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        INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

        WORLD HEALTH ORGANIZATION



        SAFETY EVALUATION OF CERTAIN
        FOOD ADDITIVES AND CONTAMINANTS



        WHO FOOD ADDITIVES SERIES 40





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



        World Health Organization, Geneva 1998



    SATURATED ALIPHATIC ACYCLIC LINEAR PRIMARY ALCOHOLS, ALDEHYDES, 
    AND ACIDS

    First draft prepared by
    Antonia Mattia, Ph.D.
    Division of Product Policy, Office of PreMarket Approval (HFS-206)
    Center for Food Safety and Applied Nutrition
    US Food and Drug Administration
    Washington, D.C., USA

        1.  Evaluation
            1.1 Introduction
            1.2 Estimated daily  per capita intake
            1.3 Absorption, metabolism and elimination
            1.4 Application of the procedure for the safety evaluation  of
                flavouring agents
            1.5 Consideration of combined intakes from use as flavouring
                agents
            1.6 Conclusions
        2.  Relevant background information
            2.1 Intake data
            2.2 Toxicological studies
                2.2.1   Acute toxicity
                2.2.2   Short-term and long-term toxicity 
                    and carcinogenicity
                              2.2.2.1  Acetaldehyde
                              2.2.2.2  Propyl alcohol
                              2.2.2.3  Butyl alcohol
                              2.2.2.4  Butyric acid
                              2.2.2.5  Amyl alcohol
                              2.2.2.6  Valeric acid
                              2.2.2.7  Hexyl alcohol
                              2.2.2.8  Hexanal
                              2.2.2.9  Hexanoic acid
                              2.2.2.10 Heptyl alcohol
                              2.2.2.11 1-Octanol
                              2.2.2.12 Octanoic acid
                              2.2.2.13 Nonyl alcohol
                              2.2.2.14 Decanoic acid
                              2.2.2.15 Undecanoic acid
                              2.2.2.16 Myristaldehyde
                              2.2.2.17 1-Hexadecanol
                     2.2.3    Genotoxicity
                     2.2.4    Reproductive and developmental toxicity
                              2.2.4.1  Propionic acid
                              2.2.4.2  Butyric acid
                              2.2.4.3  Valeric acid
         3.   References

    1.  EVALUATION

    1.1  Introduction

         The Committee evaluated a group of 38 flavouring agents that
    includes selected saturated aliphatic acyclic linear primary alcohols,
    aldehydes and acids of chain length C1-18 using the Procedure for the
    Safety Evaluation of Flavouring Agents (the "Procedure") (see Figure 1
    in the Introduction to the section on Substances Evaluated Using the
    Procedure for the Safety Evaluation of Flavouring Agents and Table 1
    in this section).

         Several substances in the group had been evaluated previously by
    the Committee. At the seventeenth meeting a group ADI "not limited"
    was allocated to acetic acid and its potassium and sodium salts, an
    ADI "not limited" was allocated to propionic acid, and a group ADI of
    0-3 mg/kg bw was allocated to formic acid and ethyl formate (Annex 1,
    reference 32). A group ADI of 0-0.1 mg/kg bw was established for
    ocatanal and nonanal, singly or in combination, at the twenty-eighth
    meeting (Annex 1, reference 66). At the twenty-ninth meeting, ADIs
    "not specified" were allocated to the aluminium, ammonium, calcium,
    magnesium, potassium, and sodium salts of lauric, myristic, palmitic,
    and stearic acids (Annex 1, reference 70). At that meeting, the
    Committee did not establish ADIs for myristic, palmitic or stearic
    acids owing to lack of information on the manufacture or use of the
    food-grade material, but noted that these substances are normal
    constituents of coconut oil, butter and other edible oils. ADIs have
    not been allocated to butyl alcohol, decanal or propyl alcohol because
    the data were considered to be inadequate (Annex 1, references 38, 14,
    and 56, respectively).

         One substance structurally related to the group, ethyl alcohol,
    was evaluated as a flavouring agent at the forty-sixth meeting of the
    Committee (reference Annex 122). The Committee determined that ethyl
    alcohol posed no safety concern at its current level of intake when
    used as a flavouring agent.

    1.2  Estimated daily  per capita intake

         The total annual production volume of the 38 substances from
    their use as flavouring substances is approximately 2100 tonnes in the
    USA (NAS, 1987). In the USA, approximately 90% of the total volume
    (NAS, 1987) is accounted for by acetic acid, which includes uses
    (aciduvant or solvent) in food other than flavour use. Data are not
    available on the specific flavour use of acetic acid in Europe.
    Disregarding the annual volume of acetic acid, the total reported
    annual volume of the remaining 37 aliphatic substances is
    approximately 200 tonnes from use as flavouring substances in the USA
    (NAS, 1987) and 300 tonnes in Europe (IOFI, 1995). In the unlikely
    event that all of the substances in this group were simultaneously
    consumed on a daily basis, the estimated daily  per capita intakes in
    Europe and the USA would be approximately 40 mg per day and 30 mg per

    day, respectively (excluding acetic acid and propionic acid which have
    ADIs "not limited"). According to the European and USA production
    statistics and derived intakes, acetaldehyde, butyl alcohol and
    butyric acid are the major flavouring substances in this group.
    Acetaldehyde and butyl alcohol constitute about 46% of the daily 
     per capita intake of flavouring agents in this group in the USA and
    acetaldehyde and butyric acid constitute about 50% of the daily intake
    in Europe. Other flavouring agents in this group that are used at
    higher intake levels (i.e., >1800 g per day) include butyric acid,
    propionic acid, propyl alcohol and stearic acid in the USA and
    octanoic acid, hexanoic acid, valeraldehyde, butyl alcohol and hexyl
    alcohol in Europe (Table 1).

         Linear saturated aliphatic alcohols, aldehydes and acids are
    ubiquitous in nature.  Low molecular weight alcohols and acids have
    been detected in almost every known fruit and vegetable (CIVO-TNO,
    1996). However, there are relatively few reports for the natural
    occurrence of the corresponding aldehydes.  In the USA, the available
    quantitative data indicate that the dietary consumption of saturated
    linear aliphatic alcohols, aldehydes and acids from naturally
    occurring sources exceeds the consumption from their use as flavouring
    substances (Stofberg & Kirschman, 1985; Stofberg & Grundschober,
    1987).

    1.3  Absorption, metabolism and elimination

         Linear aliphatic acyclic alcohols (Lington & Bevan, 1994),
    aldehydes (Brabec, 1993) and carboxylic acids (von Oettingen, 1960;
    Dawson  et al., 1964; Katz & Guest, 1994) are absorbed through the
    gastrointestinal tract. Plasma half-lives are difficult to measure
    since many low molecular weight alcohols (e.g., ethanol), aldehydes
    and carboxylic acids (e.g., acetate and propionate) are endogenous in
    humans (Lington & Bevan, 1994). Acetaldehyde has been detected in
    whole blood (<0.2 mg/litre) and acetate is a blood buffer (Tietz,
    1986).

         The flavouring agents in this group of selected saturated
    aliphatic linear alcohols, aldehydes and acids are all metabolized via
    fatty acid and tricarboxylic acid pathways. Additional information can
    be found in introduction to this chapter on flavouring agents.

    1.4  Application of the procedure for the safety
    evaluation of flavouring agents

         Step 1.  All of the flavouring agents in this group were
    classified in structural class I (Cramer  et al., 1978).

         Step 2.  All of the flavouring agents in this group are known or
    can be readily predicted to be efficiently metabolized to substances
    harmless to humans at the estimated intakes of the flavouring agents.

         Step A3.  Twenty-seven substances in this group fall below the
    human intake threshold for class I (i.e., 1800 g per day) at their

    current levels of intake; therefore, these substances were determined
    to be of no safety concern on the basis of their structural class and
    low levels of estimated intake.

         Step A4.  Eleven substances in this group exceeded the human
    intake threshold for class I.  In all cases, the substances can be
    predicted to undergo complete metabolism to endogenous products via
    the fatty acid and tricarboxylic acid pathways.  In the opinion of the
    Committee the endogenous levels of metabolites from these substances
    would not give rise to perturbations outside the physiological range. 
    Therefore, these 11 substances were also determined to be of no safety
    concern based on their structural class and known metabolism.

         Table 1 summarizes the evaluation of the 38 saturated aliphatic,
    acyclic linear primary alcohols, aldehydes and acids using the
    Procedure.



        Table 1. Summary of results of safety evaluations of saturated aliphatic acyclic linear primary alcohols, aldehydes and acids.

    Step 1:  All of the substances in the group are in structural class I, the human intake threshold of which is 1800 g per dayay.
    Step 2: All of the substances in this group are metabolized to innocuous products.

                                                                                                                                               
    Substance           Step A3                     Step A4                   Comments                                      Conclusion based
                        Does intake exceed the      Endogenous or                                                           on current levels
                        human intake threshold?1    metabolized to                                                          of intake
                        Intake estimates            endogenous substances?
                        (g per person per day)
                                                                                                                                               

    Formic acid                  No                           N/R             Formic acid is produced endogenously and it   No safety concern
                        USA:        160                                       is a normal component of intermediate
                        Europe:     800                                       metabolism.

    Acetaldehyde                 Yes                          Yes             Acetaldehyde is oxidized to acetate which     No safety concern
                        USA:         9 700                                    is metabolized via the citric acid cycle;
                        Europe:     11 000                                    acetaldehyde can also be reduced to ethanol.

    Acetic acid                  Yes                          Yes             Acetic acid is metabolized to CO2; it         No safety concern
                        USA:        360 000                                   acetylates amines and can be incorporated
                        Europe:     N/D2                                    into proteins.

    Propyl alcohol               Yes                          Yes             Propyl alcohol is oxidized to propionaldehyde No safety concern
                        USA:        2700                                      which yields propionate; propionate undergoes
                        Europe:      420                                      metabolism in the citric acid cycle.

    Propionaldehyde              No                           N/R             See propyl alcohol.                           No safety concern
                        USA:        140
                        Europe:      33

    Propionic acid               Yes                          Yes             See propyl alcohol.                           No safety concern
                        USA:        5200
                        Europe:     1100

    Butyl alcohol                Yes                          Yes             Butyl alcohol is oxidized to its              No safety concern
                        USA:        8100                                      corresponding aldehyde, which is oxidized to
                        Europe:     1900                                      the acid; metabolism via fatty acid and
                                                                              tricarboxylic acid pathways.

    Table 1.  Continued...

    Substance           Step A3                     Step A4                   Comments                                      Conclusion based
                        Does intake exceed the      Endogenous or                                                           on current levels
                        human intake threshold?1  metabolized to                                                          of intake
                        Intake estimates            endogenous substances?
                        (g per person per day)
                                                                                                                                               
    Butyraldehyde                No                           N/R             See butyl alcohol.                            No safety concern
                        USA:        17
                        Europe:     26

    Butyric acid                 Yes                          Yes             See butyl alcohol.                            No safety concern
                        USA:         5 900
                        Europe:     10 000

    Amyl alcohol                 No                           N/R             Amyl alcohol is oxidized to its corresponding No safety concern
                        USA:        44                                        aldehyde, which is rapidly oxidized to the
                        Europe:     97                                        acid; metabolism via fatty acid and
                                                                              tricarboxylic acid pathways.

    Valeraldehyde                Yes                          Yes             See amyl alcohol.                             No safety concern
                        USA:        8.8
                        Europe:     3000                                      

    Valeric acid                 No                           N/R             See amyl alcohol.                             No safety concern
                        USA:        850
                        Europe:     140

    Hexyl alcohol                Yes                          Yes             Hexyl alcohol is oxidized to its              No safety concern
                        USA:        800                                       corresponding aldehyde, which is rapidly
                        Europe:     1900                                      oxidized to the acid; metabolism via fatty
                                                                              acid and tricarboxylic acid pathways.

    Hexanal                      No                           N/R             See hexyl alcohol.                            No safety concern
                        USA:        260
                        Europe:     780

    Hexanoic acid                Yes                          Yes             See hexyl alcohol.                            No safety concern
                        USA:        1300
                        Europe:     3500

    Table 1.  Continued...

    Substance           Step A3                     Step A4                   Comments                                      Conclusion based
                        Does intake exceed the      Endogenous or                                                           on current levels
                        human intake threshold?1  metabolized to                                                          of intake
                        Intake estimates            endogenous substances?
                        (g per person per day)
                                                                                                                                               

    Heptyl alcohol               No                           N/R             Heptyl alcohol is oxidized to its             No safety concern
                        USA:        7                                         corresponding aldehyde, which is rapidly
                        Europe:     12                                        oxidized to the acid; metabolism via fatty
                                                                              acid and tricarboxylic acid pathways.

    Heptanal                     No                           N/R             See heptyl alcohol.                           No safety concern
                        USA:        3.2
                        Europe:     200

    Heptanoic acid               No                           N/R             See heptyl alcohol.                           No safety concern
                        USA:        5.3
                        Europe:     170

    1-Octanol                    No                           N/R             1-Octanol is oxidized to its corresponding    No safety concern
                        USA:        32                                        aldehyde, which is rapidly oxidized to the
                        Europe:     230                                       acid; metabolism via fatty acid and
                                                                              tricarboxylic acid pathways.

    Octanal                      No                           N/R             See 1-octanol.                                No safety concern
                        USA:         90
                        Europe:     170

    Octanoic acid                Yes                          Yes             See 1-octanol.                                No safety concern
                        USA:         650
                        Europe:     3800

    Nonyl alcohol                No                           N/R             Nonyl alcohol is oxidized to its              No safety concern
                        USA:        2.1                                       corresponding aldehyde, which is rapidly
                        Europe:     8.1                                       oxidized to the acid; metabolism via fatty
                                                                              acid and tricarboxylic acid pathways.

    Table 1.  Continued...

    Substance           Step A3                     Step A4                   Comments                                      Conclusion based
                        Does intake exceed the      Endogenous or                                                           on current levels
                        human intake threshold?1  metabolized to                                                          of intake
                        Intake estimates            endogenous substances?
                        (g per person per day)
                                                                                                                                               

    Nonanal                      No                           N/R             See nonyl alcohol.                            No safety concern
                        USA:         17
                        Europe:     130

    Nonanoic acid                No                           N/R             See nonyl alcohol.                            No safety concern
                        USA:        63
                        Europe:     64

    1-Decanol                    No                           N/R             1-Decanol is oxidized to its                  No safety
                        USA:          7                                       corresponding aldehyde, which is rapidly
                        Europe:     290                                       oxidized to the acid; metabolism via fatty
                                                                              acid pathways and tricarboxylic acid 
                                                                              pathways.

    Decanal                      No                           N/R             See 1-decanol.                                No safety concern
                        USA:         61
                        Europe:     288

    Decanoic acid                No                           Yes             See 1-decanol; at high concentrations,        No safety concern
                        USA:         980                                      decanoic acid undergoes omega-oxidation.
                        Europe:     1400

    Undecyl alcohol              No                           N/R             Undecyl alcohol is oxidized to its            No safety concern
                        USA:        11                                        corresponding aldehyde, which is rapidly
                        Europe:     0.9                                       oxidized to the acid; metabolism via fatty
                                                                              acid and tricarboxylic acid pathways.

    Undecanal                    No                           N/R             See undecyl alcohol.                          No safety concern
                        USA:        1.5
                        Europe:     480

    Table 1.  Continued...

    Substance           Step A3                     Step A4                   Comments                                      Conclusion based
                        Does intake exceed the      Endogenous or                                                           on current levels
                        human intake threshold?1  metabolized to                                                          of intake
                        Intake estimates            endogenous substances?
                        (g per person per day)
                                                                                                                                               

    Undecanoic acid              No                           N/R             See undecyl alcohol.                          No safety concern
                        USA:        8.8
                        Europe:     4.6

    Lauryl alcohol               No                           N/R             Lauryl alcohol is oxidized to its             No safety concern
                        USA:         80                                       corresponding aldehyde, which is rapidly
                        Europe:     170                                       oxidized to the acid; metabolism via fatty
                                                                              acid and tricarboxylic acid pathways.

    Lauric aldehyde              No                           N/R             See lauryl alcohol.                           No safety concern
                        USA:        21
                        Europe:     52

    Lauric acid                  No                           N/R             See lauryl alcohol.                           No safety concern
                        USA:        1200
                        Europe:      590

    Myristaldehyde               No                           N/R             Myristaldehyde is rapidly oxidized to its     No safety concern
                        USA:        25                                        corresponding acid; metabolism via fatty 
                        Europe:     9.4                                       acid and tricarboxylic acid pathways.

    Myristic acid                No                           N/R             See myristaldehyde.                           No safety concern
                        USA:         72
                        Europe:     160

    1-Hexadecanol                No                           Yes             1-Hexadecanol is oxidized to its              No safety concern
                        USA:        0.2                                       corresponding aldehyde, which is rapidly
                        Europe:     3.6                                       oxidized to the acid; metabolism via fatty 
                                                                              acid and tricarboxylic acid pathways.

    Table 1.  Continued...

    Substance           Step A3                     Step A4                   Comments                                      Conclusion based
                        Does intake exceed the      Endogenous or                                                           on current levels
                        human intake threshold?1  metabolized to                                                          of intake
                        Intake estimates            endogenous substances?
                        (g per person per day)
                                                                                                                                               

    Palmitic acid                No                           N/R             beta-Oxidation of palmitic acid yields        No safety concern
                        USA:        234                                       2-carbon units that enter the tricarboxylic 
                        Europe:      89                                       acid cycle.

    Stearic acid                 Yes                          Yes             beta-Oxidation of stearic acid yields         No safety concern
                        USA:        1900                                      2-carbon units that enter the tricarboxylic 
                        Europe:      58                                       acid cycle.
                                                                                                                                               

    1  N/R: Not required for evaluation because consumption of the substance was determined to be of no safety concern at Step A3 of the Procedure.
    2  N/D: No intake data reported.
    

    1.5  Consideration of combined intakes from use as flavouring agents

        In the unlikely event that all of the substances in this group of
    flavouring agents were simultaneously consumed on a daily basis, the
    estimated daily  per capita intake in Europe and the USA would exceed
    the human intake threshold for substances in class I. All of the
    substances in this group and their metabolites are innocuous and
    endogenous, and their combined intake was judged by the Committee not
    to give rise to perturbations outside the physiological range.

    1.6  Conclusions

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

        No toxicity data were required for the application of the
    Procedure. The Committee noted that the available toxicity data were
    consistent with the results of the safety evaluation using the
    Procedure.  In cases where ADIs were previously established, these
    ADIs were maintained at the present meeting.

    2.  RELEVANT BACKGROUND INFORMATION

    2.1  Intake data

        The most recent data on the annual production volumes of the
    flavouring agents in this group in the USA and in Europe are given in
    Table 2. The estimates of intake were calculated assuming
    under-reporting of the production data and consumption by 10% of the
    population, as indicated in the footnote to Table 2.


    Table 2.  Annual production and estimated per capita intake of saturated
    aliphatic acyclic linear primary alcohols, aldehydes and acids in the USA
    and Europe

                                                                                  

    Substance              Most recent annual         Daily Per Capita Intake2
                           production volume1         ("eaters only")
                           tonnes
                                                      g/day       g/kg bw/day
                                                                              

    1.  Formic acid
        USA                0.84                       160          2.7
        Europe             5.6                        800          13

    2.  Acetaldehyde
        USA                51                         9700         160
        Europe             78                         11 000       180

    Table 2.  Continued...

                                                                              

    Substance              Most recent annual         Daily Per Capita Intake2
                           production volume1         ("eaters only")
                           tonnes
                                                      g/day       g/kg bw/day
                                                                              
    3.  Acetic acid
        USA3               1910                       360 000      6000
        Europe             0                          0            0

    4.  Propyl alcohol
        USA                14                         2700         45
        Europe             2.9                        420          6.9

    5.  Propionaldehyde
        USA                0.72                       140          2.3
        Europe             2.29                       330          5.5

    6.  Propionic acid
        USA                27                         5200         86
        Europe             8.0                        1100         19

    7.  Butyl alcohol
        USA                43                         8100         140
        Europe             13                         1900         32

    8.  Butyraldehyde
        USA                0.09                       17           0.29
        Europe             0.19                       26           0.44

    9.  Butyric acid
        USA                31                         5900         98
        Europe             73                         10 000       170

    10. Amyl alcohol
        USA                0.23                       43           0.73
        Europe             0.68                       96           1.6

    11. Valeraldhyde
        USA                0.046                      8.7          0.15
        Europe             21                         3000         50

    12. Valeric acid
        USA                4.4                        850          14
        Europe             0.97                       140          2.3

    13. Hexyl alcohol
        USA                4.3                        810          14
        Europe             13                         1900         31

    Table 2.  Continued...

                                                                              

    Substance              Most recent annual         Daily Per Capita Intake2
                           production volume1         ("eaters only")
                           tonnes
                                                      g/day       g/kg bw/day
                                                                              
    14. Hexanal
        USA                1.4                        260          4.3
        Europe             5.4                        780          13

    15. Hexanoic acid
        USA                6.8                        1300         22
        Europe             25                         3500         59

    16. Heptyl alcohol
        USA                0.037                      7.0          0.12
        Europe             0.081                      11           0.19

    17. Heptanal
        USA                0.017                      3.2          0.05
        Europe             1.5                        210          3.5

    18. Heptanoic acid
        USA                0.028                      5.3          0.09
        Europe             1.2                        170          2.9

    19. 1-Octanol
        USA                0.17                       32           0.54
        Europe             1.6                        230          3.9

    20. Octanal
        USA                0.47                       90           1.5
        Europe             1.2                        170          2.8

    21. Octanoic acid
        USA                3.43                       650          11
        Europe             27                         3800         63

    22. Nonyl alcohol
        USA                0.011                      2.1          0.03
        Europe             0.057                      8.1          0.14

    23. Nonanal
        USA                0.09                       17           0.29
        Europe             0.91                       130          2.2

    24. Nonanoic acid
        USA                0.33                       63           1.0
        Europe             0.45                       64           1.1

    Table 2.  Continued...

                                                                              

    Substance              Most recent annual         Daily Per Capita Intake2
                           production volume1         ("eaters only")
                           tonnes
                                                      g/day       g/kg bw/day
                                                                              
    25. 1-Decanol
        USA                0.037                      7.0          0.12
        Europe             0.2                        28           0.48

    26. Decanal
        USA                0.32                       61           1.0
        Europe             2.0                        290          4.9

    27. Decanoic acid
        USA                5.1                        980          16
        Europe             9.9                        1400         24


    28. Undecyl alcohol
        USA                0.06                       11           0.19
        Europe             0.006                      0.86         0.01

    29. Undecanal
        USA                0.008                      1.5          0.03
        Europe             3.4                        480          8.0

    30. Undecanoic acid
        USA                0.046                      8.7          0.15
        Europe             0.032                      4.6          0.08

    31. Lauryl alcohol
        USA                0.42                       80           1.3
        Europe             1.2                        170          2.8

    32. Lauric aldehyde
        USA                0.011                      21           0.35
        Europe             0.36                       52           0.86

    33. Lauric acid
        USA                6.5                        1200         21
        Europe             4.2                        590          9.9

    34. Myristaldehyde
        USA                0.13                       25           0.41
        Europe             0.066                      9.4          0.16

    35. Myristic acid
        USA                0.38                       72           1.2
        Europe             1.1                        150          2.6

    Table 2.  Continued...

                                                                              

    Substance              Most recent annual         Daily Per Capita Intake2
                           production volume1         ("eaters only")
                           tonnes
                                                      g/day       g/kg bw/day
                                                                              
    36. 1-Hexadecanol
        USA                0.0009                     0.17         0.003
        Europe             0.025                      3.6          0.06

    37. Palmitic acid
        USA                1.2                        230          3.9
        Europe             0.63                       89           1.5

    38. Stearic acid
        USA                9.9                        1900         31
        Europe             0.41                       58           0.97

    Totals
        USA                2110                       400 000      6700
        Europe             300                        43 000       720

    Total excluding acetic acid
        USA                200                        38 000       640
                                                                              

    1 USA: National Academy of Science (NAS, 1987) Evaluating the safety of
    food chemicals. Washington, DC. Europe: International Organization of the
    Flavour Industry (IOFI, 1995) European inquiry on volume of use. Private
    communication to FEMA.

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

    3 The USA production volume reported for acetic acid includes use of acetic
    acid as a solvent by the flavour and food industries.
    
    2.2  Toxicological studies

    2.2.1  Acute toxicity

        Linear aliphatic alcohols, aldehydes and carboxylic acids exhibit
    low acute toxicity. For this group of saturated, aliphatic, acyclic,
    linear primary alcohols, aldehydes and acids used as flavouring
    agents, studies in rodents indicate LD50 values typically > 1 g/kg
    bw for 36 of the 38 substances. Generally, LD50 values of aldehydes
    and carboxylic acids having a carbon chain length greater than 3 are
    >2500 mg/kg bw. LD50 values were not available for undecanoic acid
    and palmitic acid. The acute toxicity studies that were available are
    summarized in Table 3.



        Table 3.  Acute toxicity studies for Saturated Aliphatic Acyclic Linear Primary Alcohols, Aldehydes and Acids

                                                                                                                  

    Substance        Species     Sex1            Route         LD50 (mg/kg bw)     Reference

                                                                                                                  

    Formic acid      mouse       NR              oral          1100                Malorny, 1969
    Acetic acid      mouse       NR              gavage        4960                Woodard et al., 1941
                     rat         NR              gavage        3310                Woodard et al., 1941
                     rat         NR              oral          3530                Smyth et al., 1951
    Propionic acid   rat         male            gavage        4290                Smyth et al., 1962
    Butyric acid     rat         male & female   oral          8790                Smyth et al., 1954
                     rat         NR              oral          2940                Smyth et al., 1951
    Valeric acid     rat         NR              oral          1844                Smyth et al., 1969a
    Hexanoic acid    rat         male            gavage        6440                Smyth et al., 1962
                     rat         male            gavage        3000                Lewis, 1989
    Heptanoic acid   rat         NR              oral          7000                Guest et al., 1982
    Octanoic acid    rat         male            gavage        1283                Smyth et al., 1962
                     rat         male & female   gavage        10 080              Jenner et al., 1964
    Nonanoic acid    rat         NR              oral          3200                Fassett, 1963
    Decanoic acid    rat         male            gavage        3301                Smyth et al., 1962
    Lauric acid      mouse       NR              oral          1238                Schafer & Bowles, 1985
    Myristic acid    rat         NR              oral          >5000               Moreno, 1977
    Stearic acid     rat         NR              oral          >5000               Moreno, 1977
    Acetaldehyde     rat         NR              oral          1930                Smyth et al., 1951
    Propionaldehyde  rat         NR              oral          1110                Smyth et al., 1951
    Butyraldehyde    rat         NR              oral          5890                Smyth et al., 1951
    Valeraldehyde    rat         male            gavage        3000-6400           Smyth et al., 1962, 1969a
    Hexanal          rat         male            gavage        7740                Smyth et al., 1962
                     rat         male & female   oral          4890                Smyth et al., 1954
    Heptanal         rat         NR              oral          >5000               Moreno, 1974
    Octanal          rat         male            gavage        4600                Smyth et al., 1962
    Nonanal          rat         male & female   gavage        >5000               Shelanski & Moldovan, 1971
    Decanal          mouse       NR              gavage        >4175               Jenner et al., 1964
                     rat         male & female   gavage        >3332               Jenner et al., 1964
    Undecanal        rat         male & female   gavage        >5000               Shelanski & Moldovan, 1971
    Lauric aldehyde  rat         male & female   gavage        >23 100             Calandra, 1971

    Table 3.  Continued...

                                                                                                                  

    Substance        Species     Sex1            Route         LD50 (mg/kg bw)     Reference

                                                                                                                  

    Myristaldehyde   rat         male & female   gavage        >4000               Lynch, 1971
                     rat         NR              oral          4500                Smyth et al., 1962
    Propyl alcohol   rat         male & female   gavage        6500                Jenner et al., 1964
                     rat         male & female   gavage        6500                Taylor et al., 1964
                     rat         NR              oral          5000                Levenstein, 1976
                     rat         male & female   oral          1870                Smyth et al., 1954
                     rat         NR              oral          5400                Rinehart et al., 1967
    Butyl alcohol    rat         male & female   gavage        2510                Jenner et al., 1964
                     rat         male & female   gavage        790 (female);
                                                               2020 (male)         Purchase, 1969
                     rat         NR              oral          4360                Smyth et al., 1951
    Amyl alcohol     rat         male & female   gavage        3030                Jenner et al., 1964
                     rat         NR              oral          5730                Carpanini et al., 1973
    Hexyl alcohol    rat         male & female   gavage        720 (female);
                                                               1800 (male)         Purchase, 1969
                     rat         NR              oral          4590                Smyth et al., 1954
    Heptyl           mouse       NR              oral          4300                Yegorov & Adrianov, 1961a
    1-Octanol        rat         NR              oral          4135                Levenstein & Wolven, 1972
    Nonyl alcohol    mouse       NR              oral          19 000              Yegorov & Adrainov, 1961a
    1-Decanol        rat         NR              oral          9800                Smyth et al., 1951
    Undecyl alcohol  rat         male            gavage        3000                Smyth & Carpenter, 1944
    Lauryl alcohol   rat         male & female   oral          1280                Lewis, 1989
    1-Hexadecanol    rat         NR              oral          8400                Coopersmith & Rutowski, 1965
                                                                                                                  


    1  NR = not reported.
    


    2.2.2    Short-term and long-term toxicity and carcinogenicity

        Although toxicity studies were not required to apply the Procedure
    to this group of flavouring agents, multiple dose toxicity studies
    lasting more than 21 days in were available for approximately half of
    the 38 substances in the group (see Table 4).  The lowest NOELs
    derived from these studies were 50-60 mg/kg bw per day, reported for
    heptyl alcohol and propyl alcohol. Few multiple dose studies are
    available for aldehydes due to their volatility and reactivity. Not
    all of these studies were designed to provide comprehensive
    toxicological assessments of the substances tested; however,
    consideration of these studies did not raise concerns regarding the
    safe use of the substances in this group as flavouring agents.

        Several studies were conducted to evaluate the irritant effects of
    alcohols and acids on the forestomach of the rat. There are several
    substances in this group for which data indicate that high doses given
    to rats cause lesions of the forestomach. These effects are not
    considered to be relevant to the human ingestion of these substances
    as flavouring agents in foods.

        A brief summary of the available data on substances not previously
    evaluated by the Committee is given below.

    2.2.2.1  Acetaldehyde

        A NOEL of 125 mg/kg bw per day was reported for acetaldehyde added
    to the drinking-water of male and female rats for 4 weeks at level of
    0, 25, 125 or 625 mg/kg bw per day (Til  et al., 1988); the only
    treatment-related effect was hyperkeratosis of the forestomach at 625
    mg/kg bw per day. No adverse effects were seen when acetaldehyde in
    drinking-water at a daily intake level of 0.5 mg/kg bw was given to
    rats (Amirkanova & Latypova, 1967).

    2.2.2.2  Propyl alcohol

        No adverse effects on the liver were observed when male rats were
    give 1 or 2 M solutions of propyl alcohol (approximately 60 or 120 
    mg/kg bw per day) as a drinking-water substitute for 6 or 2 months,
    respectively. Mallory bodies were reported in some animals (Hillbom
     et al., 1974a). In groups of rats given a 1 M solution of propyl
    alcohol as their sole source of drinking-water for 4 months, a lower
    ratio of weight gain to caloric intake compared to controls was
    observed, but there were no effects on the liver. A NOEL of 60 mg/kg
    bw per day was determined in this study (Hillbom  et al., 1974b).

        In a study of the factors affecting the distribution of propionic
    acid in the forestomach of rats, no adverse effects on the forestomach
    mucosa were reported when male rats were fed a pellet diet containing
    0 or 2-3% propionic acid (about 3800-5800 mg/kg bw per day) for 12
    weeks (Bueld & Netter, 1993).



        Table 4.  Short-term and long-term toxicity studies for saturated aliphatic acyclic linear primary alcohols, aldehydes and acids

                                                                                                                                             
    Substance              Species, sex             Route              Time                   NOEL1                    Reference
                                                                                              (mg/kg/bw per day)
                                                                                                                                             

    Formic acid            rat, male & female       oral               2 years                >400                     Malorny, 1969
    Acetic acid            rat, male                oral               63 days                350                      Pardoe, 1952
    Propionic acid         rat, male                oral               24 weeks               3800                     Bueld & Netter, 1993
    Butyric acid           rat                      oral               up to 500 days         500                      Mori, 1953
    Hexanoic acid          rat, male                diet               3 weeks                2000                     Moody & Reddy, 1978
    Decanoic acid          rat                      diet               150 days               >5000                    Mori, 1953
    Lauric acid            rat, male                diet               18 weeks               >6000                    Fitzhugh et al., 1960
    10-Undecenoic acid2    rat                      gavage             6-9 months             >400                     Tislow et al., 1950
    Palmitic acid          rats                     diet               150 days               >5000                    Mori, 1953
    Stearic acid           mice                     oral               3 weeks                >15 000                  Tove, 1964
    Acetaldehyde           rats, male & female      oral               4 weeks                125                      Til et al., 1988
    Hexanal                rat, male & female       oral               28 days                >125                     Komsta et al., 1988
    Myristaldehyde         mice                     diet               130 days               >166                     Galea et al., 1965
    Propyl alcohol         rat, male                oral               4 months               60                       Hillbom et al., 1974b
    Butyl alcohol          rat, male                oral               28 days                940                      Bio-Fax, 1969
    Amyl alcohol           rat, male & female       oral               13 weeks               >1000                    Butterworth et al., 1978
    Hexyl alcohol          dog, male & female       oral               13 weeks               230                      Eibert, 1992
    Heptyl alcohol         rabbit                   gavage             6 months               >50                      Voskovofnikova, 1966
    1-Octanol              mice                     gavage             one month              >179                     Voskovofnikova, 1966
    Nonyl alcohol          rabbit                   diet               67 days                >148                     Treon, 1963
    1-Hexadecanol          rat, male & female       diet               13 weeks               577                      Eibert, 1992
                                                                                                                                             

    1 A NOEL (no-observed-effect level) reported in this table as "greater than" (>) indicates that no adverse effects were observed at the
    highest dose level in the study, and therefore an actual NOEL was not obtained.
    2 A structurally related substance.
    

    2.2.2.3  Butyl alcohol

        No adverse effects were observed when 6.9% butyl alcohol and 25%
    sucrose (about 5.6 mg/kg bw per day butyl alcohol) were added to the
    drinking-water of male rats for 13 weeks (Wakabayashi  et al., 1984).

        In rats given control diets or diets with 0.69, 1.38, 2.75 or 5.5%
    butyl alcohol (equivalent to 690-5500 mg/kg bw), a statistically
    significant increase in the ratio of liver-to-body weight was reported
    in males at all but the lowest dose tested and in females only at the
    highest dose (PPG, 1991a).

        In a 28-day study on male rats fed diets containing 0, 1000, 3500
    or 10 000 mg butyl alcohol kg feed (about 90-940 mg/kg bw per day) in
    2% corn oil, no deaths, gross lesions at necropsy or differences in
    liver and kidney weights were reported; there was a statistically
    significant increase in the ratio of adrenals-to-body weight at all
    doses compared to controls (Bio-Fax, 1969).

    2.2.2.4  Butyric acid

        In a study of the development of gastric lesions with diets
    containing fatty acids, rats fed a rice diet with 1% butyric acid
    (equivalent to 500 mg/kg bw per day) that was gradually increase to
    10% (equivalent to 5000 mg/kg bw per day) over a period of 500 days
    had forestomach lesions  with prominent keratin cysts after being fed
    the diet for more than 50 days. No lesions were observed in the
    glandular stomach (Mori, 1953).

    2.2.2.5  Amyl alcohol

        Amyl alcohol given to rats by gavage for 13 weeks at a dose level
    of 1000 mg/kg bw per day produced no effects on body weight gain, food
    or water consumption, haematological values, serum and urine analyses,
    renal function, organ weight or histopathology (Butterworth  et al., 
    1978).

    2.2.2.6  Valeric acid

        Rats fed 5% valeric acid (about 2500 mg/kg bw per day) in a rice
    diet for 115-150 days had papillomatous growths in the forestomach
    (Mori, 1953).

    2.2.2.7  Hexyl alcohol

        Two groups of male and female rats were fed hexyl alcohol at
    dietary levels of 0.25 and 0.50% for 13 weeks; a third group was fed
    1% (reported to be equivalent to 577 mg/kg bw per day) for weeks 1-10,
    then 2, 4 and 6% for weeks 11, 12 and 13, respectively. Food
    consumption was decreased in the high-dose females, but no significant
    haematological changes, differences in urine analyses or
    histopathological effects were observed (Eibert, 1992).

        In a 13-week study, hexyl alcohol at levels of 0.5 and 1% in the
    diet, or at a dose level of 1000 mg/kg bw per day in gelatin capsules,
    was given to dogs. At a dose of 1000 mg/kg bw per day, 4 out of 5 dogs
    died. Haematology, serum chemistry and urine analyses revealed no
    differences in treated dogs relative to controls. There was
    gastrointestinal inflammation in the mid-  and high-dose groups.
    Congestion of the viscera and testicular atrophy were observed at the
    high dose. A NOAEL of 1%, which corresponds to a daily intake of
    230-695 mg/kg bw, was determined from this study (Eibert, 1992).

    2.2.2.8  Hexanal

        No adverse effects were reported when hexanal was given to rats in
    drinking-water at concentrations of 1, 10, 100 and 1000 mg/litre
    (calculated to provide doses of about 0.1, 1.2, 12.6 and 124.7 mg/kg
    bw per day) for 4 weeks (Komsta  et al., 1988).

    2.2.2.9  Hexanoic acid

        No effects on hepatic peroxisomes or peroxisomal enzymes were
    induced in male rats fed hexanoic acid in the diet at a level of 2%
    for 3 weeks (Moody & Reddy, 1978).

        In rats fed 10% (about 5000 mg/kg bw per day) hexanoic acid for
    150 days, no changes in the glandular stomach or forestomach were
    observed (Mori, 1953).

    2.2.2.10  Heptyl alcohol

        Heptyl alcohol, administered intragastrically to mice, in the form
    of a solution or suspension over a one-month period, showed no
    cumulative effects at a dose of 150 mg/kg bw per day (Voskoboinikova,
    1966). The NOEL in rabbits given 0, 1.4, 14 or 50 mg/kg bw per day
    heptyl alcohol by gavage in sunflower oil for 6 months was 50 mg/kg bw
    per day (Voskoboinikova, 1966).

    2.2.2.11  1-Octanol

        No cumulative effects were observed in a study in which 1-octanol
    was administered intragastrically to mice in the form of a solution or
    suspension over a one-month period at a dose of 180 mg/kg bw per day
    (Voskoboinikova, 1966).

    2.2.2.12  Octanoic acid

        Rats gavaged on gestation days 6-15 with octanoic acid in corn oil
    at dose levels of 0, 1125 or 1500 mg/kg bw per day exhibited maternal
    toxicity and maternal mortality. There was an decrease in the number
    of live pups on post-gestational day 6, but no developmental toxicity
    was reported (Narotsky  et al., 1994).

    2.2.2.13  Nonyl alcohol

        No adverse effects were reported when an isomeric mixture of nonyl
    alcohol, 2-methyl-1-octanol and 3-methyl-1-octanol, calculated to
    provide a daily intake level of 148 mg/kg bw, was added to the diet of
    rabbits for 67 days of an 83-day period (Treon, 1963).

    2.2.2.14  Decanoic acid

        In a study of gastric lesions, 10% decanoic acid (about 5000 mg/kg
    bw per day) in the diet of rats for 150 days resulted in no observable
    changes in the forestomach or glandular stomach (Mori, 1953).

    2.2.2.15  Undecanoic acid

        In a study with undecanoic acid,  there was a marked inhibitory
    effect on growth in rats give 2.5% (about 1250 mg/kg bw per day) for 8
    weeks (Newell  et al., 1949).

    2.2.2.16  Myristaldehyde

        No adverse effects on mortality and body and organ weights were
    reported when myristaldehyde was fed to mice at a level of 166 mg/kg
    bw per day for 130 days (Galea  et al., 1965).

    2.2.2.17  1-Hexadecanol

        Two groups of male and female rats were fed 1-hexadecanol for 13
    weeks at dietary levels of 1 or 2.5%; a third group was fed 5% for
    weeks 1-10, 7.5% for week 11, and 10% for weeks 12 and 13. Decreased
    food consumption (in females at the intermediate and high dose) and/or
    body weights (in males and females at the high dose and in females
    only at the intermediate dose) were observed at various times in rats
    in the intermediate and high-dose groups. No significant
    haematological findings, changes in urinalyses or pathological effects
    were reported between control and treated animals. A NOAEL of 1%
    (equal to 577 mg/kg bw per day) was determined from this study
    (Eibert, 1992).

        In a 13-week study in dogs, at levels of 0, 0.5, 1 or 3%, no
    effects on body weight, organ weight or food consumption were
    reported. No significant haematological findings, changes in
    urinalyses or gross pathological effects were reported between control
    and treated animals; however, serum glutamate oxaloacetate
    transaminase levels were elevated at all three doses. A NOAEL of 3%
    (equal to 807 mg/kg bw per day) was determined from this study
    (Eibert, 1992).

        In addition to the multiple dose studies described above, the
    Committee was aware of the results of a long-term inhalation study in
    which hamsters that were administered acetaldehyde developed an excess
    of upper respiratory tract tumours (Kruysse et al., 1975). Respiratory
    lesions were also observed in 2-week and 13-week  whole body

    inhalation studies on formic acid (National Toxicology Program, 1992).
    No systemic effects resulted, but the NTP recommended caution in
    extrapolating the results of these studies to man because humans do
    not metabolize formate to CO2 as rapidly as rodents. The Committee
    considered that, under conditions of use of acetaldehyde and formic
    acid as flavouring agents, these observations were not predictive of a
    response in humans because these substances are endogenous and oral
    ingestion from their use as flavouring agents is low.

    2.2.3  Genotoxicity

         In vitro and  in vivo genotoxicity studies for the flavouring
    agents in this group are listed in Tables 5 and 6. Saturated aliphatic
    acyclic linear primary alcohols, aldehydes, and carboxylic acids
    generally exhibited consistent negative results in the Ames assay, the
    unscheduled DNA synthesis test, and the  in vitro or  in vivo mouse
    micronucleus test. However, genotoxic activity has been reported for
    some low molecular weight alcohols, carboxylic acids and aldehydes in
    varied assays, including the sister chromatid exchange (SCE) assay,
    the chromosomal aberration test and the forward mutation assays with
    mouse lymphoma and Chinese hamster lung cells.

        The positive results in  in vitro genotoxicity assays for 
    aliphatic aldehydes is not surprising in light of the recognized
    reactivity of the aldehyde functional group. Acetaldehyde induced an
    increase in SCE in adult human lymphocytes (He & Lambert, 1985) and
    human peripheral lymphocytes (Helander & Lindahl-Kiessling, 1991).
    Acetaldehyde and propionaldehyde induced an increase in SCE in Chinese
    hamster embryonic diploid cells (Furnus  et al., 1990). However,
    aldehydes exhibit a short plasma half-life and are efficiently
    oxidized to the corresponding acids, which are metabolized in the
    fatty acid or citric acid pathways. These are important  in vivo 
    conditions that are difficult to establish in the above-mentioned 
     in vitro assays. In one  in vivo test, there was no evidence of an
    increase in micronucleated polychromatic erythrocytes in the bone
    marrow cells of B6C3F1 mice given a single intraperitoneal injection
    of 95 or 100 mg acetaldehyde/kg bw. Dose levels of 190 mg/kg bw
    (approximately 50% of the subcutaneous LD50 value) or more did
    increase the number of mouse micronuclei (Ozawa  et al., 1994).
    Administration via intraperitoneal injection, however, bypasses the
    liver, where 80% of the acetaldehyde from the portal circulation is
    converted to acetate.



        Table 5.  In vitro mutagenicity/genotoxicity studies for saturated aliphatic acyclic linear primary alcohols, aldehydes and acids

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

    Formic acid       modified Ames test             S. typhmiurium TA97, TA98, TA100,      10-3333 g/plate     negative1   Zeiger et al, 1992
                      (preincubation method)         TA1535, Chinese hamster ovary cells
                      Chromosomal aberration test    (CHO) K1                               8-14 mM              positive1   Morita et al, 1990

                      Chromosomal aberration test    Chinese hamster ovary cells (CHO) K1   12-14 mM             negative1   Morita et al, 1990

    Acetic acid       modified Ames test             S. typhmiurium strains TA97, TA98,     100-1000 g/plate    negative1   Zeiger et al, 1992
                      (preincubation method)         T100, TA1535, Chinese hamster
                      Chromosomal aberration test                                           10-14 mM             negative1   Morita et al, 1990

                      Chromosomal aberration test    Chinese hamster ovary K1 cells         4-10 mM              positive1   Morita et al, 1990

                      Sister chromatid exchange      Adult human lymphocytes                2.5-10 mM            positive    Sipi et al., 1992

    Propionic acid    Modified Ames test             S. typhmiurium TA97, TA98, TA1535,     100-10 000 g/plate  negative1   Zeiger et al, 1992
                      (preincubation method)         and TA1537

                      DNA repair test (spot test)    E. coli strains WP2, WP67, polA-,      125 l/plate         positive    Basler et al., 1987
                                                     uvrA-, CM871

                      SOS chromotest                 E. coli PQ37                           0.01-10 mM           negative    Basler et al., 1987

                      Ames test                      S. typhmiurium TA98, TA100, TA1535,    0.01-10 l/plate     negative    Basler et al., 1987
                                                     TA1537

                      Sister chromatid exchange      Adult human lymphocyte cells           2.5 mM               positive4   Sipi et al., 1992

                      Sister chromatid exchange      Chinese hamster V79 cells              0.1-33.3 mM          negative1   Basler et al, 1987

    Butyric acid      Chromosomal aberration test    Chinese hamster fibroblast cells       up to 1 mg/ml        negative1   Ishidate et al.,
                                                                                                                             1984

    Table 5.  Continued...

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

                      Ames test                      S. typhmiurium TA92, TA1535, TA100,    up to 10 mg/plate    negative1   Ishidate et al.,
                                                     TA1537, TA94, TA98                                                      1984

    Hexanoic acid     Mouse lymphoma assay           mouse lymphoma L5178Y TK+/-            700 g/ml            positive3   Heck et al., 1989
                                                                                            1000 g/ml           negative2

                      Unscheduled DNA synthesis      Rat hepatocytes                        1000 nl/ml           negative    Heck et al., 1989
                      Ames test (plate 
                      incorporation assay)           S. typhmiurium TA98, TA100, TA1538,    75 mg/plate          negative1   Heck et al., 1989
                                                     TA1535 and TA1537

    Heptanoic acid    Mouse lymphoma assay           Mouse lymphoma L5178Y TK +/-           900 g/ml            negative2   Heck et al., 1989
                                                                                            600 g/ml            positive3

                      Unscheduled DNA synthesis      Rat hepatocytes                        1000 nl/ml           negative    Heck et al., 1989
                      assay

                      Ames test (plate incorporation S. typhmiurium TA98, TA100,            150 mg/plate         negative1   Heck et al., 1989
                      assay)                         TA1538, TA1535 and TA1537              

                      Modified Ames test             S. typhmiurium TA97, TA98, TA100,      10 mg/plate          negative    Zeiger et al., 1992
                      (preincubation method)         TA104, TA1535 and TA1537

    Octanoic acid     Plate and suspension assays    S. typhmiurium TA1535, TA1537          at 0.0000625-        negative1   FDA, 1976
                                                     and TA1538                             0.00025%

                      Nonactivation suspension test  Saccharomyces cerevisiae D4            0.000325-0.001300%   negative    FDA, 1976

                      Unscheduled DNA synthesis      Rat hepatocytes                        300 nl/ml            negative    Heck et al., 1989

                      Ames test (plate               S. typhmiurium TA98, TA100, TA1538,    50 mg/plate          negative1   Heck et al., 1989
                      incorporation assay)           TA1535 and TA1537

    Table 5.  Continued...

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

    Decanoic acid     Rec assay                      B. subtilis strains H17 and M45        18 g/disk           negative    Oda et al., 1978

                      Modified Ames test             S. typhimurium TA98, TA100, TA1535,    up to 666 g/plate   negative1   Zeiger et al., 
                      (preincubation method)         TA97 and TA1537                                                           1988

    Lauric acid       Modified Ames test             S. typhimurium TA98, TA100, TA1535,    up to 666 g/plate   negative1   Zeiger et al, 1988
                      (preincubation method)         TA97 and TA1537

    Myristic acid     Cell mutagenesis assay         Mouse lymphoma L5178Y TK+/-            62.5 g/ml           negative2   Heck et al., 1989
                                                                                            125 g/ml            negative3

                      Ames test (plate               S. typhimurium TA98, TA100, TA1535,    10 mg/plate          negative1   Heck et al., 1989
                      incorporation assay)           TA1537 and TA1538

                      Modified Ames test             S. typhmiurium TA97, TA98, TA100,      up to 3333 g/plate  negative    Zeiger et al., 1988
                      (preincubation method)          TA1535 and TA1537

    Stearic acid      Modified Ames test             S. typhmiurium TA98, TA100, TA1535,    1-1000 g/plate      negative1   Shimizu et al.,
                      (preincubation method)         TA1537 and TA1538                                                       1985

                      Ames test                      S. typhmiurium TA98, TA100, TA1535,    50 g/plate          negative1   Blevins & Taylor,
                                                     TA1537 and TA1538                                                       1982

    Acetaldehyde      Sister chromatid exchange      Adult human lymphocytes                0.1-2.4 mM           positive    He & Lambert, 1985

                      Forward mutation assay         L5178y mouse lymphoma TK+/-            0.004-0.008          positive2   Wangenheim &
                                                                                            mol/litre                        Bolcsfoldi, 1988

                      Ames test                      S. typhmiurium TA100, TA102 and TA104  Not reported         negative1   Dillon et al, 1992

                      Chromosomal aberration test    Chinese hamster embryonic              0.002%               positive    Furnus et al., 1990
                                                     diploid cells

                      Sister chromatid exchange      Adult human peripheral lymphocytes     100-400 M           positive    Helander & Lindahl-
                                                                                                                             Kiessling, 1991

    Table 5.  Continued...

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

    Propionaldehyde   Ames test                      S. typhmiurium TA98, TA100 and TA102   0.13 nmol to 0.13    negative1   Aeschbacher et     
                                                                                            mmol/plate                       al., 1989


                      Forward mutation assay         V79 Chinese hamster lung cells         1-90 mM              positive2   Brambrilla et al,
                                                                                                                             1989
                      Ames test                      S. typhmiurium TA100, TA102 and TA104  not reported         negative3   Dillon et al, 1992

                      Unscheduled DNA synthesis      Adult human hepatocytes                10-100 mM            negative    Martelli et al.,
                      assay                                                                                                  1994

                      Chromosomal aberration test    Chinese hamster embryonic diploid      0.0005-0.002%        positive    Furnus et al., 1990
                                                     cells

    Butyraldehyde     Ames test                      S. typhmiurium TA100, TA102 and TA104  not reported         negative1   Dillon et al, 1992

                      Unscheduled DNA synthesis      Adult human hepatocytes                10-30 mM             negative    Martelli et al.,
                      assay                                                                                                  1994

                      Forward mutation assay         V79 Chinese hamster lung cells         1-30 mM              positive2   Brambrilla et al.,
                                                                                                                             1989
                      Sister chromatid exchange      Chinese hamster ovary cells            9-90 g/ml           positive1   Galloway et al.,
                                                                                                                             1987
                      Chromosome aberration test     Chinese hamster ovary cells            59-135 g/ml         negative1   Galloway et al.,
                                                                                                                             1987
                      Sister chromatid exchange      Adult human lymphocytes                0.002%               negative    Obe & Beek, 1979

    Valeraldehyde     Forward mutation assay         V79 Chinese hamster lung cells         3-30 mM              positive2   Brambilla et al.,
                                                                                                                             1989
                      Unscheduled DNA synthesis      Adult human and rat hepatocytes        3-100 mM             negative    Martelli et al.,
                      assay                                                                                                  1994

                      Rec assay                      B. subtilis strains H17 and M45        0.6 ml/plate         negative1   Matsui et al, 1989

    Table 5.  Continued...

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

    Hexanal           Forward mutation assay         V79 Chinese hamster lung cells         3-30 mM              positive2   Brambrilla et al.,
                                                                                                                             1989
                      Unscheduled DNA synthesis      Adult human and rat hepatocytes        3-100 mM             negative    Martelli et al.,
                      assay                                                                                                  1994

                      Ames test                      S. typhmiurium TA102 and TA104         up to 1 mg/plate     negative    Marnett et al.,
                                                                                                                             1985
                      Ames test (spot test)          S. typhmiurium TA98, TA100, TA1535     3 mol/plate         negative1   Florin et al, 1980
                                                     and TA1537

    Heptanal          Ames test (spot test)          S. typhmiurium TA98, TA100, TA1535     3 mol/plate         negative1   Florin et al, 1980
                                                     and TA1537

                      Ames test                      S. typhmiurium TA97, TA98, TA100,      1-3333 g/plate      negative1   Zeiger et al, 1992
                                                     TA1535 and TA1537

    Octanal           Ames test (spot test)          S. typhmiurium TA98, TA100, TA1535     3 mol/plate         negative1   Florin et al, 1980
                                                     and TA1537

    Nonanal           Sister chromatid exchange      Rat (female Fischer 344 animals)       0.1-100 M           positive    Eckl et al., 1993
                                                     hepatocytes

                      Unscheduled DNA synthesis      Adult human and rat hepatocytes        3-100 mM             negative    Martelli et al.,
                                                     assay                                                                   1994

                      Forward mutation assay         V79 Chinese hamster lung cells         0.1-0.3 mM           positive2   Brambrilla et al.,
                                                                                                                             1989
                      Modified Ames test             S. typhmiurium TA98, TA100 and TA1535  1-666 g/plate       negative1   Mortelmans et al.,
                      (preincubation method)                                                                                 1986

                      Ames test                      S. typhmiurium TA102 and TA104         up to 1 mg/plate     negative    Marnett et al.,
                                                                                                                             1985

                      Chromosomal aberration test    Rat hepatocytes                        0.4 g/ml            negative    Eckl et al., 1993

    Table 5.  Continued...

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

    Decanal           Rec assay                      B. subtilis strains H17 and M45        5 l per disk        positive    Yoo, 1986

                      Rec assay                      E. coli WP2, uvrA                      0.005-0.04 mg/plate  negative    Yoo, 1986

                      Chromosomal aberration test    Chinese hamster fibroblast cells       0.125 mg/ml          negative    Ishidate et al.,
                                                                                                                             1984
                      Ames test                      S. typhmiurium TA92, TA1535, TA100,    up to 1 mg/plate     negative1   Ishidate et al.,
                                                     TA1537, TA94 and TA98                                                   1984

    Undecanal         Ames test (spot test)          S. typhmiurium TA98, TA100, TA1535     3 mol/plate         negative1   Florin et al, 1980
                                                     and 1537

    Propyl alcohol    Ames test                      S. typhmiurium TA100                   up to 100 mol/plate negative1   Stolzenberg &
    Hine,                                                                                                                    1979
                      Sister chromatid exchange      V79 Chinese hamster lung fibroblasts   3.3-100 mM           negative2   Von der Hude et
                                                                                                                               al., 1987

                      Sister chromatid exchange      Chinese hamster ovary cells            0.01%                negative    Obe & Ristow, 1977

                      Micronucleus test              Chinese hamster lung fibroblast cells  50 l/ml             negative1   Lasne et al., 1984

    Butyl alcohol     Ames test                      S. typhimurium TA102                   up to 5000 g/plate  negative1   Muller et al, 1993

                      Sister chromatid exchange      Chinese hamster ovary cells            0.01%                negative    Obe & Ristow, 1977

                      Forward mutation assay         Chinese hamster ovary cells            0.2-1.6 l/ml        positive    PPG, 1991b

    1-Octanol         Cell mutagenesis assay         Mouse lymphoma L5178Y TK+/-            100 g/ml            negative1   Heck et al., 1989

                      Ames test                      S. typhmiurium TA1535, TA1537, TA1538, 2000 nl/plate        negative1   Heck et al., 1989
                                                     TA98 and TA100

    1-Decanol         Rec assay                      B. subtilis strains H17 and M45        17 g/disk           negative    Oda et al., 1978

    Table 5.  Continued...

                                                                                                                                               
    Substance name    Test system                    Test cells                             Concentration        Results     Reference
                                                                                                                                               

    Undecyl alcohol   Rec assay                      B. subtilis strains H17 and M45        20 g/disk           positive    Yoo, 1986

                      Rec assay                      E. coli WP2 uvrA                       0.005-0.04 mg/plate  negative    Yoo, 1986

    Lauryl alcohol    Modified Ames test             S. typhmiurium TA98, TA100, TA1535,    0.01-0.50 g/plate   negative1   Shimizu
                      (preincubation method)         TA1537 and TA1538                                                       et al., 1985

    1-Hexadecanol     Ames test                      S. typhmiurium TA98, TA100, TA1535,    50 g/plate          negative1   Blevins & Taylor,
                                                     TA1537 and TA1538                                                       1982
                                                                                                                                               


    1 Both with and without metabolic activation.
    2 Without metabolic activation
    3 With metabolic activation
    4 Positive only at middle dose (2.5 mM), negative at lower (1.25 mM) and higher doses (5 mM); no dose-response relationship

    Table 6.  Mutagenicity/genotoxicity studies for saturated aliphatic acyclic linear primary alcohols, aldehydes and acids

                                                                                                                                     
    Substance name    Test system                   Test organism            Concentration        Results        Reference
                                                                                                                                     

    Propionic acid    Micronucleus test,            Chinese hamster cells    5 ml/kg bw           negative       Basler et al., 1987
                      intraperitoneal injection

    Acetaldehyde      Mouse bone marrow             Mouse                    95-400 mg/kg bw      positive       Ozawa et al., 1994
                      micronucleus test,
                      intraperitoneal injection
                                                                                                                                     
    

        In mutation assays with mammalian cell lines, hexanoic acid and
    heptanoic acid exhibited an increase in the frequency of mutations in
    mouse lymphoma L5178Y cells with S9 metabolic activation at
    concentrations greater than 600 g/ml. The authors noted that culture
    conditions of low pH and high osmolality, which may occur upon
    incubation with acidic substances, have been shown to produce
    false-positive results in this and other assays (Heck  et al., 1989).
    Therefore, these results must be cautiously interpreted. Formic acid
    and acetic acid, which initially gave an increase in SCE in Chinese
    hamster ovary cells, were later shown to be negative when tested at
    physiological pH (Morita  et al., 1990). In a forward mutation assay,
    butyl alcohol tested at concentrations of 0.2 to 1.6 l/ml was
    mutagenic when incubated with Chinese hamster ovary cells (PPG,
    1991b). This result is also probably due to perturbations in the pH of
    the test medium.

    2.2.4  Reproductive and developmental toxicity

        Reproductive and developmental toxicity studies on low molecular
    weight aliphatic alcohols (propyl alcohol and butyl alcohol) via
    inhalation at high concentrations have been associated with
    developmental effects in the presence of maternal toxicity (Nelson 
     et al., 1990). When butyric acid, valeric acid and octanoic acid
    were given daily by tracheal intubation on days 6 to 15 of gestation,
    only fetotoxicity was reported at the highest dose level (1500 mg/kg
    bw per day) with octanoic acid; no other evidence of fetotoxicity,
    developmental toxicity or teratogenicity  associated with these three
    carboxylic acids was observed (Narotsky  et al., 1994). There is no
    evidence to conclude that, when ingested as flavouring substances,
    intake of any of the substances in the group of linear saturated
    aliphatic substances would be associated with reproductive or
    developmental toxicity.

    2.2.4.1  Propionic Acid

        Fetal abnormalities or effects on survival were not observed when
    the calcium salt of propionic acid was fed to pregnant rodents (up to
    300 mg/kg bw per day for 10 days, hamsters (up to 400 mg/kg bw per day
    for 5 days) and rabbits (up to 400 mg/kg bw per day for 13 days)
    (FDRL, 1972).

    2.2.4.2  Butyric Acid

        Maternal weight loss and respiratory effects were observed in
    female rats given 100 or 133 mg/kg bw per day of butyric acid by
    tracheal intubation on days 6 to 15 of gestation (Narotsky  et al., 
    1994). In dams with peripartum respiratory symptoms, reduced pup
    weight and decreased progeny viability were reported, but no signs of
    significant development toxicity were reported at either dose. Gastric
    irritation was noted at necropsy.

    2.2.4.3  Valeric Acid

        Female rats given 0, 75 or 100 mg/kg bw per day valeric acid by
    gavage  on days 6 to 15 of gestation exhibited signs of maternal
    toxicity including respiratory effects and decreased body weight, but
    no significant developmental toxicity at either dose. In Segment II of
    this study, valeric acid was associated with maternal toxicity and
    reduced fetal weights at dose levels from 50 to 200 mg/kg bw per day.
    No fetal skeletal malformations were reported, except for sternebrae
    variations. Gastric irritation was noted at necropsy (Narotsky 
     et al., 1994).

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    See Also:
       Toxicological Abbreviations