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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION





    SAFETY EVALUATION OF CERTAIN 
    FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES: 42





    Prepared by the Fifty-first meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)





    World Health Organization, Geneva, 1999
    IPCS - International Programme on Chemical Safety

    SATURATED ALIPHATIC ACYCLIC SECONDARY ALCOHOLS, KETONES, AND RELATED 
    SATURATED AND UNSATURATED ESTERS

    First draft prepared by Dr Jrn Gry 
    Institute of Food Safety and Toxicology
    Danish Veterinary and Food Administration, 
    Ministry of Food, Agriculture and Fisheries, 
    Sborg, Denmark


          Evaluation 
                   Introduction 
              Estimated daily  per capita intake 
              Absorption, metabolism, and elimination
              Application of Procedure for the Safety Evaluation 
                   of Flavouring Agents 
              Consideration of combined intakes from use as 
                   flavouring agents 
              Conclusions 
          Relevant background information 
              Explanation 
              Intake 
              Biological data 
                   Absorption, metabolism, and elimination
                        Ester hydrolysis 
                        gamma-Diketone formation 
                        Excretion 
                   Toxicological studies
                        Acute toxicity 
                        Short-term studies of toxicity 
                        Genotoxicity 
                        Other relevant studies 
          References 


    1.  EVALUATION

    1.1  Introduction

         The Committee evaluated 39 saturated aliphatic acyclic secondary
    alcohols, ketones and related saturated and unsaturated esters
    (Table 1) using the Procedure for the Safety Evaluation of Flavouring
    Agents (Figure 1, p. 222, and Annex 1, reference 131). The Committee
    had evaluated five members of this group previously. Acetone was
    evaluated as an extraction solvent at the fourteenth meeting (Annex 1,
    reference 22), when the Committee considered that, with good
    manufacturing practice, the residues in food would be toxicologically
    insignificant. The evaluation was tentative owing to lack of relevant
    data. Isopropyl alcohol was evaluated at the fourteenth and
    twenty-fifth meetings (Annex 1, references 22 and 56); an ADI was not
    allocated because of lack of data. Isopropyl acetate was evaluated at
    the twenty-third meeting (Annex 1, reference 50), when, because of a
    lack of data on hydrolysis and other toxicological end-points, the

    Committee was unable to establish an ADI. Isopropyl myristate,
    evaluated at the twenty-third meeting (Annex 1, reference 50), was not
    allocated an ADI owing to lack of data. 2-Butanone (ethyl methyl
    ketone) was evaluated at the twenty-third and twenty-fifth meetings
    (Annex 1, references 50 and 56), when the Committee concluded that the
    data available were not sufficient for evaluation of the substance,
    and no ADI was allocated.

    1.2  Estimated daily per capita  intake

         The total annual volume of the 39 saturated aliphatic acyclic
    secondary alcohols, ketones, and related esters in this group is
    approximately 750 tonnes in Europe (International Organization of the
    Flavor Industry, 1995) and 240 tonnes in the United States (National
    Academy of Sciences, 1989). In Europe, 92% of the total annual volume
    is accounted for by isopropyl alcohol alone. In the United States, 98%
    of the total annual volume of compounds in this group is accounted for
    by acetone and isopropyl alcohol. On the basis of the reported annual
    volumes, the estimated daily  per capita intake of acetone from use
    as a flavouring agent is approximately 7.1 mg/day in Europe and 35
    mg/day in the United States. Similarly, the total estimated daily
     per capita intake of isopropyl alcohol and its nine esters in this
    group from use as flavouring agents is about 99 mg/day in Europe and
    10 mg/day in the United States.

         Saturated aliphatic acyclic secondary alcohols, ketones, and
    related esters are the main flavouring components of alcoholic
    beverages and a wide variety of fruits (Maarse et al., 1994).
    Quantitative data on natural occurrence have been reported for 22 of
    the 39 substances in this group. In the United States, intake of 20 of
    these 22 substances from natural sources exceeds intake from their use
    as flavouring agents; two of the substances, acetone and 3-octanol,
    have greater use as flavouring agents (Stofberg & Kirschner, 1985;
    Stofberg & Grunschober, 1987).

    1.3  Absorption, metabolism, and elimination

         In general, saturated aliphatic acyclic secondary alcohols, and
    ketones are absorbed through the gastrointestinal tract and rapidly
    eliminated from the blood. Peak blood levels are normally obtained
    within 1-2 h after dosing. Related esters are anticipated to be
    hydrolysed to their component secondary alcohols and aliphatic,
    saturated, and unsaturated carboxylic acids, which are also readily
    absorbed. Isopropyl alcohol and low-molecular-mass ketones such as
    acetone and 2-buta-none are endogenous in humans as components of
    fatty acid and carbohydrate metabolism and have been detected in the
    blood (Krasavage et al., 1982; Morgott, 1993; Lington & Bevan, 1994). 

         Isopropyl esters are believed to be hydrolysed to isopropyl
    alcohol and their respective saturated aliphatic carboxylic acids.
    Hydrolysis is catalysed by classes of enzymes recognized as
    carboxylesterases. In mammals, these enzymes occur in most body
    tissues but predominate in hepatocytes (Heymann, 1980; Anders, 1989). 

         Aliphatic ketones are metabolized primarily  via reduction to
    the corresponding secondary alcohol (Leibman, 1971; Felsted & Bachur,
    1980; Bosron & Li, 1980). Secondary alcohols are metabolized by
    conjugation with glucuronic acid followed by excretion primarily in
    the urine (Neubreuer, 1901). Short-chain aliphatic ketones may also be
    metabolized  via omega- and/or (omega-1)-oxidation, and/or they may
    be excreted unchanged in expired air (Haggard et al., 1945; Scopinaro
    et al., 1947; Saito, 1975; Brown et al., 1987; Schwartz, 1989).
    omega Oxidation and/or (omega-1)-oxidation become competing pathways
    for longer-chain aliphatic ketones at high concentrations (Dietz et
    al., 1981; Topping et al., 1994). 

          An intoxication pathway (i.e. formation of a neurotoxic
    gamma-diketone) has been identified for aliphatic ketones that meet
    special structural requirements (Krasavage et al., 1980; Topping et
    al., 1994). 3-Heptanone is the only substance in this group that may
    be metabolized to a gamma-diketone; however, the threshold for
    activation of this pathway occurs at near-lethal doses (O'Donoghue et
    al., 1984), which are significantly greater than the levels at which
    3-heptanone is used as a flavouring substance. 

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

         The stepwise evaluations of the 39 saturated aliphatic acyclic
    secondary alcohols, ketones, and related esters used as flavouring
    agents are summarized in Table 1.

    Step 1.   Twenty-eight of the 39 saturated aliphatic acyclic secondary
              alcohols, ketones, and related esters are classified in
              structural class I. The remaining 11 substances, acyclic
              aliphatic 2-alkanones (Nos 283, 288, 292, 296, 298, 299, and
              301), 3-alkanones (Nos 285, 290, and 294), and 4-alkanone
              (No. 302) with four or more carbons on either side of the
              keto group, are in structural class II (Cramer et al.,
              1978).

    Step 2.   The available data indicate that 26 of the 28 secondary
              alcohols and ketones would be predicted to be metabolized to
              or are innocuous products  per se. The 11 esters in this
              group are anticipated to be hydrolysed to their component
              secondary alcohols (isopropyl alcohol or 3-octanol) and
              carboxylic acids (aliphatic saturated acids or the
              unsaturated tiglic acid). These hydrolysis products are
              either endogenous or can be predicted to be oxidized to
              innocuous substances. At current levels of  per capita 
              intake, 37 of the 39 flavouring agents in this group would
              not be expected to saturate the metabolic pathways.
              Therefore, 37 of the 39 substances in this group were
              considered to be metabolized to innocuous products. The
              remaining two substances, 3-heptanone (No. 285) and
              3-heptanol (No. 286), may undergo oxidation to neurotoxic
              gamma-diketones, and these two substances therefore proceed
              to step B3.


        Table 1. Summary of results of safety evaluations of saturated aliphatic acyclic secondary alcohols, ketones, and related esters
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    Acetone          139   7100/36 000   I              Yes             Yes              Yes                                 No safety 
                                                                                                                             concern

    CAS No. 67-64-1
    CHEMICAL STRUCTURE

    Isopropyl        277   99 000/9 900  I              Yes             Yes               Yes                                No safety 
    alcohol                                                                                                                  concern

    CAS No. 67-63-0
    CHEMICAL STRUCTURE

    2-Butanone       278   110/36        I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 78-93-3
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    2-Pentanone      279   140/42        I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 107-87-9
    CHEMICAL STRUCTURE

    2-Pentanol       280   6/0.04        I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 6032-29-7
    CHEMICAL STRUCTURE

    3-Hexanone       281   0.4/1         I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 589-38-8
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    3-Hexanol        282   13/11         I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 623-37-0
    CHEMICAL STRUCTURE

    2-Heptanone      283   110/48        II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 110-43-0
    CHEMICAL STRUCTURE

    2-Heptanol       284   8/1           I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 543-49-7
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    3-Heptanone      285   4/10          II             No              No                                 Yes               No safety 
                                                                                                                             concern

    CAS No. 106-35-4
    CHEMICAL STRUCTURE

    3-Heptanol       286   0.2/0.6       I              No              No                                 Yes               No safety 
                                                                                                                             concern

    CAS No. 589-82-2
    CHEMICAL STRUCTURE

    4-Heptanone      287   2/2           I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 123-19-3
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    2-Octanone       288   110/67        II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 111-13-7
    CHEMICAL STRUCTURE

    2-Octanol        289   13/4          I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 123-96-6
    CHEMICAL STRUCTURE

    3-Octanone       290   3/2           II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 106-68-3
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    3-Octanol        291   6/320         I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 589-98-0
    CHEMICAL STRUCTURE

    2-Nonanone       292   380/27        II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 821-55-6
    CHEMICAL STRUCTURE

    2-Nonanol        293   1/1           I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 628-99-9
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    3-Nonanone       294   0.1/0.1       II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 925-78-0
    CHEMICAL STRUCTURE

    3-Decanol        295   N/D/16        I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 1565-81-7
    CHEMICAL STRUCTURE

    2-Undecanone     296   380/21        II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 112-12-9
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    2-Undecanol      297   0.2/0.04      I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 1653-30-1
    CHEMICAL STRUCTURE

    2-Tridecanone    298   73/30         II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 593-08-8
    CHEMICAL STRUCTURE

    2-Pentadecanone  299   21/430        II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 2345-28-0
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    3-Methyl-2-      300   1/0.2         I              Yes             No                                                   No safety 
      butanol                                                                                                                concern

    CAS No. 589-75-4
    CHEMICAL STRUCTURE

    4-Methyl-2-      301   7/2           II             Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 108-10-1
    CHEMICAL STRUCTURE

    2,6-Dimethyl-4-  302   0.2/0.06      II             Yes             No                                                   No safety 
     heptanone                                                                                                               concern

    CAS No. 108-83-8
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    2,6-Dimethyl-4-  303   N/D/5         I              Yes             No                                                   No safety 
     heptanol                                                                                                                concern

    CAS No. 108-82-7
    CHEMICAL STRUCTURE

    Isopropyl        304   0.5/0.02      I              Yes             No                                                   No safety 
     formate                                                                                                                 concern

    CAS No. 625-55-8
    CHEMICAL STRUCTURE

    Isopropyl        305   41/9          I              Yes             No                                                   No safety 
     acetate                                                                                                                 concern

    CAS No. 108-21-4
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    Isoproyl         306   0.01/0.02     I              Yes             No                                                   No safety 
     propionate                                                                                                              concern

    CAS No. 637-78-5
    CHEMICAL STRUCTURE

    Isopropyl        307   7/0.08        I              Yes             No                                                   No safety 
     butyrate                                                                                                                concern

    CAS No. 638-11-9
    CHEMICAL STRUCTURE

    Isopropyl        308   4/0.02        I              Yes             No                                                   No safety  
     hexanoate                                                                                                               concern

    CAS No. 2311-46-8
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    Isopropyl        309   0.6/0.06      I              Yes             No                                                   No safety 
     isobutyrate                                                                                                             concern

    CAS No. 617-50-5
    CHEMICAL STRUCTURE

    IIsopropyl       310   0.3/0.2       I              Yes             No                                                   No safety 
     isovalerate                                                                                                             concern

    CAS No. 32665-23-9
    CHEMICAL STRUCTURE

    sopropyl         311   23/0.02       I              Yes             No                                                   No safety 
     myristate                                                                                                               concern

    CAS No. 110-27-0
    CHEMICAL STRUCTURE

    Table 1. (continued)
                                                                                                                                              
    Substance        No.   Estimated     Step 1         Step 2          Step A3/B3      Step A4            Step B4           Conclusion
                           per capita    Structural     Is the          Does intake     Is the substance   Adequate NOEL     based on
                           intake,       class          substance       exceed human    or its             for the           current levels
                           Europe/USA                   metabolized     intake          metabolites        substance         of intake
                           (g/day)                     to inoccuous    threshold?      endogenous?        or structurally
                                                        products?                                          related 
                                                                                                           substances?
                                                                                                                                              
    Isopropyl        312   0.01/0.1      I              Yes             No                                                   No safety 
     tiglate                                                                                                                 concern

    CAS No. 6284-46-4
    CHEMICAL STRUCTURE

    3-Octyl acetate  313   0.7/30        I              Yes             No                                                   No safety 
                                                                                                                             concern

    CAS No. 4864-61-3
    CHEMICAL STRUCTURE

    1-Ethylhexyl     448   0.01/29       I              Yes             No                                                   No safety 
     tiglate                                                                                                                 concern
    (3-Octyl tiglate)

    CAS No. 94133-92-3
    CHEMICAL STRUCTURE
                                                                                                                                              

    The thresholds for human intake are 1800 g/day for Class I and 540 g/day for Class II.
    N/D, No intake data reported
    

    Step A3.  The daily  per capita intakes of 25 of the 27 class-I
              substances at this step in Europe and the United States are
              below the human intake threshold for class I compounds (1800
              g/person per day), indicating that they pose no safety
              concern when used at current levels of estimated intake as
              flavouring agents. The intakes of acetone (mg/person per
              day) are 7.1 in Europe and 35 in the United States, and the
              intakes of  isopropyl alcohol are 99 in Europe and 10 in the
              United States; these are greater than the human intake
              threshold of 1800 g/person per day (National Academy of
              Sciences, 1989; International Organization of the Flavor
              Industry, 1995). The intakes of 10 class II substances at
              this step in Europe and in the United States are below the
              human intake threshold for that class (540 g/person per
              day), indicating that they pose no safety concern at current
              levels of estimated intake as flavouring agents. 

                   The total intake of isopropyl alcohol and its nine
              esters from use as flavouring agents is also greater than
              the human intake threshold for compounds in class I (1800
              g/person per day). 

                   The intake of three additional esters of isopropyl
              alcohol (isopropyl benzoate, isopropyl cinnamate, and
              isopropyl phenyl-acetate), which were not evaluated as part
              of this group, would add about 15 g/day in Europe and 5
              g/day in the United States to the total intake of isopropyl
              alcohol. This potential additional intake is minor and would
              not alter the safety evaluation.

    Step A4.  This step needs to be considered only for acetone and
              isopropyl alcohol, the two flavouring agents in this group
              for which estimated intake exceeds the class I threshold of
              1800 g/person per day. They are both endogenous, as
              components of fatty acid and carbohydrate metabolism, and
              have been detected in the blood.

    Step B3.  The current  per capita intake of 3-heptanone (No. 285),
              class II, and 3- heptanol (No. 286), class I, do not exceed
              the human intake thresholds, 540 and 1800 g/day,
              respectively. Accordingly the evaluation proceeds to step
              B4.

    Step B4.  On the basis of a limited study of the neurotoxic effects of
              orally administered 3-heptanone (No. 285) to male rats, the
              NOEL was 1000 mg/kg bw per day (O'Donoghue et al., 1984).
              This NOEL provides a large safety margin (> 1 000 000 for
              3-heptanone and even higher for 3-heptanol) in relation to
              current levels of estimated intake of 3-heptanone and
              3-heptanol (No. 286) (which might be metabolized to
              3-heptanone).

         On the basis of the results of the safety evaluation sequence, 28
    of the saturated aliphatic acyclic secondary alcohols and ketones and
    11 of the related esters of saturated and unsaturated carboxylic acids
    evaluated do not pose a safety concern when used at current levels of
    intake as flavouring agents. 

    1.5  Consideration of combined intakes from use as flavouring agents

         In the unlikely event that all 39 saturated aliphatic acyclic
    secondary alcohols, ketones, and related esters of saturated and
    unsaturated carboxylic acids were consumed concomitantly on a daily
    basis, the estimated combined intake would exceed the human thresholds
    for classes I and II. All of the 39 substances except two (3-heptanone
    and 3-heptanol) are expected to be metabolized  via well-known
    biochemical pathways to innocuous metabolic and/or endogenous
    substances; 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. The combined intake of the two
    substances that could potentially form gamma-diketones would also 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.

         Data on toxicity were required only for 3-heptanone (No. 285) and
    3-heptanol (No. 286) when applying the procedure to this group of
    flavouring agents. The Committee noted that these data and others are
    consistent with the results of the safety evaluation using the
    procedure.


    2.  RELEVANT BACKGROUND INFORMATION

    2.1  Explanation

         Twenty-eight saturated aliphatic acyclic ketones and secondary
    alcohols with chain lengths from C3 to C15 (Nos 139 and 277-303) and
    11 related saturated and unsaturated esters (Nos 304-313 and 448) are
    included in this group of flavouring agents (see Table 1). The group
    comprises 16 saturated aliphatic acyclic ketones (10 2-alkanones, four
    3-alkanones, and two 4-alkanones), 12 saturated aliphatic acyclic
    secondary alcohols (seven 2-alkanols, four 3-alkanols, and one
    4-alkanol), nine esters of isopropyl alcohol, and two esters of
    3-octanol in which the component carboxylic acids are six saturated
    and one unsaturated carboxylic acid (tiglic acid). 

         The substances in this group are structurally related because
    they are saturated, aliphatic acyclic ketones, secondary alcohols, or
    esters formed from secondary alcohols and aliphatic, saturated or
    unsaturated carboxylic acids.

    2.2  Intake

         The total annual production and the estimated current  per 
     capita intake in Europe and the United States of the 39 saturated
    aliphatic acyclic secondary alcohols, ketones, and related esters are
    shown in Table 2. 

    2.3  Biological data

    2.3.1  Absorption, metabolism, and elimination

         Generally, saturated aliphatic acyclic secondary alcohols and
    ketones are absorbed through the gastrointestinal tract and rapidly
    eliminated from the blood. The related esters in this group of
    flavouring agents are anticipated to be hydrolysed to their component
    secondary alcohols and aliphatic saturated and unsaturated carboxylic
    acids, which are also readily absorbed, as considered above in section
    1.3 and 'General aspects of metabolism', p. 223. 

         In addition to oxidation and reduction pathways,
    low-molecular-mass ketones (carbon chain length, < C-5) may be
    excreted unchanged in expired air (Brown et al., 1987). In mammals,
    oral doses of volatile ketones or their corresponding alcohols are
    eliminated principally as the ketone in expired air; lesser amounts
    are excreted in the urine (Haggard et al., 1945; Scopinaro et al.,
    1947; Saito, 1975). In rats, 2-pentanone in expired air was the major
    metabolite after administration of 2-penta-nol by intraperitoneal
    injection; lesser amounts of 2-pentanol were exhaled, and both
    metabolites were detected in urine (Haggard et al., 1945). Some of the
    flavouring agents in this group may be oxidized to form neurotoxic
    gamma-diketones (see below).

    2.3.1.1  Ester hydrolysis

         Generally, isopropyl esters are anticipated to be hydrolysed to
    isopropyl alcohol and their component saturated or unsaturated
    aliphatic carboxylic acids (see section 1.3 and 'General aspects of
    metabolism', p. 223). Isopropyl tiglate (No. 312) and the two 3-octyl
    esters (Nos 313 and 448) may be hydrolysed at a lower rate in the
    gastrointestinal tract, but esters that reach the general circulation
    intact will be hydrolysed by tissue esterases to the component
    carboxylic acid and alcohol.

         In general, the ketones and secondary alcohols in this group of
    flavouring agents are metabolized by reversible reduction/oxidation of
    the ketone/alcohol group and/or side-chain oxidation and/or
    conjugation of the alcohol groups, primarily with glucuronic acid (see
    'General aspects of metabolism', p. 222).


        Table 2. Most recent annual usage of saturated aliphatic acyclic secondary alcohols, ketones, 
    and related esters as flavouring substances in Europe and United States

                                                                                                     

    Substance (No.)                    Most recent       Per capita intakeb     Per capita intakec, 
                                       annual volumea                           alcohol equivalents
                                       (kg)              g/day     g/kg bw    (g/kg bw per day)
                                                                    per day
                                                                                                     

    Acetone (139)
      Europe                           50 000            7 100      120         NA
      United States                    190 000           36 000     590         NA

    Isopropyl alcohol (277)
      Europe                           690 000           99 000     1 600       NA
      United States                    52 000            9 900      170         NA

    2-Butanone (278)
      Europe                           790               110        2           NA
      United States                    190               36         0.6         NA

    2-Pentanone (279)
      Europe                           1 000             140        2           NA
      United States                    220               42         0.7         NA

    2-Pentanol (280)
      Europe                           44                6          0.1         NA
      United States                    0.2               0.04       0.0         NA

    3-Hexanone (281)
      Europe                           3                 0.4        0.01        NA
      United States                    5                 1          0.02        NA

    3-Hexanol (282)
      Europe                           94                13         0.22        NA
      United States                    60                11         0.19        NA

    Table 2. (continued)

                                                                                                     

    Substance (No.)                    Most recent       Per capita intakeb     Per capita intakec, 
                                       annual volumea                           alcohol equivalents
                                       (kg)              g/day     g/kg bw    (g/kg bw per day)
                                                                    per day
                                                                                                     

    2-Heptanone (283)
      Europe                           790               110        2           NA
      United States                    250               48         0.11        NA

    2-Heptanol (284)
      Europe                           56                8          0.13        NA
      United States                    5                 1          0.02        NA

    3-Heptanone (285)
      Europe                           27                4          0.06        NA
      United States                    50                10         0.16        NA

    3-Heptanol (286)
      Europe                           1                 0.02       0.0         NA
      United States                    3                 0.6        0.01        NA

    4-Heptanone (287)
      Europe                           16                2          0.04        NA
      United States                    13                2          0.04        NA

    2-Octanone (288)
      Europe                           760               110        2           NA
      United States                    350               67         1           NA

    2-Octanol (289)
      Europe                           94                13         0.22        NA
      United States                    19                4          0.06        NA

    Table 2. (continued)

                                                                                                     

    Substance (No.)                    Most recent       Per capita intakeb     Per capita intakec, 
                                       annual volumea                           alcohol equivalents
                                       (kg)              g/day     g/kg bw    (g/kg bw per day)
                                                                    per day
                                                                                                     

    3-Octanone (290)
      Europe                           23                3          0.05        NA
      United States                    12                2          0.04        NA

    3-Octanol (291)
      Europe                           39                6          0.09        NA
      United States                    1 700             320        5           NA

    2-Nonanone (292)
      Europe                           2 600             380        6           NA
      United States                    140               27         0.44        NA

    2-Nonanol (293)
      Europe                           5                 1          0.01        NA
      United States                    3                 1          0.01        NA

    3-Nonanone (294)
      Europe                           1                 0.1        0.0         NA
      United States                    0.5               0.1        0.0         NA

    3-Decanol (295)
      Europe                           NR                N/D        0           NA
      United States                    82                16         0.26        NA

    2-Undecanone (296)
      Europe                           2 700             380        6           NA
      United States                    110               21         0.35        NA

    2-Undecanol (297)
      Europe                           2                 0.2        0.0         NA
      United States                    0.2               0.04       0.0         NA

    Table 2. (continued)

                                                                                                     

    Substance (No.)                    Most recent       Per capita intakeb     Per capita intakec, 
                                       annual volumea                           alcohol equivalents
                                       (kg)              g/day     g/kg bw    (g/kg bw per day)
                                                                    per day
                                                                                                     

    2-Tridecanone (298)
      Europe                           510               73         1           NA
      United States                    160               30         0.51        NA

    2-Pentadecanone (299)
      Europe                           150               21         0.3         NA
      United States                    2 300             430        7           NA

    3-Methyl-2-butanol (300)
      Europe                           4                 1          0.01        NA
      United States                    0.9               0.2        0.0         NA

    4-Methyl-2-pentanone (301)
      Europe                           50                7          0.12        NA
      United States                    8                 2          0.03        NA

    2,6-Dimethyl-4-heptanone (302)
      Europe                           1.5               0.2        0.0         NA
      United States                    0.3               0.06       0.0         NA

    2,6-Dimethyl-4-heptanol (303)
      Europe                           NR                N/D        0           NA
      United States                    25                5          0.08        NA

    Isopropyl formate (304)
      Europe                           3.7               0.5        0.01        0.01
      United States                    0.1               0.02       0.0         0.00

    Isopropyl acetate (305)
      Europe                           290               41         0.69        0.45
      United States                    46                9          0.15        0.06

    Table 2. (continued)

                                                                                                     

    Substance (No.)                    Most recent       Per capita intakeb     Per capita intakec, 
                                       annual volumea                           alcohol equivalents
                                       (kg)              g/day     g/kg bw    (g/kg bw per day)
                                                                    per day
                                                                                                     

    Isopropyl propionate (306)
      Europe                           0.1               0.01       0.01        0.00
      United States                    0.1               0.02       0.0         0.00

    Isopropyl butyrate (307)
      Europe                           49                7          0.12        0.05
      United States                    0.4               0.08       0.0         0.00

    Isopropyl hexanoate (308)
      Europe                           26                4          0.06        0.03
      United States                    0.1               0.02       0.0         0.00

    Isopropyl isobutyrate (309)
      Europe                           4                 0.6        0.01        0.01
      United States                    0.3               0.06       0.0         0.00

    Isopropyl isovalerate (310)
      Europe                           2                 0.3        0.01        0.00
      United States                    0.9               0.2        0.0         0.00

    Isopropyl myristate (311)
      Europe                           160               23         0.38        0.10
      United States                    0.1               0.02       0.0         0.00

    Isopropyl tiglate (312)
      Europe                           0.1               0.01       0.0         0.00
      United States                    0.5               0.1        0.0         0.00

    3-Octyl acetate (313)
      Europe                           5                 0.7        0.01        0.00
      United States                    160               30         0.51        0.20

    Table 2. (continued)

                                                                                                     

    Substance (No.)                    Most recent       Per capita intakeb     Per capita intakec, 
                                       annual volumea                           alcohol equivalents
                                       (kg)              g/day     g/kg bw    (g/kg bw per day)
                                                                    per day
                                                                                                     

    3-Octyl tiglate (448)
      Europe                           0.1               0.01       0.0         0.00
      United States                    150               29         0.48        0.30

    TOTAL
      Europe                           750 000           NA         NA          NA
      United States                    240 000           NA         NA          NA

    TOTAL Isopropyl alcohol
      Europe                           NA                99 000     1  600
      United States                    NA                10 000     170
                                                                                                     

    NA, not applicable; NR, not reported
    a Europe, International Organization of the Flavor Industry (1995); United States, 
      National Academy of Sciences (1989)
    b Intake (g/day) calculated as follows: 
      [(annual volume, kg)  (1  109 g/kg)]/[population  0.6  365 days], where 
      population (10% 'eaters only') = 32  106 for Europe and 24  106 for the United 
      States; 0.6 represents the assumption that only 60% of the flavour volume was 
      reported in the survey.
      Intake (g/kg bw per day) calculated as follows: [(g/day)/body weight], where body 
      weight = 60 kg. Slight variations may occur due to rounding off.
    c Calculated as follows: (molecular mass alcohol/molecular mass ester)  daily 
      per capita intake ester
    

    2.3.1.2  gamma-Diketone formation

         Oxidation, primarily (omega-1)-oxidation, of certain aliphatic
    ketones may yield gamma-diketones (e.g. 2-hexanone and 3-heptanone may
    yield 2,5-hexanedione and 2,5-heptanedione, respectively), which, when
    administered at high concentrations to experimental animals, may
    result in peripheral neuropathy, commonly recognized as 'giant' axonal
    neuropathy (Krasavage et al., 1980; Topping et al., 1994). The
    structural features of diketone metabolites that induce peripheral
    neuropathy have been shown to include gamma-diketone spacing.
    gamma-Diketones with terminal methyl substituents (e.g.
    2,5-hexanedione) and/or methyl substituents at the 3 and 4 positions
    have the most pronounced effects. The severity of the peripheral
    neuropathy depends on the size and position of alkyl substituents on
    the gamma-diketone. For example, the strongest neurotoxic effects have
    been observed with 3,4-dimethyl-substituted 2,5-hexanedione (not a
    flavouring substance). When the chain length is increased (i.e. C-7
    and greater), the neurotoxic response is generally significantly
    reduced (Topping et al., 1994). 

         3-Heptanone and 3-heptanol (Nos 285 and 286) are the only
    compounds in this group of flavouring substances that may be
    metabolized to yield a neurotoxic gamma-diketone (Topping et al.,
    1994); however, the longer chain length of 3-heptanone reduces its
    neurotoxic effect , which is observed only at high doses.

         In a poorly described study of the neurotoxic effects of some
    aliphatic ketones, 3-heptanone administered to female Wistar rats in
    the drinking-water for 120 days did not produce significant
    neurological alterations (Homan & Maronpot, 1978). 

         Groups of five male Crl rats were exposed to atmospheres
    containing 700 mg/kg 3-heptanone for two 20- and two 16-h periods per
    week, for a total of 88 exposures over 164 days (approximately
    24 weeks). After the fourth, thirtieth, and eighty-fifth exposures,
    serum was analysed for 2,5-heptanedione. The maximum mean serum
    concentrations reached 10 g/ml after four exposures but decreased to
    6-7 g/ml after 30 and 85 exposures. No neurotoxicity was observed
    (Katz et al., 1980). 

         Groups of two Crl rats were given 250, 500, 1000, 2000, or
    4000 mg/kg bw 3-heptanone by gavage on five days per week for
    14 weeks. No peripheral neuropathy was observed at doses
    < 1000 mg/kg bw. At 2000 mg/kg bw, approaching the LD50 in rats
    (2760 mg/kg bw), 3-heptanone induced peripheral neuropathy (O'Donoghue
    et al., 1984).

    2.3.1.3  Excretion

         In studies limited to the identification of urinary glucuronide
    metabolites, a series of aliphatic secondary alcohols was administered
    by stomach tube to rabbits, and the urinary excretion of glucuronic
    acid conjugates was determined after 24 h. The compounds, doses, and
    average urinary output of glucuronide are listed in Table 3. The

    results show that secondary alcohols, either administered directly or
    formed  via ketone reduction as demonstrated in one case with
    2-heptanone (41 % urinary glucuronide), are largely excreted as
    glucuronic acid conjugates (Kamil et al., 1953).

    Table 3. Urinary excretion of glucuronides after 
    administration of aliphatic secondary alcohols to 
    rabbits by gavage

                                                               

    Substance        No.        Dose          Urinary 
                                (mg/kg bw)a   glucuronide (%)
                                                               

    2-Propanol       277        1002          10.2
    2-Butanol        -          618           14.4
    2-Pentanol       280        735           44.8
    2-Heptanol       284        965           54.6
    3-Heptanol       286        965           61.9
    4-Heptanol       -          965           67.4
    2-Octanol        289        1081          15.5
                                                               

    From Kamil et al. (1953)
    a Calculated from dose of 25 mmol/3-kg rabbit (for 
      2-propanol, 50 mmol/3 kg)


         Generally, secondary alcohols (and ketones, by reduction to
    secondary alcohols) are excreted after their conjugation with
    glucuronic acid, primarily in the urine, or in the bile, depending on
    the relative molecular mass and the animal species (see 'General
    aspects of metabolism', p. 222). After hydrolysis of the esters in
    this group, see above, the component secondary alcohols are
    metabolized and excreted, and the component acids are metabolized in
    the fatty acid -oxidation and other well-known metabolic pathways.

    2.3.2  Toxicological studies

    2.3.2.1  Acute toxicity

         Oral LD50 values have been reported for 25 of the 39 substances
    in this group and range from 400 to 9800 mg/kg bw. The vast majority
    of the values are > 1000 mg/kg bw, demonstrating that the acute
    toxicity of saturated aliphatic acyclic secondary alcohols, ketones,
    and related esters given orally is extremely low (see e.g. Tanii et
    al., 1986).

    2.3.2.2  Short-term studies of toxicity

         The results of short-term studies with six saturated aliphatic
    acyclic secondary alcohols and ketones are summarized in Table 4 and
    described below, together with some further studies. There were no
    adequate studies available on the related esters. 

     Acetone

         In a 14-day study, groups of five male and five female Fischer
    344/N rats were given drinking-water  ad libitum containing acetone
    at concentrations of 0, 5000, 10 000, 20 000, 50 000, or 100 000 mg/kg
    (equivalent to 0, 500, 1000, 2000, 5000, and 10 000 mg/kg bw per day).
    Water consumption was depressed in females at 2000 mg/kg bw per day
    and in all animals at 5000 or 10 000 mg/kg bw per day, but this was
    not accompanied by signs of dehydration. The body weights of males at
    5000 or 10 000 mg/kg bw per day and females at 10 000 mg/kg bw per day
    were depressed. Statistically significant increases in relative kidney
    and liver weights were observed n both male and female rats at a dose
    of 2000 or 5000 mg/kg bw per day. In addition, statistically
    significant increases in relative testis weight were observed at 5000
    mg/kg bw per day but not at 10 000 mg/kg bw per day. No
    histopathological abnormalities were observed in rats at any dose
    tested (Dietz, 1991).

         Groups of five male and five female B6C3F1 mice were exposed to
    acetone in drinking-water  ad libitum at concentrations of 0, 5000,
    10 000, 20 000, 50 000, or 100 000 mg/kg (equivalent to 0, 1250, 2500,
    5000, 12 500, and 25 000 mg/kg bw per day) for 14 days. Water
    consumption was depressed at 12 500 or 25 000 mg/kg bw per day as
    compared with controls. Growth retardation was seen in males and
    females at 25 000 mg/kg bw per day but was more pronounced in males.
    Statistically significant increases in relative kidney weights were
    seen in both males and females at 12 500 or 25 000 mg/kg bw per day,
    and statistically significant changes in relative liver weights were
    observed in males at 1250, 2500, 5000, 12 500, or 25 000 mg/kg bw per
    day and in females at 5000, 12 500, or 25 000 mg/kg bw per day.
    Minimal to mild centrilobular hepatocellular hypertrophy was observed
    at doses of 5000, 12 500, and 25 000 mg/kg bw per day in males and 12
    500 and 25 000 mg/kg bw per day in females. Moderate centrilobular
    hepatocellular hypertrophy was observed in males at 25 000 mg/kg bw
    per day (Dietz, 1991). 

         In a 13-week study, groups of 10 male and 10 female rats were
    given drinking-water  ad libitum containing acetone at concentrations
    of 0, 2500, 5000, 10 000, 20 000, or 50 000 mg/kg (equivalent to 0,
    250, 500, 1000, 2000, and 5000 mg/kg bw per day). Water consumption
    was depressed in males at 5000 mg/kg bw per day and in females at 2000
    or 5000 mg/kg bw per day, but this was not accompanied by signs of
    dehydration. Body-weight gain was significantly decreased in males and
    females at 5000 mg/kg bw per day. Relative kidney weights were
    significantly increased in both male and female rats exposed to
    acetone at 5000 mg/kg bw per day and in females at 2000 mg/kg bw per

    day. Increased incidences of neuropathy were seen in all males,
    including the controls, but at greatest incidence and severity at the
    two highest doses. Relative liver weights were significantly increased
    in males and females at 2000 or 5000 mg/kg bw per day. No significant
    differences in relative organ weight were observed at doses below 2000
    mg/kg bw per day. At 5000 mg/kg bw per day, the relative testis
    weights were significantly increased. The authors noted that such
    organ weight changes are difficult to interpret because of the effect
    of high doses of acetone on body weight; they therefore may not be
    biologically significant. Furthermore, testicular toxicants typically
    decrease testis weights. Decreased sperm motility, caudal weight, and
    epididymal weight and an increased incidence of abnormal sperm were
    also seen in males at 5000 mg/kg bw per day. The NOEL was 1000 mg/kg
    bw per day (Dietz, 1991).

         In a 13-week study, groups of 10 female and 10 male B6C3F1 mice
    were given drinking-water containing acetone. Females received acetone
    at concentrations of 0, 2500, 5000, 10 000, 20 000, or 50 000 mg/kg,
    equivalent to 0, 625, 1250, 2500, 5000, or 12 500 mg/kg bw per day.
    Males received acetone at a concentration of 0, 1250, 2500, 5000,
    10 000, or 20 000 mg/kg, equivalent to 0, 313, 625, 1250, 2500, and
    5000 mg/kg bw per day. The fluid intake of all females was depressed
    as compared with controls. Absolute and relative liver weights and
    absolute and relative spleen weights were significantly increased in
    female mice at 12 500 mg/kg bw per day. Centrilobular hepatocellular
    hypertrophy of minimal severity was seen in two female mice receiving
    12 500 mg/kg bw per day, but no compound-related lesions were found in
    male mice. The NOEL was 2500 mg/kg bw per day (Dietz, 1991).          
    Acetone was administered to groups of 30 male and 30 female
    Sprague-Dawley rats by gavage for 90 days at doses of 100, 500, or
    2500 mg/kg bw per day. Female rats at the two highest doses had
    increased absolute kidney weights, and relative weight increases were
    seen in the kidney, liver, and brain of both males and females at the
    highest dose. Red blood cell parameters were significantly increased
    in males at 45 days and animals of each sex at 90 days, at the highest
    dose. Histopathological examination showed a significant increase in
    tubular degeneration and hyalin droplet accumulation in males at
    500 mg/kg bw per day and in animals of each sex at 2500 mg/kg bw per
    day. Histolopathological examination of the liver and kidneys revealed
    no treatment-dependent abnormalities. The NOEL was 100 mg/kg bw per
    day (Sonawane et al., 1986). 

     Isopropyl alcohol

         The potential toxicity of isopropyl alcohol was investigated in a
    12-week study with 110 three-month-old male Wistar rats given 0, 1, 2,
    3, or 5% in their drinking-water for the duration of the study. The
    highest concentration was lowered to 4% during week 2 because of
    unpalatability. The average daily intakes were reported to be 0, 870,
    1300, 1700, and 2500 mg/kg bw. Body weights were statistically
    significantly decreased in rats at 1700 or 2500 mg/kg bw per day.
    Statistically significant, dose-related changes in relative liver
    weights were observed at the three highest doses; significant

    increases in testis weights were observed at 2500 mg/kg bw per day;
    significant increases in relative kidney weights were seen at the
    three highest doses; and statistically significant increases in
    relative adrenal weights were observed at the two highest doses.
    Increased formation of hyaline casts and increased hyaline droplet
    content were observed in the proximal tubules of the kidneys in a
    dose-dependent fashion. The NOEL was 870 mg/kg bw per day (Pilegaard &
    Ladefoged, 1993). 

          Isopropyl alcohol was ingested by groups of eight adult men at
    doses of 0, 2.6, or  6.4 mg/kg bw per day for six weeks. No
    significant changes were observed in the chemical or cellular
    composition of blood or urine, in the ability of the liver to excrete
    sulfobromophthalein, in the optical properties of the eye, or in the
    general well-being of the volunteers (Wills et al., 1969). 

     2-Heptanone

         Groups of 15 male and 15 female CFE rats were given 2-heptanone
    by gavage for 13 weeks at doses of 0, 20, 100, or 500 mg/kg bw per
    day. In addition, groups of five male and five female rats received
    doses of 0, 100, or 500 mg/kg bw per day for two and six weeks,
    respectively. At week 13, the absolute and relative liver weights were
    significantly increased in animals of each sex at 500 mg/kg bw per
    day, and the absolute and relative kidney weights were significantly
    increased in male rats at this dose; however, histological examination
    showed no treatment-related damage to the liver or kidney. Significant
    increases in the excretion of cells in the urine and enlarged kidneys
    were observed in animals at 100 and 500 mg/kg bw per day. As no
    abnormal function was detected in concentration tests, and there was
    no histopathological damage in the kidneys, the significance of the
    excretion of cells in the urine is unclear. The NOEL was 20 mg/kg bw
    per day (Gaunt et al., 1972).

         In a study of the role of the chain length of aliphatic ketones
    in the causation of central and peripheral distal axonopathy, five
    Sprague-Dawley rats of unspecified sex were given 0.5% 2-heptanone
    (500 mg/kg bw per day) in their drinking-water for 12 weeks. The
    animals were observed for hindlimb weakness, and pathological
    examinations were conducted on tissues removed from the nervous
    system. No giant axonal swelling or secondary myelin changes were
    observed in treated animals (Spencer et al., 1978).

     3-Heptanone 

         3-Heptanone, the only ketone in the group that is able to form a
    gamma-diketone by (omega-1)-oxidation, was also the only ketone in
    this group that caused axonal neuropathy in test animals. In a 14-week
    study of the neurotoxic effects of oral exposure to 3-heptanone, 44
    male rats were dosed by gavage on five days a week for the duration of
    the study with 250, 500, 1000, 2000, or 4000 mg/kg bw per day of
    3-heptanone alone; 3-heptanone followed by 1500 mg/kg bw per day
    methyl ethyl ketone; 750 mg/kg bw per day methyl ethyl ketone; or 1500

    mg/kg bw per day 5-methyl-2-octanone. Animals in many treated groups
    developed central nervous system depression or narcosis, and those
    given 2000 or 4000 mg/kg bw per day 3-heptanone in combination with
    methyl ethyl ketone or 5-methyl-2-octanone died after one or two
    doses. Histopathological analysis revealed central-peripheral distal
    axonopathy characterized by 'giant' axonal swelling and
    neurofilamentous hyperplasia in rats at 2000 mg/kg bw per day
    3-heptanone. It was concluded that 3-heptanone has low neurotoxic
    potential, as oral doses of < 1000 mg/kg bw per day did not induce
    axonal neuropathy or the associated clinical signs. The NOEL was 1000
    mg/kg bw per day (O'Donoghue et al., 1984).

     4-Heptanone

         4-Heptanone was administered to eight male Charles River rats by
    gavage for 90 days at a dose of 2000 mg/kg bw per day, determined in a
    previous study of acute toxicity to be the maximum tolerated dose
    (Krasavage & O'Donoghue, 1979). After one week, however, four of the
    rats had died, and the dose was reduced to 1000 mg/kg bw per day. The
    mean relative liver weight was statistically significantly greater
    than that of controls. Statistically significant increases in the
    relative weights of the kidneys, adrenal glands, and testes were also
    observed. Histopathological examination revealed hepatocyte
    hypertrophy, adrenal gland congestion, and macroscopically enlarged
    livers (O'Donoghue & Krasavage, 1980). 

     2,6-Dimethyl-4-heptanone

         2,6-Dimethyl-4-heptanone (purity, 67%) was administered to eight
    male Charles River rats by gavage for 90 days at 0 or 2000 mg/kg bw
    per day, which was determined in a previous study to be the maximum
    tolerated dose (Krasavage & O'Donoghue, 1979). The absolute and
    relative liver weights, the relative kidney weights, and the absolute
    and relative adrenal gland weights were statistically significantly
    greater than those of controls; the absolute (but not the relative)
    weights of the brain and heart were significantly depressed.
    Histopathological examination revealed compound-related changes in the
    stomach, liver, and kidneys. The stomachs of all animals showed
    hyperkeratosis with or without pseudoepitheliomatous hyperplasia
    associated with irritation due to direct contact with the solvent. In
    the liver, minor or moderate hepatocyte hypertrophy was observed. In
    the kidney, hyalin droplet formation was present in the proximal
    tubular epithelium, with sporadic occurrence of regenerating tubular
    epithelium and tubular dilation with casts (O'Donoghue & Krasavage,
    1980). 

    2.3.2.3  Genotoxicity

         Seven representative aliphatic acyclic secondary alcohols,
    ketones, and related esters in this group have been tested for
    genotoxicity. The results are summarized in Table 5 and described
    below. 


        Table 4. Short-term studies of the toxicity of saturated aliphatic acyclic secondary alcohols and ketones

                                                                                                                                            

    Substance                  No.    Species    Sex           Test      Route            Time         NOEL          Reference
                                                               groupsa                                 (mg/kg bw
                                                                                                       per day)

                                                                                                                                            

    Acetone                    139    Rat        Male/female   5/20      Drinking-water   91 days      1000          Dietz (1991)
    Acetone                    139    Mouse      Male/female   5/20      Drinking-water   91 days      2500          Dietz (1991)
    Acetone                    139    Rat        Male/female   3/60      Gavage           90 days      100           Sonawaneet al. (1986)
    Isopropyl alcohol          277    Human      Male          2/8       Oral             6 weeks      6.4b          Wills et al. (1969)
    Isopropyl alcohol          277    Rat        Male          4/22      Drinking-water   90 days      870           Pilegaard & 
                                                                                                                     Ladefoged (1993)
    2-Heptanone                283    Rat        Male/female   3/30      Gavage           91 days      20            Gaunt et al. (1972)
    3-Heptanone                285    Rat        Male          5/9       Gavage           14 weeks     1000          O'Donoghue et al. 
                                                                                                                     (1984)
    4-Heptanone                287    Rat        Male          1/8       Gavage           90 days      < 1000c       O'Donoghue & 
                                                                                                                     Krasavage (1980)
    2,6-Dimethyl-4-heptanone   302    Rat        Male          1/8       Gavage           90 days      < 2000c       O'Donohgue & 
                                                                                                                     Krasavage (1980)
                                                                                                                                            

    a  No. of test groups/No. of animals per group
    b  This study was performed at either a single dose or multiple doses that induced no adverse effects. Therefore, this dose is not a true NOEL
       but is the highest dose tested that produced no adverse effects. The actual NOEL would be higher.
    c  No NOEL established

    Table 5. Results of assays for the genotoxicity of saturated aliphatic secondary alcohols, ketones, and related esters 

                                                                                                                                              

    Compound             No.    End-point                  Test object                  Concentration     Result      Reference
                                                                                                                                              

    Acetone              139    rec Gene mutation          B. subtilis                  NR                Negativea   Kawachi et al. (1980)
                                rec Gene mutation          B. subtilis                  NR                Negative    Ishizaki et al. 
                                                                                                                      (1979)
                                Reverse mutation           S. typhimurium TA100         0.1-1000 g/plate Negative    Rapson et al. 
                                                                                                                      (1980)
                                Reverse mutation           S. typhimurium TA98,         3 mol/plate      Negativea   Florin et al. (1980)
                                                           TA100, TA1535, TA1537        (174 g/plate)
                                Reverse mutation           S. typhimurium TA98,         NR                Negativea   Kawachi et al. (1980)
                                                           TA100 
                                Reverse mutationb          S. typhimurium TA98,         30 l/plate       Negativec   Yamaguchi (1985)
                                                           TA100                        (24 mg/plate)
                                Reverse mutation           S. typhimurium TA97,         < 10 000 g/plate Negativea   McCann et al. (1975)
                                                           TA98, TA100, TA1535, 
                                                           TA1537 
                                Reverse mutationb          S. typhimurium TA97,         < 10 000 g/plate Negativea   Zeiger et al. (1992)
                                                           TA98, TA100, TA1535, 
                                                           TA1537
                                Reverse mutation           S. typhimurium TA100         500 g/plate      Negativea   Yamaguchi (1982)
                                Sister chromatid exchange  Human embryo fibroblasts     NR                Negativec   Kawachi et al. (1980)
                                Sister chromatid exchange  Hamster lung fibroblasts     NR                Negativec   Kawachi et al. (1980)
                                Sister chromatid exchange  Chinese hamster ovary        < 10 g/ml        Negative    Sasaki et al. (1980)
                                                           cells 
                                Sister chromatid exchange  Chinese hamster ovary        < 5020 g/ml      Negativea   Loveday et al. (1990)
                                                           cells 
                                Sister chromatid exchange  Diploid human fibroblasts    5 g/ml           Negative    Sasaki et al. (1980)
                                Sister chromatid exchange  Human lymphocytes            6.8 mmol/plate    Negative    Norppa et al. (1983)
                                                                                        (395 g/ml)
                                Chromosomal aberration     Chinese hamster ovary        < 5020 g/ml      Negativea   Loveday et al. (1990)
                                                           cells 
                                Chromosomal aberration     Hamster lung fibroblasts     NR                Positivec   Kawachi et al. (1980)

    Table 5. (continued)

                                                                                                                                              

    Compound             No.    End-point                  Test object                  Concentration     Result      Reference
                                                                                                                                              

    Isopropyl alcohol    277    Reverse mutation           S. typhimurium TA98,         3 mol/plate      Negativea   Florin et al. (1980)
                                                           TA100, TA1535, TA1537        (174 g/plate)
                                Reverse mutationb          S. typhimurium TA98,         5-5000 g/plate   Negativea   Shimizu et al. (1985)
                                                           TA100, TA1535, TA1537, 
                                                           TA1538, E. coli WP2uvrA 
                                Reverse mutationb          S. typhimurium TA97,         < 10 mg/plated    Negativea   Zeiger et al. (1992)
                                                           TA98, TA102, TA104, 
                                                           TA1535, TA100, TA1537
                                Forward mutation           Chinese hamster ovary        0.5-5 mg/ml       Negativea   Chemical Manufacturers' 
                                                           cells, hprt locus                                          Association (1990)
                                Forward mutation           Chinese hamster ovary        0.5-5 mg/ml       Negativea   Kapp et al. (1993)
                                                           cells, hprt locus

    2-Butanone           278    Reverse mutation           S. typhimurium TA98,         10 000 g/plate   Negativea   Douglas et al. (1980)
                                                           TA100, TA1535, TA1537, 
                                                           TA1538
                                Reverse mutation           S. typhimurium TA102,        1 mg/plate        Negative    Marnett et al.(1985)
                                                           TA104 
                                Reverse mutationb          S. typhimurium TA98,         5-5000 g/plate   Negativea   Shimizu et al. (1985)
                                                           TA100, TA1535, TA1537, 
                                                           TA1538 
                                Reverse mutation           S. typhimurium TA98,         0.05-32 l/plate  Negativea   O'Donoghue et al. (1988) 
                                                           TA100, TA1535, TA1537,       (0.04-26 g/plate)
                                                           TA1538
                                Reverse mutationb          S. typhimurium TA97,         < 10 000 g/plate Negativea   Zeiger et al. (1992)
                                                           TA98, TA100, TA104, 
                                                           TA1535, TA1537
                                Reverse mutation           S. typhimurium TA102         5000 g/plate     Negativec   Mller et al. (1993)
                                Reverse mutation           S. typhimurium TA98,         4000 g/plate     Negativee   Brooks et al. (1988)
                                                           TA100, TA1535, TA1537, 
                                                           TA1538; E. coli WP2uvrA
                                Gene conversion            S. cerevisiae                5 mg/ml           Negativea   Brooks et al. (1988)
                                Forward mutation           L5178Y/tk+/-  mouse          0.67-12 l/ml     Negativea   O'Donoghue et al. (1988)
                                                           lymphoma cells               (0.54-10 mg/ml)

    Table 5. (continued)
                                                                                                                                              

    Compound             No.    End-point                  Test object                  Concentration     Result      Reference
                                                                                                                                              
    2-Butanone (contd)   278    Unscheduled DNA            Human lymphocytes            0.01 mol/L        Negativea   Perocco et al. (1983)
                                synthesis                                               (0.72 mg/ml)
                                Unscheduled DNA            Rat hepatocytes              0.1-5 l/ml       Negative    O'Donoghue et al. (1988)
                                synthesis                                               (7.2-360 mg/ml)
                                Chromosomal aberration     Rat hepatocytes              1000 g/ml        Negative    Brooks et al. (1988)
                                Chromosomal aberration     Chinese hamster ovary cells  1000 g/ml        Negativea   Brooks et al. (1988)
    4-Methyl-2-pentanone 301    Reverse mutation           S. typhimurium TA98,         0.04-4 l/plate   Negativea   O'Donoghue et al. (1988)
                                                           TA100, TA1535, TA1537,       (0.03-3 mg/plate)
                                                           TA1538
                                Reverse mutationb          S. typhimurium TA97, TA98,   < 6667 g/plate   Negativea   Zeiger et al. (1992)
                                                           TA100, TA1535
                                Reverse mutation           E. coli WP2uvrA              8000 g/plate     Negativec   Brooks et al. (1988)
                                Gene conversion            S. cerevisiae                5 mg/ml           Negativea   Brooks et al. (1988)
                                Forward mutation           L5178Y/tk+/-  mouse          0.32-4.2 l/ml    Negativea   O'Donoghue et al. (1988)
                                                           lymphoma cells               (0.26-3.4 mg/ml)
                                Unscheduled DNA            Rat hepatocytes              0.01-1 l/ml      Negative    O'Donoghue et al. (1988)
                                synthesis                                               (8-80 g/ml)
                                Chromosomal aberration     Rat hepatocytes              1000 g/ml        Negative    Brooks et al. (1988)
                                Chromosomal aberration     Chinese hamster ovary        1000 g/ml        Negativea   Brooks et al. (1988)
                                                           cells
    2,6-Dimethyl-        302    Reverse mutationb          S. typhimurium TA98,         1-333 g/plate    Negativea   Mortelmans et al. (1986)
     4-heptanone                                           TA100, TA1535, TA1537

    Isopropyl acetate    305    Reverse mutationb          S. typhimurium TA97, TA98,   < 10 mg/plate     Negativea   Zeiger et al. (1992)
                                                           TA100, TA1537, TA1538

    Isopropyl myristate  311    Reverse mutation           S. typhimurium TA98, TA100,  50 g/plate       Negativea   Blevins & Taylor 
                                (spot test)                TA1535, TA1537, TA1538                                     (1982) 
                                                                                                                                              

    a   With and without metabolic activation
    b   Modified (pre-incubation) protocol
    c   Without metabolic activation
    d   Maximum non-toxic dose
    e   With metabolic activation
    

     In vitro

         No evidence of mutagenicity was reported for eight aliphatic
    acyclic secondary alcohols, ketones, and related esters in multiple
    assays in the standard Ames or preincubation protocol with
     Salmonella typhimurium strains TA97, TA98, TA100, TA102, TA104,
    TA1535, TA1537, and TA1538 or  Escherichia coli strain WP2 uvrA,
    with or without metabolic activation (McCann et al., 1975; Douglas et
    al., 1980; Florin et al., 1980; Kawachi et al., 1980; Rapson et al.,
    1980; Blevins & Taylor, 1982; Yamaguchi, 1982; Marnett et al., 1985;
    Shimizu et al., 1985; Yamaguchi, 1985; Mortelmans et al., 1986; Brooks
    et al., 1988; O'Donoghue et al., 1988; Zeiger et al., 1992; Mller et
    al., 1993). The concentrations tested ranged from 0.1 to 10 000
    g/plate and often approached cytotoxic levels. The results of other
    bacterial assays, such as the  rec assay in  Bacillus subtilis and
    the  E. coli reversion assay also indicated that saturated aliphatic
    secondary alcohols are not mutagenic (Ishizaki et al., 1979; Kawachi
    et al., 1980). In the yeast  Saccharomyces cerevisiae, 2-butanone and
    methyl isobutylketone did not induce gene conversion at concentrations
    up to 5 mg/ml either with or without metabolic activation (Brooks
     et al., 1988). 

         In the L5178Y/ tk+/- mouse lymphoma assay, 2-butanone was not
    mutagenic when tested with and without metabolic activation at 11
    concentrations ranging from 0.67 l/ml (non-toxic) to 12 l/ml (100%
    toxic) (O'Donoghue  et al., 1988). In the same study,
    4-methyl-2-pentanone was not mutagenic at 10 concentrations ranging
    from 0.6 l/ml (non-toxic) to 3.7 l/ml (100% toxic) with and without
    metabolic activation, even though equivocal, non-dose-related
    responses were observed at high concentrations without activation.
    Isopropyl alcohol was tested at eight concentrations ranging between
    0.5 and 5 mg/ml with and without metabolic activation in an assay for
    forward mutation at the hypoxanthine-guanine phosphoribosyl
    transferase  (hprt) locus in Chinese hamster ovary cells (Chemical
    Manufacturers' Association, 1990). Statistically significantly
    increased mutant frequencies were seen in two of 34 treated cultures,
    but these were not dose-related and not reproducible in subsequent
    trials (Kapp et al., 1993). 

         In standard assays for cytogeneticity, acetone did not increase
    the frequency of sister chromatid exchange in Chinese hamster ovary
    cells (Loveday et al., 1990), hamster lung fibroblasts, or Don-6
    cells, (Kawachi et al., 1980; Sasaki et al., 1980) and did not
    increase the frequency of sister chromatid exchange in human
    lymphocytes (Norppa et al., 1983) with and without metabolic
    activation at concentrations up to 5000 g/ml (Loveday et al., 1990).
    Acetone did not induce chromosomal aberrations in Chinese hamster
    ovary cells at concentrations up to a maximum of 5000 g/ml (Loveday
    et al., 1990). In a test conducted at an unspecified concentration,
    acetone induced chromosomal aberrations in hamster lung fibroblasts
    (Kawachi et al., 1980), whereas 2-butanone and methyl isobutylketone
    gave negative results in assays in rat hepatocytes and Chinese hamster

    ovary cells when tested at concentrations up to 1 mg/ml (Brooks et
    al., 1988). 

         2-Butanone did not induce unscheduled DNA synthesis in human
    lymphocytes treated with concentrations up to 0.01 mol/L, with and
    without metabolic activation (Perocco et al., 1983). 2-Butanone and
    4-methyl-2-pentanone did not induce unscheduled DNA synthesis in rat
    hepatocytes when tested at concentrations up to 5 and 1 l/ml,
    respectively (O'Donoghue et al., 1988). 

     In vivo

         Acetone, isopropyl alcohol, 2-butanone, and methyl-2-pentanone
    did not induce micronucleus formation at doses of 400-2500 mg/kg bw
    (Basler, 1986; O'Donoghue et al., 1988; Kapp et al., 1993), which
    approximated the LD20 (O'Donoghue et al., 1988) and the LD50 (Basler,
    1986) of the tested compounds. 

    2.3.2.4  Other relevant studies

     Isopropyl alcohol

         The effects of long-term consumption of isopropyl alcohol on
    gonad function and embryonic and perinatal development were studied
    during an investigation to establish the maximum permissible
    concentrations of isopropyl alcohol in water bodies. The compound was
    administered for 20 days to 869 inbred white rats and for 45 days to
    488 rats which had progeny at doses of 1008 and 252 mg/kg bw per day,
    respectively; for three months at a dose of 1800 mg/kg bw per day; and
    for six months at doses of 18, 1.8, or 0.18 mg/kg bw per day. The
    embryos were examined macroanatomically on day 21 of gestation to
    determine embryotoxicity, and the offspring of treated male and female
    rats mated with treated or untreated controls were observed for
    developmental abnormalities. 

         Dams given 252 or 1008 mg/kg bw per day isopropyl alcohol before
    the onset of pregnancy had a significantly reduced number of embryos,
    but a similar effect was not seen in those given 1800 mg/kg bw per
    day. Total embryonic mortality was significantly increased only in
    dams given 1008 mg/kg bw per day; however, no essential differences in
    embryonic development were noted. The reproductive function of females
    receiving isopropyl alcohol for six months was adversely affected. The
    percentage mortality of the progeny of treated male and female
    pairings and treated male and control female pairings reached a
    significant level only in the groups receiving 18 mg/kg bw per day for
    six months. The weights of the progeny of treated males and females
    were also significantly reduced. The authors concluded that long-term
    intake of isopropyl alcohol can affect generative function, however
    only at concentrations that far exceed the current maximum allowable
    concentration of isopropyl alcohol (0.25 mg/litre) in water supplies
    (Antonova & Salmina, 1978).

         Groups of 25 timed-pregnant Sprague-Dawley rats were given 0,
    400, 800, or 1200 mg/kg bw per day isopropyl alcohol by gavage on days
    6-15 of gestation. Deaths were observed in the groups at 800 mg/kg bw
    (4%) and 1200 mg/kg bw (8%) per day. Reduced maternal gestational
    weight gain on days 0-20 associated with significantly reduced gravid
    uterine weights were noted at 800 and 1200 mg/kg bw per day. There
    were no adverse maternal or developmental effects at 400 mg/kg bw per
    day and no teratogenic effects at any dose (Tyl et al., 1994). 

         Groups of 15 artificially inseminated New Zealand white rabbits
    were given isopropyl alcohol at 0, 120, 240, or 480 mg/kg bw per day
    by gavage on days 6-18 of gestation. Four does at 480 mg/kg bw per day
    died, and severe clinical signs of toxicity and statistically
    significantly reduced food consumption were observed. No
    treatment-related maternal or developmental effects were observed at
    120 or 240 mg/kg bw per day, and no teratogenicity was seen at any
    dose (Tyl et al., 1994). 

         Rats were exposed to isopropyl alcohol in the drinking-water for
    three generations, with average intakes of 1470, 1380, and 1290 mg/kg
    bw per day for the first, second, and third generations, respectively.
    The growth of the first generation was retarded initially but had
    returned to normal by the 13th week. There were no other effects on
    growth and no effects on reproduction (Lehman et al., 1945).

     Methyl ethyl ketone

         Groups of 10 virgin and 30 plug-positive female Swiss CD-1 mice
    were exposed to 0, 400, 1000, or 3000 mg/kg methyl ethyl ketone
    vapours for 10 consecutive days. The pregnant mice appeared to be
    relatively insensitive, but the offspring of mice at the highest dose
    showed significant signs of toxicity. No maternal or developmental
    toxicity was observed at doses < 1000 mg/kg vapour (Mast et al.,
    1989). 


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    See Also:
       Toxicological Abbreviations