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    (+)-and (-)CARVONE

    First draft prepared by Dr J.C. Larsen
    Institute of Technology, National Food Agency of Denmark

    1.  EXPLANATION

         (+)-Carvone and (-)carvone were evaluated for acceptable daily
    intake for man (ADI) by the Joint FAO/WHO Expert Committee on Food
    Additives (JECFA) in 1967, 1979, 1981, 1986 and 1988 (Annex 1,
    references 15, 50, 56, 62, 73, 83).  Toxicological monographs have
    been issued in 1968 and 1980 (Annex 1, references 15 and 51).  At
    the twenty-third meeting of the committee (Annex 1, reference 50) a
    temporary ADI of 0-1 mg/kg of body weight was allocated (as sum of
    the isomers), pending submission of further relevant biochemical and
    metabolic studies.  This temporary ADI was continued by the twenty-
    fifth meeting (Annex 1, reference 56).  At the twenty-seventh
    meeting (Annex 1, reference 62) the committee was informed that
    lifetime studies with (+)-carvone in rats and mice were in progress. 
    The committee therefore extended the temporary ADI, pending
    submission of the results from these studies.  The temporary ADI was
    again extended at the thirtieth and the thirty-third meetings of the
    committee still awaiting the results of the long term studies.

         Since the previous evaluation a long term study in mice with
    (+)-carvone has become available along with other studies.  The
    existing monograph has been extended and is presented in its
    entirety.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         Carvone was found to be present in the urine of healthy adult
    humans.  The authors stated that urine profiles were compared over a
    period of two months.  The diets consumed by the subjects were not
    discussed (Zlatkis & Liebich, 1971; Zlatkis  et al., 1973a,b). 

    2.1.2  Biotransformation

         When there is unsaturation in the ring, hydroxylation of that
    ring is the primary metabolic pathway (F.E.M.A., 1976).  This has
    been shown to be true for carvone (Hildebrandt, 1902; Williams,
    1959).  Carvone was metabolized by the rabbit to 1,5-dimethyl-1,5-
    hexadien-1,6-dicarboxylic acid and a carbinol in which one ethylene
    linkage was saturated and the keto group was reduced (Fischer &
    Bielig, 1940; Opdyke, 1973; Opdyke, 1978).

    2.1.3  Effects on enzymes and other biochemical parameters

         When (-)carvone was administered orally to male albino rats at
    a dose level of 600 mg/kg bw/day for three days no effects were
    observed on the levels of either cytochrome P-450 or cytochrome b5
    (Moorthy  et al., 1989).

         Carvone (isomer not specified) was administered to three or
    four male Wistar rats for 14 days at a dietary level of 1%,
    corresponding to approximately 500 mg/kg bw/day.  Increased serum
    cholesterol and triacylglycerol levels were seen in the dosed rats
    compared to controls.  Decreased food consumption and body weight
    gain were observed over the 14-day period (Imaizumi  et al., 1985).

         Groups of ten 6-week old male Wistar rats were administered
    (+)-carvone or (-)-carvone  at levels of 80 or 160 mg/kg bw/day for
    28 days.  Plasma creatinine was determined in all rats on days 0, 13
    and 28 using a specific HPLC-method.  A dose related decrease in
    plasma creatinine was observed on day 28 in the rats receiving (+)-
    carvone.  (-)-Carvone had no effect (Lam, 1988).

    2.2  Toxicological Studies

    2.2.1  Acute toxicity studies
                                                                 
                              LD50
    Species       Route       (mg/kg b.w.)     References
                                                                 

    Mouse         s.c.        2675             Wenzel & Ross, 1957

    Rat           Oral        1640a            Jenner et al., 1964

    Rat           oral        3710b            Opdyke, 1978

    Guinea-Pig    Oral        766c             Jenner et al., 1964

    Rabbit        Dermal      3860             Opdyke, 1978
                                                                 

    a   Oral LD50 reported on "carvone", identified as 
          p-mentha-6,8-dien-2-one.
    b   Oral LD50 reported on (+)-carvone.
    c   Dermal LD50 reported as 4 ml/kg body weight for
          (+)-carvone.

         Single intraperitoneal injections of (+)-carvone to male Swiss-
    Webster albino mice did not result in any observed hepatotoxic or
    pulmonary effects.  (+)-Carvone was administered in graded doses
    (not given) up to 800 mg/kg body weight at which level significant
    convulsive effects occurred (Gordon  et al., 1982).

    2.2.2  Short-term studies

    2.2.2.1  Mouse

         Groups of five B6CBF1 mice (7-8 weeks old) of each sex were
    administered 0, 150, 328, 723, 1,590 or 3,500 mg/kg body weight (+)-
    carvone in corn oil by gavage, 5 days per week, total 12 doses over
    16 days.  Animals were housed five per cage.  Water and feed were
    given  ad libitum.  The mice were observed twice per day and were
    weighed before the study and on days 1, 7 and 14 and at the end of
    the study.  A necropsy was performed on all animals.  All mice
    receiving 1,590 or 3,500 mg/kg body weight died on day 2 or 3.  At
    necropsy the mean body weights of the treated animals were similar
    to controls.  Ataxia, impaired grasping reflex, ocular discharge,
    corneal opacity, body tremors, prostration, gasping, clonic or tonic
    convulsions, or impaired righting reflex were observed at 1,590 and
    3,500 mg/kg body weight; and lacrimation, piloerection,
    hypoactivity, bradypnea, or ptosis were observed at 723, 1,590 and
    3,500 mg/kg body weight.  Relative liver weights were increased in

    all groups of dosed male mice and relative thymus weights were
    decreased in all groups of dosed female mice.  Relative weights of
    brain, heart, right kidney, lungs and bronchi were not changed. 
    Histological examinations were carried out on all animals in the
    control group and the highest dosed group.  However, the lungs and
    livers of all dosed mice were examined.  No compound-related changes
    were seen (details on pathology not given) (NTP, 1989).

         Groups of 10 female and 30 male B6CBF1 mice (5-7 weeks old)
    were given 0, 93, 375 or 1,500 mg/kg body weight (+)-carvone in corn
    oil by gavage, 5 days per week, for 13 weeks.  The 20 extra males
    per group were included to be used for other studies, and except the
    highest dosed group they are not relevant for this evaluation. 
    Additional groups of 10 mice of each sex were administered 187 or
    750 mg/kg body weight on the same schedule.  Animals were housed
    five per cage and feed and water were available  ad libitum.  The
    mice were observed twice per day.  The animals were weighed at the
    beginning of the study and then once per week, and at the end of the
    study.  A necropsy was performed on all animals.  All male and 8/10
    female mice that received 1,500 mg/kg body weight and 1/10 males at
    93 mg/kg body weight died during the first week of the study.  An
    additional female mouse died during week 12 of the study.  Final
    mean body weights of dosed and control animals were similar. 
    Hypoactivity, ataxia, and hypersensitivity to touch were seen at
    1,500 mg/kg body weight.  The female that received 1,500 mg/kg body
    weight and survived to the end of the study had body tremors,
    hypersensitivity to touch, and impaired hind limb function during
    the study.  The relative liver weights for male and female mice that
    received 750 mg/kg body weight were significantly greater than of
    vehicle controls.  Relative weights of brain, thymus, lungs/bronchi,
    heart, right kidney, and right testis (males) were not altered. 
    Histological examinations were carried out on vehicle controls, mice
    receiving 750 mg/kg body weight, and all animals that died or were
    killed before the end of the study.  No compound-related changes
    were seen (details on pathology not given) (NTP, 1989).

    2.2.2.2  Rat

         Groups of five male and five female Osborne-Mendel rats were
    maintained on diets containing carvone (p-mentha-6,8-dien-2-one)
    (isomer not specified) at a level of 1000 ppm (approximately
    equivalent to 50 mg/kg bw/day) for 27-28 weeks, and at a level of
    2500 ppm (approximately equivalent to 125 mg/kg bw/day) for one
    year.  No adverse effects were observed in these rats as judged by
    growth, appearance, food intake, haematology, final body weights, or
    gross and microscopic examination of the major organs.  Rats
    maintained on a diet containing carvone at a level of 10,000 ppm
    (approximately equivalent to 500 mg/kg bw/day) for 16 weeks showed
    growth depression and testicular atrophy (Hagan  et al., 1967).

         Total doses of 2450-2950 mg carvone/kg body weight (isomer not
    specified) through seven daily subcutaneous injections were not able
    to increase liver regeneration in five to 15 partially
    hepatectomized Charles River rats (Gershbein, 1977).

         Groups of five F344/N rats (6-7 weeks old) of each sex were
    administered 0, 150, 328, 723, 1,590 or 3,500 mg/kg body weight (+)-
    carvone in corn oil by gavage, 5 days per week, for 12 doses over 16
    days.  The animals were housed five per cage and water and feed were
    given  ad libitum.  The rats were observed twice per day and were
    weighed on days 1, 7 and 14 and at the end of the study.  A necropsy
    was performed on all animals.  All rats that received 1,590 or 3,500
    mg/kg body weight died during the first week of the study.  The male
    rats that received 723 mg/kg body weight had 9% lower mean necropsy
    bodyweight than controls.  Relative liver weights for male rats in
    the group receiving 723 mg/kg body weight and the female mice in the
    groups receiving 328 or 723 mg/kg body weigh were significantly
    higher than those of the vehicle controls.  Relative kidney weights
    for rats of either sex that received 328 or 723 mg/kg body weight
    were significantly higher than those for the vehicle controls.  The
    relative weights of the thymus of male rats at 723 mg/kg body weight
    and of brain in female rats at 723 mg/kg body weight were decreased. 
    No histopathology was reported (NTP, 1989).

         Groups of 10 female and 30 male F 344/N rats (4-5 weeks old)
    were administered 0, 93, 375, or 1,500 mg/kg body weight (+)-carvone
    in corn oil by gavage, 5 days per week, for 13 weeks.  The 20 extra
    males per group were included to be used for other studies, and are,
    except those in the high dose group, of no relevance for this study. 
    Additional groups of 10 rats of each sex were included at dose
    levels of 187 or 750 mg/kg body weight on the same schedule. 
    Animals were housed five per cage and allowed feed and water  ad
     libitum.  The rats were observed twice per day and were weighed at
    the beginning of the study, once per week thereafter, and at the end
    of the study.  A necropsy was performed on all animals.  All rats
    that received 1,500 mg/kg body weight died during the first weeks
    and 9/10 males and 10/10 females that received 70 mg/kg body weight
    died before the termination of the study (weeks 7-12).  Final mean
    body weights of male rats that received 187 or 375 mg/kg body weight
    were lower (7% or 11%, respectively) than those of the controls. 
    The relative liver weights for dosed males and females that received
    93, 187 or 375 mg/kg body weight were increased.  The relative
    kidney weights of males administered 187 or 375 mg/kg, and of
    females that received 375 mg/kg body weight, were also increased. 
    The relative weight of the right testis and lungs/bronchi of males
    were increased at dose levels of 187 or 375 mg/kg body weight.  In
    females receiving 375 mg/kg body weight the relative brain weights
    were decreased.

         Histopathology was performed on vehicle controls, rats
    receiving 375 mg/kg body weight and all animals dying or killed
    before the end of the study.  Testicular degeneration was seen in
    the male rats at 750 mg/kg body weight.  This lesion was
    characterized by moderate to marked loss of germinal epithelium in
    the seminiferous tubules and an absence of sperm in the epididymal
    ducts.  In some rats, syncytial giant cells of spermatids were
    present in seminiferous tubules.  Atrophy of the thymic cortex was
    present in rats of each sex which received 750 mg/kg body weight. 
    Hyaline droplets and granular casts commonly associated with the
    accumulation of alpha2u-globulin were not observed in the kidney
    tissue of dosed rats.  No further information was given on
    pathology.

         A planned 2 year chronic toxicity/carcinogenicity study in rats
    using doses of 0, 187 or 375 mg/kg body weight (+)-carvone in corn
    oil by gavage, 5 days per week, had to be terminated after 60 weeks
    due to low survival of dosed animals (males: vehicle control, 48/50;
    low dose, 41/50; high dose, 16/50; females: 50/50; 48/50; 38/50). 
    No further details are given (NTP, 1989).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mouse

         Groups of 50 male and 50 female B6C3F1 (C57BL/6N, female x
    C3H/HeN MTV male) mice (7 week old) were administered 0, 375, or 750
    mg/kg body weight (+)-carvone in corn oil by gavage, 5 days per week
    for 103 weeks.  Animals were housed five per cage.  Feed and water
    were available  ad libitum.  All animals were observed twice per
    day for clinical signs.  No clinical signs were observed.  Body
    weights were recorded once per week for the first 13 weeks of the
    study, and then at least once per month thereafter.  The mean body
    weights of dosed and control male mice were similar throughout most
    of the study; the mean body weights of the dosed female mice were
    within 7% of those of the vehicle controls throughout most of the
    study.  The survival of both the low dose (29/50 after week 101) and
    the high dose (38/50 after week 92) groups of female mice was
    significantly greater than that of the controls (14/50).  This was
    probably caused by a very high death rate in the control females. 
    The low survival of female vehicle control mice was related to a
    high incidence (52%) of ovarian abscesses similar to those seen in
    studies associated with  Klebsiella sp. infections.  Whether the
    lower incidence of ovarian abscesses in dosed female mice was
    related to (+)-carvone administration is uncertain.  No differences
    in survival were observed between any groups of male mice.  A
    necropsy was performed on all animals, including those found dead,
    except for tissues that were autolyzed.  All organs and tissues were
    examined for grossly visible lesions and subjected to
    histopathology.

         Several lesions occurred in the nasal cavities of male and
    female mice with dose-related increased incidences and/or severity. 
    Atrophy of the olfactory epithelium and hyperplasia of the
    underlying Bowman's glands occurred together with high incidence in
    either sex in both dosed groups.

         The effect on the nasal mucosa was probably due to a local
    effect of (+)-carvone caused by reflux of the gavage material when
    the gavage needle was withdrawn, since inflammatory exudate and
    evidence of the corn oil vehicle was found in over 50% of all dosed
    and control animals.  No increases in tumour incidences were seen in
    mice administered (+)-carvone.  The incidence of female control mice
    with primary neoplasms was 9/50 and the total number of primary
    neoplasms was 9.  These numbers are low compared to 15/50 and 18 in
    the low dose female mice and 14/50 and 18 in the high dose mice and
    may be related to the early deaths of female control mice.  The
    incidences of male mice with primary neoplasms (control, 27/50; low
    dose, 15/50; high dose, 16/50) and the total numbers of primary
    neoplasms (control, 38; low dose, 18; high dose, 20) were
    significantly lower in dosed groups than in vehicle controls.  The
    lowered incidence of tumours in dosed male mice was primarily due to
    a lower incidence of subcutaneous fibromas, sarcomas, fibrosarcomas,
    or neurofibrosarcomas (NTP, 1989).

    2.2.4  Reproduction studies

         No information available.

    2.2.5  Special studies on in vitro toxicity

         The toxicity of carvone (isomer not specified) to Ascites
    sarcoma BP8 cells (originating from inoculated C3H mice) cultured in
    suspension was examined.  Carvone was incubated with the cells at
    37C for 48 hours at levels of 0.1 or 1.0 uM.  The percent culture
    growth inhibition at these levels was 13 and 100%, respectively
    (Pilotti  et al., 1975).

         The effect of carvone (isomer not specified) on cell metabolism
    was investigated by measuring the inhibition of noradrenaline-
    induced oxidative metabolism in isolated hamster brown fat cells. 
    At a level of 1 mM carvone, there was a 42% inhibition of
    noradrenaline-induced oxidative metabolism (Petterson  et al.,
    1980).

         Carvone (isomer not specified) was reported to be ciliotoxic at
    a concentration of 5 mM in chicken tracheal organ cultures, with
    complete cessation of ciliary activity occurring six minutes after
    the addition of carvone to the culture (Petterson  et al., 1982).

         Carvone, (isomer not specified), at a concentration of 25 mM,
    was incubated for 30 minutes at 37 C with labelled human lung
    fibroblasts.  The degree of membrane damage, as measured by the
    release of an intracellular nucleotide marker, was significantly
    increased, with 95% of the nucleotides being released in 30 minutes
    (Thelestam  et al., 1980).

         When carvone (isomer not specified) was incubated with
    microsomes from phenobarbital pretreated rats a 25% conversion of
    cytochrome P-450 to cytochrome P-420 was observed.  This conversion
    was not observed when rats were dosed (dose not specified) with
    carvone  in vivo (Madyastha  et al., 1985).

         The eggs of the insect  Earias vittella were arranged in
    groups of 20 and exposed  in vitro to various terpenoids. 
    Appropriate controls were conducted and each experiment was
    replicated five times.  Carvone (isomer not specified) did not
    inhibit embryonic development at any of the concentrations (not
    given) tested (Metha, 1979).

    2.2.6  Special studies on carcinogenicity

         Groups of female A/He mice were given intraperitoneal
    injections of (+)- or (-)-carvone three times weekly for eight
    weeks.  The mice were then observed for a further 16 weeks until the
    end of the study.  The total doses given of each compound were 1200
    or 6000 mg/kg body weight.  No increases in tumour incidences in the
    lung, liver, kidney, spleen, thymus, intestine, salivary or
    endocrine glands were observed.  Approximately 20 and 40% of the
    (+)- and (-)-carvone treated animals, respectively, did not survive
    until the end of the study regardless of dose.  Approximately 20% of
    the control animals died.  The vehicle, tricaprylin, used to
    administer carvone was found to be impure and resulted in a weight
    loss of three to four grams in the control animals during the first
    week of the study (Stoner  et al., 1973).

         A group of approximately 15 female A/J mice was administered
    0.2 mmol (approximately 30 mg) (+)-carvone by gavage one hour before
    oral administration of 20 mg/N-nitrosodiethylamine (NDEA)/kg body
    weight.  This dosing schedule was repeated once a week for eight
    weeks, and the experiment terminated 26 weeks after the first dose
    of NDEA.  Forestomach tumour formation was significantly inhibited
    in (+)-carvone treated mice, with more than a 63% reduction in the
    mean number of papillomas per mouse compared to the controls.  A
    significant reduction (34%) in the number of pulmonary adenomas per
    mouse was also observed in the (+)-carvone treated mice (Wattenberg
     et al., 1989).

    2.2.7  Special studies on genotoxicity

         (+)-Carvone at concentrations up to 333 g/plate was negative
    for induction of gene mutations in  Salmonella typhimurium strains
    TA 100, TA 1535, TA 1537 and TA 98 when tested in a preincubation
    assay in the presence or absence of Aroclor 1254 induced male
    Sprague Dawley rat or Syrian hamster liver S9 (Mortelmans  et al.,
    1986; NTP, 1989).

         (+)-Carvone induced slight increases in sister chromatid
    exchanges and chromosomal aberrations in Chinese hamster ovary (CHO)
    cells with and without addition of Aroclor 1254 induced male Sprague
    Dawley rat liver S9.  Results were statistically positive but in two
    of three sister chromatid exchange trials there were no correlation
    of dose with response.  This phenomenon of no dose/response
    relations also occurred in the second trial of the chromosomal
    aberration test conducted without S9.  In the chromosomal aberration
    test without S9 a chemical-induced delay in cell cycle was observed. 
    This was not observed in the test for sister chromatid exchanges
    (NTP, 1989).

    2.3  Observations in humans

         No irritation was observed in humans exposed to concentrations
    of 1% (-)-carvone in petrolatum in a 48-hour closed patch test
    (Opdyke, 1973).  A maximization test was carried out on 25
    volunteers.  (-)-Carvone at a concentration of 1% in a petrolatum
    produced no sensitization reactions (Opdyke, 1973).

         In one of 80 patients suffering from the condition of orofacial
    granulomatosis, characterized by swelling of the lips and lower half
    of the face, an association with intolerance to carvone (isomer not
    specified) was indicated from patch testing (Patton,  et al.,
    1985).

         Three out of 33 patients tested for contact allergy to
    toothpaste flavors, experienced a positive allergic response in a
    patch-test using 5% carvone (isomer not specified) in petrolatum
    (Anderson, 1978).

    3.  COMMENTS

         At its present meeting, the Committee considered that optical
    enantiomers should not  per se be regarded as toxicologically
    identical compounds, and therefore (+)-carvone and (-)-carvone
    should be evaluated separately.  Although both compounds were placed
    on the agenda, sufficient data for toxicological evaluation had been
    submitted only for (+)-carvone.

         In a long-term toxicity/carcinogenicity study in mice in which
    (+)-carvone was administered by gavage, no evidence of
    tumorigenicity was observed.  Additional short-term studies in mice
    and rats, in which (+)-carvone was administered by gavage, and  in
     vitro mutagenicity tests, were also considered .  Rats appear to
    be more susceptible to (+)-carvone than mice.  The no-observed-
    effect level for (+)-carvone in rats was 93 mg per kg of body weight
    based on the study in which the substance was administered by gavage
    for 3 months.  The Committee noted that, in an earlier 1-year
    feeding study in rats in which a no-effect-level of 125 mg per kg of
    body weight per day was observed, it was not specified which isomer
    had been used.

         The Committee noted that only limited data were available on
    the metabolism and pharmacokinetics of (+)-carvone.

    4.  EVALUATION

         An ADI of 0-1 mg per kg of body weight per day was established
    for (+)-carvone based on a no-observed-effect level of 93 mg per kg
    of body weight per day in rats.  The temporary ADI for (-)-carvone
    was not extended, because insufficient data were available for
    toxicological evaluation.

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    See Also:
       Toxicological Abbreviations