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    4-HEXYLRESORCINOL

    First draft prepared by
    Professor R. Walker
    School of Biological Sciences, University of Surrey,
    Guildford, Surrey, England

    Explanation
    Biological data
         Biochemical aspects
         Absorption, distribution, and excretion
         Biotransformation
    Toxicological studies
         Acute toxicity studies
         Short-term toxicity studies
         Long-term toxicity/carcinogenicity studies
         Reproductive toxicity studies
         Special studies on teratogenicity
         Special studies on genotoxicity
         Special studies on delayed contact sensitization
         Special studies on spermicidal activity
         Observations in humans
    Comments
    Evaluation
    References

    1.  EXPLANATION

         This substance is used as a processing aid to prevent the
    development of melanosis (black spot) in shrimps and related
    crustacea, and was evaluated for this specific use only. It had not
    been previously evaluated by the Committee.

         4-Hexylresorcinol is applied as an aqueous solution at
    concentrations of 50 mg/litre, resulting in residue levels in the
    edible portion of crustacea of approximately 1 mg/kg. The estimated
    intake of the compound resulting from this use was 1-8 g per person
    per day. Against this background, the Committee evaluated 4-hexyl-
    resorcinol on the basis of previously established principles for
    substances consumed in small amounts. The Committee was informed that
    throat lozenges containing 2.4-4 mg per lozenge of 4-hexylresorcinol
    for use as an oral antiseptic are available over the counter in some
    countries (Gilman  et al., 1985).

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1.  Absorption, distribution, and excretion

         Dogs were given single doses of 1 or 3 g 4-hexylresorcinol
    (equivalent to 100 or 300 mg/kg bw) as crystals in gelatin capsules or
    as a solution in olive oil, and excretion monitored in urine and
    faeces. After administration of 1 g crystalline compound, 29% of the
    dose was detected in urine and 67% in faeces; when the dose was
    increased to 3 g, 17% was excreted in urine and 73% in faeces. Urinary
    excretion was rapid, mainly in the first 6 h, and levels were
    virtually undetectable 12 h after the lower dose and 24-36 h following
    the higher dose. When 4-hexylresorcinol was administered in olive oil,
    a dose of 1 g resulted in 17% being excreted in urine and 76% in
    faeces, while 10% was excreted in urine and 80% in faeces following a
    dose of 3 g (Robbins, 1931).

         When two men received doses of 1 g 4-hexylresorcinol, an average
    of 18% of the dose was recovered in urine within the first 12 h;
    thereafter the compound was not detected in urine samples. Faecal
    excretion accounted for 64% of the dose (Robbins, 1935).

    2.1.2.  Biotransformation

         It has been reported that 4-hexylresorcinol is excreted via the
    urine mainly in the form of an ethereal sulfate conjugate (Goodman &
    Gilman, 1970) but the origin of this secondary report is not
    referenced.

    2.2.  Toxicological studies

    2.2.1.  Acute toxicity studies

         The results of acute toxicity studies with 4-hexylresorcinol are
    summarized in Table 1.

         When 4-hexylresorcinol was administered to cats orally in alcohol
    or olive oil, no pathological effects were observed at doses up to
    60 mg/kg bw, but a dose of 260 mg/kg bw was lethal to all animals
    (Maplestone & Chopra, 1934)

         No deaths occurred in dogs given single doses of 88-140 mg/kg bw
    (Christensen & Lynch, 1933)

        Table 1:  Acute toxicity studies with 4-hexylresorcinol
                                                                                              

    Animal         Route                              LD50           Reference
                                                      mg/kg bw
                                                                                              

    Mouse          s.c. (5% in olive oil)             750-1000       Dittmer, 1959
                   i.p. (5% in olive oil)             200
                   i.p. (1% aqueous emulsion)         300

    Rat            oral                               550            Lamson et al., 1935;
                                                                     Dittmer 1959

    Guinea-pig     oral                               475            Anderson et al., 1931

    Rabbit         oral (10% in ethylene glycol)      > 7501         Anderson et al., 1931
                   oral (solid in gelatin capsules)   < 7502
                                                                                              

    1    6 animals; all survived
    2    6 animals; all died
        2.2.2.  Short-term toxicity studies

    2.2.2.1  Mice

         In a range-finding study for subsequent short- and long-term
    toxicity studies, groups of five B6C3F1 mice of each sex, 7-9 weeks
    of age, were given 4-hexylresorcinol by gavage in corn oil at doses of
    0 (vehicle control), 31, 63, 125,250 or 500 mg/kg bw daily for 12 days
    (not including week-ends), i.e. 16 days overall. No dose-related
    effects were observed (NTP, 1988).

         In a 13-week study, 4-hexylresorcinol was administered by gavage
    in corn oil, 5 days/week, to groups of 10 B6C3F1 mice of each sex,
    starting at age 8-9 weeks. The dose levels administered were 0
    (vehicle control), 63, 125, 250, 500 or 1000 mg/kg bw/day. Where
    possible, animals dying during the course of the study were autopsied
    and subjected to histological examination. At termination, detailed
    histological examinations were performed on control animals and on all
    animals in the two highest dose groups.

         All male mice and 9/10 female mice in the 1000 mg/kg bw/day dose
    group died during the first week of the study. No clinical signs were
    reported. Final mean body weights were 6% and 5% lower than controls
    (not significant) in males of the 250 and 500 mg/kg bw/day dose
    groups; female body weights were comparable to controls. Mild to
    moderate nephropathy was seen in 1/10 males at 63 mg/kg bw/day, 4/10
    males and 1/10 females at 125 mg/kg bw/day, 8/10 males and 7/10
    females at 250 mg/kg bw/day, and 7/10 males and 10/10 females at
    500 mg/kg bw/day. A NOEL of 31 mg/kg bw/day was estimated in this
    study by extrapolation from the dose-response data (NTP, 1988).

    2.2.2.2  Rats

         In a range-finding study for subsequent short- and long-term
    toxicity studies, groups of five F344/N rats of each sex, 8 weeks of
    age, were given 4-hexylresorcinol by gavage in corn oil at doses of 0
    (vehicle control), 31, 63, 125, 250 or 500 mg/kg bw daily for 12 days
    (not including week-ends), i.e. 16 days overall. No deaths occurred as
    a result of treatment but final mean body weights of males in the top
    two dose groups were 8% and 16% lower than that of the controls; body
    weights of females were comparable. Rats receiving 500 mg/kg bw/day
    were described as being hyperexcitable (NTP, 1988).

         In a 13-week study, 4-hexylresorcinol was administered by gavage
    in corn oil, 5 days/week, to groups of F344/N rats (10/sex), starting
    at age 7 weeks. The dose levels administered were 0 (control), 63,
    125, 250, 500 or 1000 mg/kg bw/day. Where possible, animals dying
    during the course of the study were autopsied and subjected to
    histological examination. At termination, detailed histological
    examinations were performed on all animals of the control and two
    highest dose groups.

         All rats in the 1000 mg/kg bw/day dose group died during the
    first week of the study. At termination, final mean body weights in
    rats receiving 250 mg/kg bw/day were 22% and 9% lower than controls in
    males and females, respectively. At 500 mg/kg bw/day, the decreases
    were 38% and 16% for males and females, respectively. Clinical signs
    seen during the study included nasal discharge, ocular irritation,
    alopecia, diarrhoea and cachexia. At necropsy, reduction in size of
    the seminal vesicles was reported in 4/10, 6/10 and 1/10 males in the
    1000, 500 and 250 mg/kg bw/day groups, respectively. Hyposperma-
    togenesis was seen microscopically in 4/10 animals in the highest dose
    group and hypoplasia of the seminal vesicles was reported in 5/10 and
    3/10 males in the 1000 mg/kg bw/day and 500 mg/kg bw/day groups,
    respectively (presumably in the highest dose group these effect were
    seen when the animals were autopsied after dying during week 1 but no
    comparisons with controls were possible at that time and the animals
    were only 7-8 weeks old). No histopathological lesions were identified
    in rats given doses of 125 mg/kg bw/day or less (NTP, 1988).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Mice

         In a study of the potential carcinogenicity of spermicides,
    groups of 20 female BALB/c mice were given intravaginal applications
    of 0.1 ml of a 1% suspension of 4-hexylresorcinol in aqueous gum
    tragacanth twice weekly for 31 weeks. During the observation period of
    20 months, one mouse developed squamous carcinoma of the vagina
    compared with none in the control group (Boyland  et al., 1966).

         A carcinogenicity study was conducted with B6C3F1 mice in which
    groups of 50 mice of each sex were given 4-hexylresorcinol at dose
    levels of 0 (vehicle control), 63 or 125 mg/kg bw/day by oral gavage
    in corn oil (10 ml/kg bw), 5 days/week, for 102 weeks. The mice were
    7-8 weeks of age when administration of the test compound commenced.
    The animals were observed twice daily and body weights were recorded
    weekly for 13 weeks and monthly thereafter. Necropsy was performed on
    all animals at termination and, where possible, on those dying during
    the study. Complete histological examinations were performed on all
    mice of the control and high-dose groups; limited examinations were
    conducted on the low-dose animals involving liver, kidneys, lungs,
    bone, from both sexes, adrenal (males only) and pituitary and thyroid
    (females only).

         There was a treatment-related effect on body-weight gain. After
    week 80, mean body weights of mate mice from the high- and low-dose
    groups were 9-11% and 6-8% lower than controls; mean body weights of
    low-dose females were 6-16% lower after week 67, and high-dose females
    were 4-10% lower after week 88. No compound-related clinical signs
    were noted and there was no significant differences in survival
    between any group of either sex. Focal hyperplasia of the adrenal
    medulla was observed with increased frequency in treated male mice and
    phaeochromocytomas occurred with a positive trend but the incidences
    of the latter were not significantly different from controls. The
    incidences of carcinoma and of combined adenomas and carcinomas of the
    Harderian gland were significantly greater in low-dose males than in
    controls (Table 2). Treated females did not show an increased
    incidence of proliferative changes in either adrenal or Harderian
    glands. In contrast, in male mice, hepatocellular adenomas, carcinomas
    or adenomas and carcinomas combined occurred with a negative trend,
    being significantly lower with regard to hepatocellular adenomas in
    the low-dose group, hepatocellular carcinomas in the high-dose, and
    combined adenomas and carcinomas in treated males. Haemangiomas and
    combined haemangiomas and haemangiosarcomas also occurred with lower
    incidence in high-dose male and female mice, and the incidences of
    alveolar/bronchiolar adenomas or carcinomas (combined) were lower in
    the low-dose females than in controls. Based on these data, the
    authors concluded that there was equivocal evidence of carcinogenic
    activity of 4-hexylresorcinol in male mice but no evidence of

    carcinogenic activity in female mice. Decreased incidences of two
    tumour types were considered to be related to administration of
    4-hexylresorcinol, namely hepatocellular neoplasms in male mice and
    circulatory system tumours in mice of both sexes.

         Non-proliferative pathological changes observed at termination
    included nephropathy at increased incidences and severity in dosed
    mice of both sexes (males: control, 39/50; low dose, 43/50; high dose
    47/50; females: 7/50; 40/49; 47/50, respectively). The nephropathy
    varied from mild focal tubular atrophy in the outer cortex to severe
    atrophy with tubular cysts, tubular regeneration, dilatation of
    the tubular lumen and Bowman's space and variable inflammatory
    infiltration. Osteosclerosis was also reported at increased incidences
    in high-dose males and females. A NOEL was not established for
    nephropathy in female mice (NTP, 1988).

         In a review and evaluation of the NTP study, it was concluded
    that the proliferative changes in the adrenal medulla were unlikely to
    be due to treatment with 4-hexylresorcinol since (a) undiagnosed
    medullary hyperplasia was detected in 4 vehicle control animals, (b)
    questionable diagnosis between focal hyperplasia and phaeochromocytoma
    in some cases and (c) there were no observations supportive of
    progression since the only malignant phaeochromocytoma occurred in the
    low-dose group and bilateral lesions occurred primarily in the
    low-dose group. It was also claimed that the statistically positive
    trend in incidence of phaeochromocytomas was borderline and incidences
    were within the historical control range (Sauer, 1990; ENVIRON, 1990).
    With regard to the tumours of the Harderian gland, all 8 were
    considered to be adenomas, compared to the diagnosis of 6 as
    carcinomas by the study pathologists (Sauer, 1990).

    2.2.3.2  Rats

         A carcinogenicity study was conducted with F344/N rats in which
    groups of 50 rats of each sex were given 4-hexylresorcinol at dose
    levels of 0 (vehicle control), 63 or 125 mg/kg bw/day by oral gavage
    in corn oil (10 ml/kg bw), 5 days/week, for 103 weeks. The rats were
    6-7 weeks of age when administration of the test compound commenced.
    The animals were observed twice daily and body weights were recorded
    weekly for 13 weeks and monthly thereafter. Necropsy was performed on
    all animals at termination and, where possible, those dying on test.
    Complete histological examinations were performed on all rats of the
    control and high-dose groups; limited examinations were conducted on
    the low-dose animals involving liver, kidneys, lungs, spleen, from
    both sexes, and adrenal, pancreas and thyroid from males only.

    Table 2.  Proliferative changes in adrenal and Harderian glands of
              male mice treated with 4-hexylresorcinol (NTP, 1988)
                                                                          

                             Control        63 mg/kg bw/day     125 mg/kg
                                                                bw/day
                                                                          

    Adrenal

    Focal hyperplasia
    overall rate             5/50 (10%)     16/50 (32%)         10/49
    (20%)

    Phaeochromocytoma1
    overall rate             1/50 (2%)      2/50% (4%)          5/49 (10%)
    adjusted rate            2.8%           4.7%                15.4%

    Harderian gland

    Adenoma
    overall rate             0/50 (0%)      1/50 (2%)           1/50 (2%)

    Carcinoma
    overall rate             0/50 (0%)      4/50 (8%)           2/50 (4%)
    adjusted rate            0.0%           13.5%               6.7%

    Adenoma + Carcinoma2
    overall rate             0/50 (0%)      4/50 (8%)           3/50 (6%)
    adjusted rate            0.0%           13.5%               10.0%
                                                                          

    1    Historical incidence of phaeochromocytomas or malignant
         phaeochromocytomas (combined) in
         NTP studies = 1  2%
    2    Historical incidence in NTP studies = 4  3%

         Mean body weights in high-dose males were 7-11% lower than
    controls throughout the study; mean body weights of low-dose male and
    treated females of both groups were similar to controls. No
    compound-related clinical signs were noted and there no significant
    differences in survival between any group of either sex although a
    number of females (3 control, 8 low-dose and 14 high-dose) died during
    the first year before they were at risk of developing tumours. The
    tumour incidences did not provide evidence of carcinogenicity of
    4-hexylresorcinol in rats. There was a marginal increase in the
    adjusted rates of adenomas and of combined adenomas and carcinomas in
    the anterior pituitary gland of female rats but this reflected the
    early deaths in the high-dose group and was not considered by the
    authors to be of biological significance since these tumours occur

    commonly with a variable incidence in female F344/N rats. Two
    astrocytomas and an oligodendroglioma were observed in 3 high-dose
    males, a glioma in 1 low-dose male, and an oligodendroglioma in 1
    control male. The high-dose incidence was not statistically
    significantly different from controls and the neoplasms were detected
    only by microscopic examination; these neoplasms were not considered
    to be related to 4-hexylresorcinol administration. Negative trends
    were observed with respect to incidences of mononuclear cell leukaemia
    in male and female rats and of thyroid C-cell neoplasms in males; the
    incidences of pancreatic islet cell adenomas, mammary gland fibromas
    and endometrial stromal polyps were also reduced. No significant
    treatment-related non-neoplastic changes were seen in rats of either
    sex (NTP, 1988).

    2.2.4  Reproductive toxicity studies

         No data available

    2.2.5  Special studies on teratogenicity

         No data available.

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity studies on 4-hexylresorcinol are
    summarized in Table 3.

         In a review classifying chemicals according to their structure,
    mutagenicity and level of carcinogenicity, it was concluded that
    4-hexylresorcinol did not have a structure that was classified as
    "alerting" and was not mutagenic, however only data from the
     Salmonella typhimurium assay were considered (Ashby  et al., 1989).

    2.2.7  Special studies on delayed contact sensitization

         4-hexylresorcinol did not induce delayed contact sensitivity in
    male Hartley strain guinea-pigs sensitized by the cutaneous route
    (Baer  et al. 1966).

    2.2.8 Special studies on spermicidal activity

         In an assay in which spermicidal activity was assayed by
    titration against human spermatozoa using a cytoplasmic stripping
    end-point, 4-hexylresorcinol was characterized as a potent spermicide
    (Brotherton, 1977).

    2.3  Observations in humans

         The probable oral LD50 of 4-hexylresorcinol in humans has been
    estimated to be between 500 and 5000 mg/kg bw (Gosselin  et al.,
    1984).

        Table 3.  Results of genotoxicity studies on 4-hexylresorcinol
                                                                                                             

    Test system            Test object         Concentration of      Results         Reference
                                               hexylresorcinol
                                                                                                             

    Ames test              S. typhimurium      0-30 g/plate         Negative1       Cortinas de Nava
                           TA98, TA100,                                              et al,, 1983
                           TA1535, TA1537,
                           TA 1538

    Ames test              S. typhimurium      0.3-333 g/plate      Negative1,2     Mortelmans et al.,
                           TA98. TA100,                                              1986
                           TA1535, TA1537

    E. coli                E.coli W3110 pol    20-60 nmol/plate      Positive1,4     Espinosa-Aguirre
    pol A+/pol             A+/p3478 pol A-     3000 g/disc                          et al, 1987
    A- assay

    Mammalian cell         Mouse L5178Y        1.25-40 g/ml         Negative1       National
    mutation               lymphoma cells                                            Toxicology
    (trifiuorothymidine                                                              Program, 1988
    resistance)

    Sister chromatid       Chinese hamster     5-50 g/ml            Positive1,3     National
    exchange               ovary cells                                               Toxicology
                                                                                     Program, 1988

    Chromosomal            Chinese hamster     5-50 g/ml            Negative1       National
    aberrations            ovary cells                                               Toxicology
                                                                                     Program, 1988
                                                                                                             

    1    with and without metabolic activation
    2    toxicity at or above 100 g/plate
    3    negative in the presence of S9 mix
    4    positive in disc diffusion and liquid suspension assays, negative in microsuspension assay
    
         Adverse acute effects reported to occur following exposure to
    high levels of 4-hexylresorcinol include irritation and erosion of
    gastric and intestinal mucosa, respiratory mucosa, and skin (Gosselin
     et al., 1984; Gilman  et al., 1985; Hoover, 1975).

         A patient with contact dermatitis following occupational exposure
    reacted strongly to 4-hexylresorcinol in a patch test at 48 and 72
    hours; 20 controls were all negative. The patient did not cross-react
    with resorcinol (Burrows & Irvine, 1982).

         In a study of cross-reactivity in patients with resorcinol-
    induced dermatitis, 2 out of 8 subjects reacted positively to
    4-hexylresorcinol in patch tests; a further 3 responded with one-degree
    irritation and 2 were negative (Keil, 1962).

         Negative reports have been published for teratogenic activity of
    4-hexylresorcinol anthelmintic use (Heinonen  et al., 1977, cited in
    Schardein, 1985) but no details were available.

         No specific epidemiological studies have been conducted to
    investigate the relationship between 4-hexylresorcinol exposure and
    carcinogenicity in humans but in relation to its use in antiseptic
    mouthwashes, a retrospective study in women did not demonstrate an
    association between daily mouthwash use and oral cancer
    (Wynder  et al., 1983).

    3.  COMMENTS

         The Committee noted that toxicological information on this
    substance was limited, but recent 13-week and 2-year carcinogenicity
    studies in mice and rats were available. Nephrotoxicity was reported
    in mice in both the 13-week and 2-year carcinogenicity studies, female
    mice being affected at all dose levels. In the 2-year carcinogenicity
    study in mice, the lowest dose tested, 63 mg/kg bw/day, caused a high
    incidence of nephropathy. Nephrotoxicity was not reported in rats and
    4-hexylresorcinol was not carcinogenic in either mice or rats.

    4.  EVALUATION

         On the basis of the available data in animals, the Committee was
    unable to establish a numerical ADI but concluded that the treatment
    of crustaceans at concentrations of up to 50 mg/litre, resulting in
    residue levels of approximately 1 mg/kg in the edible portion, was not
    of toxicological concern.

         The Committee emphasized that, for more extensive use or higher
    levels of application, further toxicological data would be required,
    including a long-term toxicity study in mice that establishes a clear
    NOEL and the results of reproductive toxicity/teratogenicity studies.

    5.  REFERENCES

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     Immunochem., 3: 479-485.

    BOYLAND, E., ROE, F.J.C. & MITCHLEY, B.C.V. (1966). Test of certain
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    of female mice.  Br. J. Cancer, 20: 184-189.

    BROTHERTON, J. (1977). Assessment of spermicides by a stripping
    technique against human spermatozoa.  J. Reprod. Fert., 51: 383-391.

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    ENVIRON (1990). Review and evaluation of carcinogenesis studies of
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    Unpublished report prepared by ENVIRON Corporation submitted to WHO by
    Pfizer Inc.

    ESPINOSA-AGUIRRE, J.J., AROUMIR, C., MEZA, M.T., CIENFUEGOS, E. &
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    F344/N Rats and B6C3F1 mice (gavage studies).  Technical Report
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    Park, N.C.

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    excretion of hexylresorcinol and heptylresorcinol under different
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    ROBBINS, B.H. (1935). Quantitative studies on the absorption and
    excretion of certain resorcinols and cresols in dogs and man.
     J. Pharmacol. Exper. Ther., 53: 54-60.

    SAUER, R.M. (1990). Pathology review of adrenal medullary and
    Harderian gland proliferative lesions in male B6C3F1 mice from a
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    SCHARDEIN, J.L. (1985). Antiparasitical drugs, in  Chemically induced
     birth defects Chapter 12 Marcel Dekker, Inc. New York, N.Y.
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    WYNDER, E.L., KABAT, G., ROSENBERG, S. & LEVENSTEIN, M. (1983). Oral
    cancer and mouthwash use.  J. Natl. Cancer Inst., 70: 255-260.
    


    See Also:
       Toxicological Abbreviations