacrificed and
    necropsied. Body weights were slightly lower for high-dose male and
    female rats as compared to controls, but were generally not
    statistically significant. This was therefore considered by the
    authors to be a borderline treatment-related effect. Similarly, mean
    food consumption values for high-dose males and females were slightly
    lower than controls but, in general, were not statistically
    significant. This finding paralleled the changes in body weight.

        In the high-dose group, there was an increase in the relative
    liver and kidney weights in males and females. An increase in the
    relative liver weight was also evident in the mid-dose group in both
    sexes. All other organ weights were normal. The increased liver
    weights of rats were not associated with liver pathology or
    hepatotoxicity as reflected by microscopic examination and serum
    enzyme parameters, respectively. The authors attributed the effect to
    a compensatory response of the liver to an increased metabolic load
    from the exogenous octyl acetate and not a reflection of true
    hepatotoxicity. This type of compensatory response to exogenous
    substances was reported previously by Golberg (Golberg, 1966). The
    increased liver weights in the high-dose and intermediate-dose animals
    were judged by the authors to be of minimal toxicological
    significance.

        Mild tubular nephropathy was reported in the kidneys of high-dose
    males only. The specific findings consisted of increased incidence of
    dilated renal tubules in the cortical-medullary zone, containing
    granular casts and regenerative hyper-plasia in proximal convoluted
    tubules. This effect has been observed with aliphatic hydrocarbons in
    male rats and has been found to be associated with a minimal change in
    kidney function (Alden  et al., 1984; Halder  et al., 1984; Phillips
    & Cockrell, 1984; Phillips & Egan, 1984a,b). Therefore, the finding of
    nephropathy in the high-dose group of male rats was not believed by
    the authors to have significant toxicological implications for humans
    (Daughtrey  et al., 1989a).

     f) Hexyl alcohol

        Two groups of 10 male and 10 female rats were fed hexyl alcohol
    for 13 weeks at dietary levels of 0.25 or 0.50%; a third group was fed
    1% for weeks 1-10 and 2%, 4% and 6% for weeks 11, 12 and 13,
    respectively. Decreased food consumption was observed in females at
    the high-dose level, but body weights for all animals were normal. No
    significant haematological changes or differences in urine analyses
    were observed for the test or control groups. Gross pathology and
    microscopic evaluation were performed and revealed no
    treatment-related effects. The 1% level was reported to be equivalent
    to an intake of 577 mg/kg bw per day (Eibert, 1992).

        Three groups of 2 male and 2 female pure bred beagle dogs were fed
    hexyl alcohol for 13 weeks at levels of 0.5%, 1% or 1000 mg/kg bw per
    day (high-dose group) via gelatin capsules. A fourth group of 4 males
    and 4 females served as controls. Body weight, organ weight and food
    consumption for the treated animals did not differ from controls. All
    animals in the high-dose group displayed gross signs of toxicity
    intermittently after treatment, including salivation, excitation,
    ataxia, tremors and anaesthesia. The animals generally returned to
    normal within 4 hours of treatment. One female dog in the high-dose
    group died on the first day of treatment and was replaced by another
    female. Three of the four remaining animals in the high-dose group
    died during the study. No signs of toxicity were observed in the other
    test animals. Haematology, serum chemistry and urinalysis showed no
    significant difference as compared to controls. Animals in the
    high-dose group exhibited gastrointestinal inflammation and congestion
    of other visceral organs. Some gastric irritation was observed in the
    mid-dose group. Both males treated at the 1000 mg/kg bw per day level
    exhibited significant testicular atrophy. Effects on the testes and
    other reproductive tissue have been observed with other aliphatic
    alcohols at high-dose levels (Lington & Bevan, 1994). A finding of
    nodules on the lung surface of some animals was reported to be non-
    treatment-related. The NOEL was 1% in the diet, equal to 230 to 695
    mg/kg bw per day (Eibert, 1992).

     g) cis-3-Hexenol

        Groups of 15 male and 15 female weaning rats were given
    drinking-water containing 0, 310, 1250 or 5000 mg/litre

     cis-3-hexenol for 98 days. A statistically significant reduction in
    water intake was reported in male rats in the high-dose group only.
    Tissues from all rats in the high-dose group and from 50% of the
    controls were examined microscopically. Statistically significant
    increases in relative kidney and adrenal gland weights were observed
    in males only at the 5000 mg/litre level, but were not accompanied by
    any evidence of histopathology. No other treatment-related
    abnormalities were reported. The NOEL was 1250 mg/litre, which
    corresponds to an intake level of 150 mg/kg bw per day (Gaunt  et 
     al., 1969).

     h) 2-Methyl-1-propanol (isobutyl alcohol)

        Groups of 10 male and 10 female Wistar rats were given 2-methyl-1-
    propanol in their drinking-water for 3 months. The test substance was
    administered at concentrations of 0, 1000, 4000 or 16 000 mg/kg diet,
    which was reported to correspond to approximate dose levels of 0, 60,
    340 or 1450 mg/kg bw per day.

        Food and drinking-water consumption, body weight gain, haematology
    and clinical chemistry parameters revealed no treatment-related
    adverse effects. Gross pathology and histopathological examinations
    were normal. The authors concluded that results of this study
    demonstrated a lack of toxicity associated with administra-tion of 2-
    methyl-1-propanol in the drinking-water of rats, and that the NOEL was
    1450 mg/kg bw per day the top dose (BASF, 1992).

     i) 3-Methylbutyl alcohol (isoamyl alcohol)

        3-Methylbutyl alcohol was administered to groups of 15 male and 15
    female Ash/CSE rats in corn oil by gavage, providing daily dose levels
    of 0, 150, 500 or 1000 mg/kg bw per day for 17 weeks. Examination of
    haematology, serum analyses, urinalysis, renal concentration tests and
    organ weights revealed no treatment-related effects. The animals were
    examined for macroscopic abnormalities, and the major organs were
    weighed. Microscopic examination was performed on the major organs and
    several tissues of the control and high-dose animals. No treatment-
    related abnormalities were observed (Carpanini  et al., 1973).

    2.3.2.3  Long-term toxicity

        Butyl stearate was administered to groups of 16 male rats at
    dietary concentrations of 0.01, 0.05, 0.25, 1.25 or 6.25% for 2 years.
    Two additional groups of male rats were fed a control diet. No adverse
    effects on growth or survival were observed. Haematology studies did
    not reveal any significant changes. At the end of one year, necropsies
    were performed on 3 animals from each group and revealed no
    treatment-related effects. Gross pathology and detailed histopathology
    studies on the control groups, and animals in the 1.25 and 6.25%
    groups (equivalent to 625 and 3125 mg/kg bw per day) revealed no
    treatment-related effects (Smith, 1953).

    2.3.2.4  Genotoxicity

        Genotoxicity studies have been performed  in vitro using the
    following esters of aliphatic acyclic primary alcohols and aliphatic
    linear saturated carboxylic acids: methyl acetate, butyl acetate,
    butyl stearate and the structurally related isoamyl formate (Table 5)
    and demonstrates that these substances are not genotoxic.

        Blood samples from male Swedish industrial workers, 13 of whom
    were exposed to butyl acetate at a median concentration of 12 mg/m3
    and 8 of whom were exposed to methyl acetate at a median concentration
    of 14 mg/m3, were cultured for 72 hours and examined for sister
    chromatid exchanges (SCE). There was no difference in the frequencies
    of SCE between the exposed group and the matched reference group
    (Haglung  et al., 1980).

    2.3.2.5  Reproductive toxicity

     a) Butyl acetate

        In a limited reproductive toxicity study, 48 adult white rats were
    given a 0.1 ml "oil"solution containing 2 mg butyl acetate by gavage
    on alternating days for 8 months. The animals were given total doses
    of 24, 84 and 208 mg prior to the first, second and third generations,
    respectively. The first offspring also received 15 mg before mating.
    The administration of butyl acetate produced no statistically
    significant changes on the number of pregnant females, the number of
    born offspring, the number of viable offspring, the birth weight of
    the offspring, or the weight of the offspring after 7 and 21 days
    (Sporn  et al., 1963).

     b) Butyl stearate

        Groups of 20 male and 20 female rats received diets providing
    6.25% butyl stearate (equivalent to 3125 mg/kg bw per day) for 10
    weeks prior to mating. A group of 12 male and 12 female rats of the
    same age were fed a control diet for 10 weeks prior to mating. No
    adverse effects on fertility, litter size or survival of offspring
    were observed, but significantly reduced growth during preweaning and
    postweaning periods was reported. Litters were weaned 21 days
    post-partum, and their weights determined. Twenty-four male and 24
    female weanlings from each group were fed the test diet for 12 days.
    After 21 days, the rats were sacrificed and necropsied. No gross
    pathological changes were reported (Smith, 1953).

    2.3.2.6  Developmental toxicity

         Octyl acetate

        In a teratogenicity study, groups of pregnant Sprague-Dawley rats
    were given octyl acetate by gavage on gestation days 6-15 providing
    dose levels of 0, 100, 500 or 1000 mg/kg bw per day. Statistically

    significant reductions in body weight gain and food consumption were
    observed in dams in the mid- and high-dose groups. No statistically
    significant effects on embryo-fetal lethality or fetal growth were
    observed for any treatment group. In the high-dose group only, the
    incidence of litters with at least one malformed fetus and the mean
    percentage of the litter malformed was significantly elevated
    (P<0.05). These observations occurred only at a dose level that was
    maternally toxic. The results demonstrate that octyl acetate does not
    exhibit developmental toxicity in rats under the study conditions
    (Daughtrey  et al., 1989b).



        Table 5.  Mutagenicity/genotoxicity studies for esters of saturated aliphatic acyclic primary alcohols with linear aliphatic acyclic acids

                                                                                                                                                
    Substance name    Test system              Test object                    Concentration of             Results      Reference
                      in vitro                                                substance
                                                                                                                                                

    Isoamyl formate   Rec assay                B. subtilis                    up to 18 g/disk             Negative     Oda et al., 1978
                      Rec assay                B. subtilis                    20 l/disk in DMSO           Negative1    Yoo, 1986
                      Chromosomal aberration   Chinese hamster fibroblast     up to 2 mg/ml in DMSO        Negative2    Ishidate et al., 1984
                      test                     cells
                      Ames test                S. typhimurium TA92, TA1535,   up to 10 mg/plate in DMSO    Negative1    Ishidate et al., 1984
                                               TA100, TA1537, TA94, TA98,
                                               TA2637

    Methyl acetate    Ames test                S. typhimurium TA97, TA98,
                                               TA102, TA104, TA1535,TA1538    up to 10 mg/plate            Negative1    Zeiger et al., 1992

    Butyl acetate     Chromosomal aberration   Chinese hamster fibroblast
                      test                     cells                          2 mg/ml in DMSO              Negative2    Ishidate et al., 1984

                      Ames test                S. typhimurium TA97, TA98,
                                               TA102, TA104, TA1535,TA1538    up to 10 mg/plate in DMSO    Negative1    Zeiger et al., 1992

                      Ames test                S. typhimurium TA92, TA94,     up to 10 mg/plate in DMSO    Negative1    Ishidate et al., 1984
                                               TA98, TA100, TA153,TA1535,
                                               TA2637

                      Modified Ames test       S. typhimurium TA98, TA100,    1-5000 g/plate              Negative1    Shimizu et al., 1985
                                               TA1535,TA1537, TA1538
                                               E. coli WP2 uvrA

    Butyl stearate    Reversion assay          TA 97, TA98, TA100, TA102,     100-5000 g/plate in         Negative1    Hachiya, 1987
                                               TA1537, WP2/pKM102             acetone with Tween 80
                                                                                                                                                

    1 Both with and without S-9 activation
    2 Without S-9 activation
    

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    See Also:
       Toxicological Abbreviations