Sabtu, 18 Februari 2012

Hydroquinone sebabkan barah

Hydroquinone sebabkan barah!

7.7  Carcinogenicity

         The available studies on the carcinogenicity of hydroquinone
    are summarized in Table 17.

    7.7.1  Long-term bioassays

         In an NTP study (NTP, 1989; Kari  et al., 1992), groups of 65
    F-344/N rats of each sex were given hydroquinone (0, 25 or 50 mg/kg
    body weight) in deionized water by gavage 5 days/week for up to 103
    weeks, and groups of 65 B6C3F1 mice of each sex were administered
    0, 50 or 100 mg/kg body weight according to the same schedule. A
    15-month interim kill of ten animals from each group showed that the
    kidney of male rats was a target organ forthe toxicity (see also
    section 7.4), since there was a compound-related increased severity
    of nephropathy. The lesions were less severe in female rats, in
    which a mild regenerative anaemia was also found (slightly decreased
    haematocrit, haemoglobin and erythrocyte count). After termination
    of the experiment, a dose-related increase in the incidence of renal
    tubular cell adenomas was observed in male rats (controls 0/55, low
    dose 4/55, high dose 8/55; P = 0.003). The incidence of adenomas was
    closely associated with the severity of chronic nephropathy. No
    renal adenomas were observed in animals examined at 15 months, when
    the severity of nephropathy was less severe, or in female rats,
    which developed nephropathy to a lesser degree. In the male rats,
    9/12 adenomas were seen in kidneys with marked nephropathy, two were
    seen in animals with moderate nephropathy, and only one was seen in
    an animal with mild nephropathy. In the high-dose group single
    tubules exhibited tubular cell hyperplasia. No renal tumours were
    seen in females. A dose-related increase in the incidence of
    mononuclear cell leukaemia was found in female rats (controls 9/55,
    low dose 15/55, high dose 22/55) (P < 0.01 in the high-dose group
    versus controls). However, this was not observed in the animals
    killed at 15 months. The incidence in controls was lower than the
    historical control mean incidence but was within the historical
    control group range.

    Table 17.  Carcinogenicity studies in animals
    Species  Route of      Number of    Dosage            Time of        Result                           Remarks                Reference
                           exposure     animals           treatment

    Long-term bioassays

    Mouse    oral          64 or 65 of  50 or 100         103 weeks      liver lesions (males),           some evidence of       NTP (1989);
                           each sex     mg/kg                            hepatocellular adenomas          carcinogenic activity  Kari et al.
                           per group    5 days/week                      (females)                        for female mice        (1992)

    Mouse    oral          30 m, 30 f   0.8% in           96 weeks       squamous cell hyperplasia of     potential of           Shibata et al.
                                        the diet                         the forestomach epithelium;      hepatocarcinogenicity  (1991)
                                                                         renal tubular hyperplasia and    in male mice
                                                                         adenomas (males); increased
                                                                         incidence of liver foci and
                                                                         hepatocellular adenomas

    Rat      oral          65 of each   25 or 50          103 weeks      nephropathy (more severe in      some evidence of       NTP (1989);
                           sex per      mg/kg                            males), renal tubular cell       carcinogenic activity  Kari et al.
                           group        5 days/week                      hyperplasia and adenomas         for male and female    (1992)
                                                                         (males), leukaemia (females)     rats

    Rat      oral          30 m, 30 f   0.8% in           104 weeks      renal tubular hyperplasia,       potential of renal     Shibata et al.
                                        the diet                         adenomas and epithelial          carcinogencity in      (1991)
                                                                         hyperplasia of the renal         male rats
                                                                         papilla (males); decreased
                                                                         incidence of liver foci

    Table 17. (contd).
    Species  Route of      Number of    Dosage            Time of        Result                           Remarks                Reference
                           exposure     animals           treatment

    Carcinogenicity-related studies

    Mouse    skin          24 m         0.3 ml of 6.7%    one            skin papilloma (1/24)            no initiating          Roe & Salaman
             application                solution;         application;                                    activity               (1955)
                                        0.3 ml of         then three
                                        0.5% croton       weeks later,
                                        oil               18 weekly

    Mouse    skin          50 f         5 mg three        368 days       papilloma (7/50), squamous       no co-carcinogenic     van Duuren &
             application   times                                         carcinoma (3/50)                 or tumour-promoting    Goldschmidt
                           weeklya                                       activity; partial                (1976)
                                                                         inhibition of BP

    Mouse    implantation  not stated   2 mg              25 weeks       carcinomas (6/19)                                       Boyland et al.
             in urinary                                                                                                          (1964)

    Rat      oral          20 f         0.8% in           32 weeks       no preneoplastic lesions                                Kurata et al.
                                        basal dietb                      or papillomas of the                                    (1990)
                                                                         urinary bladder

    Rat      oral          15-16 m      0.8% in           51 weeks       no increase in forestomach or                           Hirose et al.
                                        dietc                            glandular stomach neoplasms                             (1989)

    Rat      oral          5 m                            8 weeks        no proliferative changes                                Shibata et al.
                                                                         in forestomach or glandular                             (1990)

    Table 17. (contd).
    Species  Route of      Number of    Dosage            Time of        Result                           Remarks                Reference
                           exposure     animals           treatment

    Rat      oral          7-10 m per   100 mg/kg         7 weeks        increased number of liver foci   relatively weak        Stenius et al.
                           group        diet per dayd                    decreased number of liver foci   inducer of enzyme-     (1989)
                                        200 mg/kg                        compared to the 100 mg/kg        altered liver foci
                                        diet per dayd                    dose

    Hamster  oral          15 m         0.5% in basal     20 weeks       no proliferative changes in                             Hirose et al.
                                        diet                             forestomach                                             (1986)

    a  after initiating dose of benzo[ a] pyrene (BP)
    b  after initiating with  N-butyl-2 N-(4-hydroxybutyl) nitrosamine for four weeks
    c  one week after 150 mg/kg body weight
    d  after partial hepatectomy

         In male mice centrilobular fatty changes and cytomegaly were
    found in the animals killed at 15 months, but these findings were
    not seen in mice killed at 2 years. The authors reported that
    hydroquinone dosing stopped two weeks before necropsy and that the
    microscopic lesions were likely to be reversible after cessation of
    treatment. There was a significantly (P=0.0005) increased incidence
    of hepatocellular adenomas in female mice given hydroquinone for 2
    years (controls 2/55, low dose 15/55, high dose 12/55) and the
    incidences of hepatocellular carcinomas were 1/55, 2/55 and 2/55,
    respectively. In males the incidence of adenomas was increased in
    treated mice but the incidence of hepatocellular carcinomas was
    decreased. Preneoplastic changes (anisokaryosis, multinucleated
    hepatocytes, and basophilic foci) were increased in high-dose male
    mice. Treatment-related, but not statistically significant,
    follicular cell hyperplasia of the thyroid gland was observed in
    both male and female mice (NTP, 1989; Kari  et al., 1992).

         The NTP concluded that there was "some evidence of carcinogenic
    activity" of hydroquinone for male F-344/N rats (tubular cell
    adenomas of the kidney) and also for female F-344/N rats
    (mononuclear cell leukaemia). There was "no evidence of carcinogenic
    activity" for male B6C3F1 mice and "some evidence of carcinogenic
    activity" for female B6C3F1 mice (hepatocellular adenomas and
    carcinomas combined).

         Shibata  et al. (1991) administered hydroquinone at dietary
    levels of 0.% or 8 g/kg to groups of 30 Fischer-344 rats and
    B6C3F1 mice of each sex. The rats were dosed for 104 weeks and the
    mice for 96 weeks. Average daily intakes were reported to be 351 and
    368 mg/kg body weight per day in male and female rats, respectively,
    and 1046 and 1486 mg/kg per day in male and female mice,
    respectively. No treatment-related clinical signs and no significant
    differences in mortality were found between treated and control
    animals of either species. The final body weight was significantly
    (P < 0.05) lower in treated female rats than in corresponding
    controls. In male rats the absolute and relative liver and kidney
    weights were significantly (P < 0.01) increased, but in females
    this applied only to the relative kidney weights (P < 0.05).
    Histologically, chronic nephropathy was seen in both control and
    treated groups of male rats. However, treated males were more
    severely affected than the controls, while treated females showed
    only slight nephropathy. The incidence of epithelial hyperplasia of
    the renal papilla was significantly (P < 0.05) increased in treated
    male rats as was the incidence of renal tubular hyperplasia (30/30)
    and renal tubular adenomas (14/30).

         The authors found that renal cell tumour development in male
    rats under the long-term influence of hydroquinone was not
    associated with alpha2u-globulin nephropathy. The incidence of liver
    foci showed a tendency to decrease in treated males. A quantitative

    analysis showed a statistically significant (P < 0.05 in males, P<
    0.01 in females) reduction in both sexes given hydroquinone. The
    authors did not find an increased incidence of mononuclear cell
    leukaemia in female rats (personal communication).

         In mice, the final body weight was significantly (P < 0.05)
    lower in females given hydroquinone; the relative liver and kidney
    weights were significantly (P < 0.05) increased. Histologically,
    the incidence of squamous cell hyperplasia of the forestomach
    epithelium was significantly (P < 0.01) increased in both sexes. A
    significant increase in the incidence of renal tubular hyperplasia
    (P < 0.01) and three renal cell adenomas were seen in 30 males
    given hydroquinone. In treated males the incidence of liver foci and
    hepatocellular adenomas (14/30) was also significantly (P < 0.05)

    7.7.2  Carcinogenicity-related studies  Skin

         In a study by Roe & Salaman (1955), stock albino mice (24
    males, "S" strain) were given a single skin application of 0.3 ml of
    a 6.7% solution of hydroquinone in acetone (total dose 20.0 mg).
    Three weeks later the mice received 18 weekly applications of 0.3 ml
    of 0.5% croton oil in acetone as a promoter on the same area of the
    skin. Of the 24 treated animals, two died during the experiment and
    one mouse developed a skin papilloma.

         In a two-stage carcinogenesis test on mouse skin using
    benzo[ a]pyrene (BP) as the initiating agent, no tumour-promoting
    activity was shown (Van Duuren & Goldschmidt, 1976). Hydroquinone (5
    mg) was applied to mouse skin (50 female ICR/Ha Swiss mice/group;
    both positive and negative controls) three times weekly for 368
    days, together with 5 µg BP. Hydroquinone showed no potential as a
    co-carcinogen when applied simultaneously with BP; in fact, it
    partially inhibited BP carcinogenicity.  Bladder

         Implantation of cholesterol pellets containing hydroquinone
    into the urinary bladder of mice (strain and sex unspecified) has
    been studied by Boyland  et al. (1964). The amount of hydroquinone
    was 20% in 10 mg cholesterol pellets (2 mg hydroquinone per mouse).
    Bladder carcinomas were produced in 6 out of 19 mice (32%) surviving
    25 weeks. The incidence of urinary bladder carcinomas in survivors
    of the dosed group was significantly (P=0.03) higher than in
    controls (11.7%) given cholesterol pellets only. However, the number
    of animals surviving the study was low, and the original number of
    animals and their sex distribution were not specified.

         In a study by Kurata  et al. (1990), groups of 20 male
    Fischer-344 rats received 0.05%  N-butyl- N-(4-hydroxybutyl)
    nitrosamine in the drinking-water for four weeks (as initiation)
    followed by 8 g hydroquinone/kg in the basal diet for 32 weeks. No
    increase in the incidence of preneoplastic lesions or
    papillomas/carcinomas of the urinary bladder was observed when
    compared to the incidences in rats given nitrosamine alone.  Stomach

         Hirose  et al. (1989) examined the promotion activity and the
    carcinogenic potential of some dihydroxybenzenes, such as
    hydroquinone, in the glandular stomach and forestomach of F-344
    rats. Groups of 15-16 male rats were given a single intragastric
    dose of 150 mg/kg body weight  N-methyl- N'-nitro- N-
    nitrosoguanidine (MNNG), followed one week later by powdered diet
    containing hydroquinone (8g/kg) or basal diet alone for 51 weeks.
    Further groups of 10 and 15 animals, respectively, were administered
    the basal diet alone or a diet containing hydroquinone (8 g/kg) for
    51 weeks without pretreatment with MNNG. Hydroquinone did not cause
    an increased incidence of forestomach or glandular stomach lesions,
    either with or without pretreatment with MNNG, in comparison with
    the control groups.

         In studies performed by Hirose  et al. (1986), hydroquinone
    did not produce proliferative lesions in the stomach of hamsters.
    Male Syrian golden hamsters (15/group, seven weeks old at the
    beginning of the study) were given basal diet with hydroquinone (5
    g/kg) added or basal diet alone for 20 weeks. The dose was chosen as
    approximately a quarter of the LD50. Tissues from forestomach and
    glandular stomach showed mild to moderate hyperplasia in the group
    given hydroquinone, but at the same incidence as in the controls.
    Similar results were obtained by Shibata  et al. (1990) in an
    8-week oral study using five male F-344 rats. Hydroquinone did not
    induce any proliferative changes in the forestomach or the glandular
    stomach epithelium.  Liver

         Hydroquinone has been shown to be a relatively weak inducer of
    enzyme-altered foci in rat liver when tested for tumour-promoting
    activity in a liver focus test (Stenius  et al., 1989). Male
    Sprague-Dawley rats (7-10/group) given diethylnitrosamine (30 mg/kg
    intraperitoneally) after partial hepatectomy were treated with
    hydroquinone (0, 100 and 200 mg/kg per day) in their diet for 7
    weeks. At 100 mg/kg there was a significantly (P < 0.01) increased
    number of liver foci and an increased focus volume. The 200-mg dose
    caused less foci (0.34 ± 0.16 per cm2) than the 100-mg dose (0.65
    ± 0.25 per cm2), but the incidence was higher than in the control
    group (0.08 ± 0.08 per cm2).

         A study by Kurata  et al. (1990) yielded similar results
    concerning the tumour-promoting potential of hydroquinone in rats.
    Dietary administration of hydroquinone (8g/kg in basal diet) for 32
    weeks, after initiation for four weeks with  N-butyl- N-
    (4-hydroxybutyl) nitrosamine, caused no preneoplastic lesions or
    papillomas of the urinary bladder.

    7.8  Special studies

    7.8.1  Effects on spleen and bone marrow cells; immunotoxicity

         The bone marrow is the target in benzene toxicity; among the
    many metabolites of benzene, hydroquinone has received increased
    scrutiny as one of the possible contributing factors. Intravenous or
    intraperitoneal administration of hydroquinone (100 mg/kg) for three
    consecutive days to male C57BL/6 CRIBR mice significantly (P <
    0.05) reduced the spleen and bone marrow cellularity, with bone
    marrow demonstrating the greatest sensitivity (Wierda & Irons,
    1982). Laskin  et al. (1989) found that after injection in Balb/c
    mice hydroquinone (50 mg/kg) caused a 30-40% decrease in bone marrow

          In vitro studies have demonstrated direct myelotoxic effects
    of hydroquinone toward mouse bone marrow stromal cells (Gaido &
    Wierda, 1984; Gaido & Wierda 1987). Hydroquinone inhibited stromal
    cell colony growth along with the ability of these cells to support
    granulocyte/monocyte colony formation in co-culture. The bone marrow
    stroma predominantly consists of macrophages and fibroblastoid
    stromal cells which interact to regulate myelopoiesis. Treatment
    with hydroquinone thus results in reduced capacity of the stroma to
    support myelopoiesis.

         In addition to this cytotoxic effect, Wierda & Irons (1982)
    found in  in vivo studies that hydroquinone also affected the
    immune function by reducing the number of progenitor B-lymphocytes
    in the spleen and bone marrow in mice, thus demonstrating an
    immunosuppressive potential. The rapid generation and maturation of
    progenitor B cells renders them highly susceptible to toxic agents
    that affect dividing cells. Evidence has accumulated concerning the
    effect of hydroquinone on the cellular activity of the immune system
     in vitro. Exposure of lymphocytes  in vitro to hydroquinone has
    been shown to result in a dose-dependent inhibition of RNA synthesis
    in the lymphocytes (Post  et al., 1985). A hydroquinone
    concentration of 1-2 x 10-5 mol/litre inhibited the RNA synthesis
    by 50%.

          In vitro exposure (one hour) of mouse bone marrow cells to
    hydroquinone (10-7-10-5 mol/litre) inhibited the maturation of
    B-lymphocytes from pre B-cells after 24 and 48 h in culture (King
     et al., 1987). More recent data have demonstrated that
    hydroquinone-induced inhibition of pre-B cell maturation results

    from toxicity to adherent stromal cells, and that bone marrow
    macrophages may be the primary target for hydroquinone
    myelotoxicity, rather than fibroblastic stromal cells or pre-B cells
    (King  et al., 1989; Thomas  et al., 1989a). Results also indicate
    a dose-related reduction of macrophage interleukin-1 (IL-1)
    secretion in cultures of bone marrow macrophages exposed to
    hydroquinone (King  et al., 1989; Thomas  et al., 1989b). IL-1 is
    necessary for the induction of interleukin-4 (IL-4), which is
    produced by fibroblastic stromal cells and is required for
    maturation of pre-B cells to B cells (King  et al., 1989).

         Fan  et al. (1989) demonstrated that hydroquinone can inhibit
    the natural killer activity of mouse spleen cells  in vitro at low
    concentrations. Concentrations of 1 x 10-5 mol/litre and 1 x
    10-6 mol/litre inhibited 29 and 22% of the activity, respectively.
    Lewis  et al. (1988b) found that hydroquinone had a selective
    effect on macrophage functions important in host defense. At
    concentrations of 3-100 µmol/litre, hydroquinone significantly
    (P < 0.05) inhibited the release of hydrogen peroxide and at 100
    µmol/litre it significantly (P < 0.05) inhibited priming by
    interferon for tumour cell cytolysis. Cheung  et al. (1989) have
    shown a concentration-dependent inhibition of interferon-alpha/ß
    production following exposure to hydroquinone in murine L-929 cell

    7.8.2  Effects on tumour cells

         The cytotoxic activity of hydroquinone has been tested on
    different tumour cells. Chavin  et al. (1980) studied the effect on
    melanoma transplants in female BALB/c mice. The incidence of
    melanoma transplants was reduced and the survival significantly (P
    < 0.0005) increased in mice that received hydroquinone treatment
    (80 mg/kg).

         Vladescu & Apetroae (1983) studied the molecular mechanisms of
    antitumour action and the possibilities of using hydroquinone as a
    toxic agent against cancer cells. In H 18R tumour-bearing male
    Wistar rats treated with hydroquinone (5 mg/kg per day) for seven
    days, the catalase activity was markedly depressed in liver, spleen,
    blood and H 18R tumour.  In vitro studies on tumour and liver
    homogenates from normal and tumour-bearing rats showed a marked
    inhibition of catalase activity in the tumour, which was less
    evident in the liver. The activity was less reduced in normal liver
    homogenates. It was suggested that the mechanism of action of
    hydroquinone as an antitumour agent is achieved mainly via peroxide

         When tested on cultured rat hepatoma cells hydroquinone showed
    a dose-dependent cytotoxic activity (Assaf  et al. 1987). A dose of
    33 mg/litre (300 µmol/litre) caused cellular mortality of 40% after

    24 h of incubation and 66 mg/litre (600 µmol/litre) resulted in 100%
    cellular mortality.

    7.8.3  Neurotoxicity

         Hydroquinone, given as single oral or subcutaneous lethal
    doses, causes nonspecific effects on the nervous system such as
    hyperexcitability, tremor and convulsions in several experimental
    animal species (see section 7.1). Animals given sublethal oral doses
    recover within a few days.

         These central nervous system stimulation effects were confirmed
    in a 90-day oral study on rats (Eastman Kodak Company, 1988) (see
    also section 7.3). Male and female weanling rats (CD(SD)BR),
    initially seven weeks old, were treated with hydroquinone (20, 64 or
    200 mg/kg per day) dissolved in water at a concentration of 5%.
    Doses were given by gavage 5 days per week. Functional-observational
    battery examinations were performed throughout the study. The
    battery included observations of body position, activity level,
    coordination of movement and gait, behaviour, presence of
    convulsions, tremors, lacrimation, salivation, piloerection,
    pupillary dilatation or constriction, respiration, diarrhoea,
    urination, vocalization, forelimb/hindlimb grip strength and sensory
    function. Tremors and depression of general activity were observed
    in both sexes shortly after dosing with 64 or 200 mg
    hydroquinone/kg. Functional-observational battery examinations did
    not result in any evidence of neurotoxicity as assessed by
    quantitative grip strength measurement, brain weight or
    neuropathological examination. The NOEL was considered to be 20 mg
    hydroquinone/kg body weight.

         Otsuka & Nonomura (1963) reported that hydroquinone reversed
    curare blockage at neuromuscular junctions in frog sciatic nerve -
    sartorius muscle preparations. The authors suggested that this
    effect was due to an increased release of transmitter at the
    neuromuscular junction induced by hydroquinone.

    7.8.4  Nephrotoxicity

         Until recently, exposure to hydroquinone has not been
    associated with nephrotoxicity. Nephrotoxicity has not been reported
    following either occupational exposure to hydroquinone or acute
    exposures in humans. Carlson & Brewer (1953) gave human volunteers
    daily hydroquinone doses of 300 or 500 mg/day for periods of up to
    20 weeks without effects on urinalysis parameters. Exposure of five
    male mixed-breed dogs to 100 mg hydroquinone/kg per day for 26 weeks
    had no effect on urinalysis parameters or renal histopathology
    (Carlson & Brewer, 1953). Christian  et al. (1976) reported that
    exposure of Carworth rats to hydroquinone in the drinking-water at
    concentrations of up to 10 g/litre (6 rats of each sex per group for
    8 weeks) or up to 4 g/litre (20 rats of each sex per group for 15

    weeks) resulted in slight changes in kidney weight but no
    histopathological changes. Carlson & Brewer (1953) also reported no
    evidence of renal histopathological changes in Sprague-Dawley rats
    fed diets containing 10g hydroquinone/kg for 104 weeks.

         NTP (1989) reported that oral gavage of hydroquinone (0, 25,
    50, 100, 200 or 400 mg/kg) in corn oil for 13 weeks resulted in
    toxic nephropathy in F-344 rats at the two highest dose levels (200
    mg/kg: 7/10 males, 6/10 females; 100 mg/kg: 1/10 females). Oral
    gavage of 0, 25 or 50 mg/kg in water for 15 months resulted in an
    increased incidence of chronic nephropathy in male F-344 rats (25
    mg/kg: 5/5 males; 50 mg/kg: 6/10 males). When male F-344 rats were
    dosed at 0, 25 or 50 mg/kg for two years, there was an increased
    severity of chronic progressive nephropathy in 20/55 animals given
    50 mg/kg. At a dosage level of 50 mg/kg for either 15 months or 2
    years, male rats had heavier relative kidney weights.

         Shibata  et al. (1991) also reported that F-344 rats developed
    chronic nephropathy when fed 8g hydroquinone/kg diet for 2 years.
    Male rats showed increased relative and absolute kidney weight, as
    well as an increased severity of chronic nephropathy (14/30
    animals). Female rats showed an increased relative kidney weight,
    but only a minimal increase in severity of chronic nephropathy in
    7/30 animals.

         Boatman  et al. (1992) reported on the urinalysis changes
    observed in male and female F-344 rats and Sprague-Dawley rats given
    single doses of 0, 200 or 400 mg hydroquinone/kg in water by oral
    gavage. B6C3F1 mice were examined after receiving doses of 0 or
    350 mg/kg in a similar fashion. The placement of venous catheters in
    F-344 rats increased their response to hydroquinone. At 400 mg/kg,
    male and female F-344 rats, but not Sprague-Dawley rats, displayed
    pronounced enzymuria and glucosuria, which resolved in 72-96 h. At
    200 mg/kg, enzymuria and glucosuria were present in female F-344
    rats but not males. Epithelial cell counts in the urine were
    statistically significantly increased (P < 0.05) at 400 mg/kg
    (male and female F-344 rats only) and 200 mg/kg (female F-344 rats
    only). Statistically significant (P < 0.05) decreases in
    osmolality were reported at 400 mg/kg for F-344 (both sexes) and
    female Sprague-Dawley rats. Diuresis (ml urine/h) was statistically
    significant (P < 0.005) only for female F-344 rats at 200 mg/kg
    and 400 mg/kg. Although differences were observed in some of the
    urinary parameters measured, mice were generally not responsive to

         To characterize the early development of renal toxicity in
    rats, cell proliferation was quantified within the proximal (P1, P2
    and P3) and distal tubular segments of the kidney in rats given 0,
    2.5, 25 or 50 mg hydroquinone/kg by oral gavage. Male and female
    F-344 rats were treated for 1, 3 or 6 weeks, and male Sprague-Dawley
    rats were treated for 6 weeks. At 6 weeks, an 87% increase in cell

    proliferation was measured in the P1 segment, a 50% increase in the
    P2 segment, and a 34% increase in the P3 segment from kidneys of
    male F-344 rats dosed with 50 mg/kg. Urinalysis indicated increased
    enzymuria in this same dose group, and mild histological changes
    were present in the kidneys. Animals examined at other time points
    or from other dose groups were not affected by hydroquinone.

         The increased incidence of renal adenomas only in male F-344
    rats (NTP, 1989) has led to speculation that the tumours observed
    may be related to alpha2u-globulin-induced nephropathy. This
    mechanism of action for induction of kidney tumours does not appear
    to be relevant for hydroquinone as none of the studies cited above
    has reported finding evidence of hyalin droplet nephropathy
    following subacute, subchronic or chronic hydroquinone exposure.

         Glutathione metabolites, which are at least partially formed in
    the liver and transported to the kidney, are reported to be involved
    in the nephrotoxicity observed. Some of the potential glutathione

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