IPCS INCHEM Home

    CLOFENTEZINE

    EXPLANATION

         Clofentezine is an acaricide used for the residual control of
    mites. It acts primarily as an ovicide, with some activity on early
    motile stages. It was considered for the first time by the present
    meeting.

    IDENTITY AND PROPERTIES

    CHEMICAL NAME

    3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine (IUPAC)
    3,6-bis(0-chlorophenyl)-1,2,4,5-tetrazine

    SYNONYMS                    Apollo, Apolo, Acaristop; FBC code number
                                NO 21314

    STRUCTURAL FORMULA
    CHEMICAL STRUCTURE 1

    EMPIRICAL FORMULA           C14 H8 Cl2 N4

    MOLECULAR MASS              303.15

    PHYSICAL STATE              Both pure and technical materials are
                                magenta-coloured crystalline solids.

    MELTING POINT               182 - 186C (pure compound)
                                179 - 182C (technical product)

    VAPOUR PRESSURE             Approximately 10-16 mm Hg = 10-14 Pa at
                                25C.

    SOLUBILITY                  Solubility (pure a.i.) at 20C:
                                chloroform             5   %
                                dichloromethane        3.5 %
                                acetone                0.5 %
                                benzene                0.25%
                                ethanol              < 0.1 %
                                hexane               < 0.1 %
                                solvesso 200           0.25%
                                water                < 1  g/1

    OCTANOL/WATER PARTITION
        COEFFICIENT             log P = 3.1

    STABILITY (a.i.)            The stability in aqueous solutions is pH-
                                and temperature-dependent; at pH 7 and
                                22C, the half-life is approximately
                                35 hours, whereas at pH 5 and 22C the
                                half-life is approximately 250 hours.

    STABILITY (formulations)    50% wettable powder: stable under storage
                                conditions at 40C for 6 months; 50%
                                aqueous suspension concentrate: stable
                                under storage conditions at 12 - 38C for
                                12 months.

    SPECIFICATION OF
        TECHNICAL MATERIAL      The technical material has a purity in
                                excess of 96% w/w, with the main
                                impurities being:

        (a)  4-amino-3,5-bis(2-chlorophenyl)-4H-1,2,4-triazole      <1%
        (b)  3,6-bis(2-chlorophenyl)-1,2-dihydro-1,2,4,5-tetrazine  <1%
        (c)  2,5-bis(2-chlorophenyl)-1,3,4-oxadiazole               <1%
        (d)  total volatiles (water and acetic acid)                <1%.

    FORMULATIONS AVAILABLE
        COMMERCIALLY            50% wettable powder; 50% aqueous
                                suspension concentrate.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Mice

         14C-Labelled clofentezine was administered orally at single
    doses of 10 mg/kg b.w. to 8 male and 8 female mice. Ninety-six hours
    after dosing, 91 - 95% of the administered dose had been recovered in
    the excreta, particularly in the faeces. Residues after 96 hours were
    highest in the liver (0.11 g/g in males and 0.18 g/g in females).
    All other tissues (including plasma) contained substantially lower
    residues, in most cases below the limit of detection (Campbell &
    Needham, 1982a).

    Rats

         Groups of 5 male and 5 female rats received single oral doses of
    0.1, 10, or 1000 mg 14C-clofentezine/kg b.w. or 0.1 mg
    14C-clofentezine (in ethanol)/kg b.w. i.v. Eighty-nine hours after
    dosing, 22  29% of the administered 14C-clofentezine in the low-dose
    groups had been recovered in the urine. Tissue residues were generally
    below the detection limit (< 0.01 g/g), with occasional samples
    of liver, kidney, spleen, and heart tissues containing measurable
    residues (0.01 - 0.02 g/g). Urinary excretion accounted for 19%
    (males) and 20% (females) of the administered dose after administra-
    tion of 10 mg 14C-clofentezine/kg b.w., with the highest residues
    in the liver (0.22 - 0.46 g/g) and kidneys (0.12-1.28 g/g). Plasma
    levels were 0.07 - 0.22 g/ml, and the remaining tissues contained
    0.02 - 0.2 g/g in the mid-dose group. Urinary excretion fell to only
    2.0% (males) and 4.5% (females) after the administration of 1000 mg
    14C-clofentezine/kg b.w. In the faeces these percentages amounted
    to 99% and 96%, respectively. The highest residues were found in
    plasma (9.2-19.5 g/ml), adrenals (2.9-17.1 g/g), liver (2.8-14.0
    g/g), and fat (3.6 - 9.4 g/g) (Challis & Needham, 1981a; 1982a,b).

         Ninety-six hours after i.v. administration of 0.1 mg 14C-clofen-
    tezine/kg b.w., 25 - 29% of the administered dose had been recovered
    in the urine, while in the faeces the residues were 82-85%. Tissue
    residues were very low (< 0.01 g/g) (Challis & Needham, 1983).

         An examination of the distribution of radioactivity using
    whole-body autography, 24 hours after the oral administration of 10 mg
    14C-clofentezine/kg b.w. to rats, showed that the liver, kidneys,
    and gut contain significant amounts of radioactivity. The carcass was
    clear of residues 96 hours after dosing (Needham, 1982).

         Rats (25/sex) received single oral doses of 10 mg 14C-clofen-
    tezine/kg b.w. Residues in plasma were measured 5 minutes to 18 hours
    after dosing. Total radioactivity showed maximum values of 1.3 - 1.6
    g/ml between 4 and 6 hours after dosing, which declined to 0.02 g/ml
    at 18 hours after dosing. The concentration of clofentezine reached a
    maximum at 4 - 6 hours after dosing and then declined, with a half
    life of 2.5 - 2.7 hours (Campbell & Challis, 1982).

         Total radioactivity and unchanged clofentezine in plasma of rats
    dosed with 1000 mg 14C-clofentezine/kg b.w. rose to a maximum of
    14-16 mg/l and 6 - 8 mg/l, respectively, between 6 and 8 hours after
    dosing. Unchanged clofentezine declined, with a half-life of 3.6 hours
    (Campbell & Needham, 1985b).

         When rats were fed daily oral doses of 20 mg clofentezine/kg b.w.
    for 25 days, the highest residues were found in the liver (3.2-4.4
    g/g). After 5 - 10 days a plateau was reached in the liver, kidneys,
    skin, and ovaries, with residues being 2 - 4 times higher than after
    1 day. For residues in the adrenals, muscle, lung, and fat, no
    definite plateau could be established, but residues in fat were 8
    times higher after 25 days than after 1 day. No accumulation occurred
    in bone, brain, spleen, testes, or blood (Challis & Needham, 1981c).

         Pre-treatment with clofentezine (27 g/kg diet for 28 days) prior
    to an i.v. dose of 0.1 mg 14C-clofentezine/kg b.w. resulted in an
    increase in urinary excretion (34% of the radiolabelled dose in both
    sexes). Tissue levels were not significantly altered (Challis &
    Needham, 1981b).

         Pre-treatment with clofentezine (10 mg/kg diet for 14 days) prior
    to an oral dose of 10 mg/kg 14C-clofentezine/kg diet did not change
    the excretion profile nor the residues disposition. The concentration
    of unchanged clofentezine in plasma reached a maximum of 0.11-0.19
    g/ml and declined, with a half-life of 1.6 hours. These results are
    consistent with an increase in the rate of metabolism when compared
    to a single dose (Challis & Needham, 1982c) (Campbell & Needham,
    1985a).

         Pregnant rats received single oral doses of 10 mg 14C-clofen-
    tezine/kg b.w. on day 20 post-coitum (p.c.) after being orally dosed
    with 3200 mg clofentezine/kg b.w. from days 7 to 13 p.c., 320 mg/kg
    b.w. on day 14 p.c., and then remaining untreated from days 15 to
    19 p.c. Residue levels were much lower in the fetus (0.7-1.2 g/g)

    than in the maternal plasma (3.7 - 6.4 g/g) 6 hours after dosing,
    showing that clofentezine and/or its metabolites do not readily cross
    the placenta. The clearance rate from the fetus appeared to be slower
    than from the maternal tissues (Needham, 1981).

    Rabbits

         Rabbits (3/sex) were orally dosed with 10 mg 14C-clofen-
    tezine/kg b.w. Urine and faeces were collected over 96 hours. In the
    first 48 hours, 88% of the dose was excreted (35% in the urine and 53%
    in the faeces). Residues after 96 hours were highest in the liver and
    kidneys (0.24 g/g and 0.90 g/g, respectively) (Campbell & Needham,
    1982b).

    Dogs

         After oral administration of 10 mg/kg 14C-clofentezine to dogs
    (3/sex), 96% of the dose was excreted in the first 48 hours, mainly in
    the faeces (94%). Nearly complete excretion (99%) was observed after
    96 hours, with only 2.0% in the urine. Residues were highest in bile
    (1.56 g/ml), liver (0.21 g/g) and thyroid (0.15 g/g). All other
    tissues contained substantially lower residues. Peak plasma
    concentration (0.06 g/ml) occurred 4 - 8 hours after dosing and by 72
    hours it was reduced to 0.01 g/ml or less (Campbell & Needham,
    1982c).

         Dogs (2/sex) received single i.v. doses of 0.1 mg 14C-clofen-
    tezine/kg b.w. The bulk of the dose was excreted in the first 48
    hours, mainly in the faeces (69%), and 21% in the urine. Tissue
    residues measured 144 hours after dosing were, with few exceptions,
    below the limit of detection (< 0.01 /g) (Campbell & Needham, 1981).

    Baboons

         A male and a female baboon were each given a single oral dose of
    10 mg 14C-clofentezine/kg b.w. Ninety-six hours after dosing 15 -
    28% of the administered dose was excreted in the urine and 42 - 44% in
    the faeces. Cage debris and wash together accounted for 9%. Tissue
    concentrations of radioactivity 96 hours after a second oral dose of
    14C-clofentezine (following 52 daily doses of up to 400 mg
    unlabelled clofentezine starting 96 hours after the first oral dose)
    were similar in both baboons. The highest concentrations were detected
    in fat, liver, and kidneys (0.06 - 0.23% of administered
    radioactivity/kg wet tissue) while tissue-to-plasma ratios were
    on the order of 3 - 10 (Sortwell et al., 1983).

    Biotransformation

         The metabolism of clofentezine was studied in rats. Urine and
    faeces were collected 24 hours after dosing in a series of experiments
    in which rats received 14C-clofentezine orally at 10 mg/kg b.w.
    Absorbed clofentezine was extensively metabolized, with only 3% of the
    radioactivity in the urine present as the parent compound. Two major
    urinary pathways have been identified, one leading to a monochloro
    sulfur-containing derivative, 3-(2'-methylthio-3'-hydroxyphenyl)-
    6-(2'-chlorophenyl)-1,2,4,5-tetrazine (in free and conjugated forms
    this metabolite accounted for 35% of the urinary radioactivity), and
    the other involving hydroxylation of clofentezine at the 3, 4, or 5
    positions (see Figure 1). At least half of the administered dose was
    excreted in the faeces unchanged. The remaining clofentezine was
    extensively metabolized to more than 20 minor metabolites (Challis &
    Needham, 1985).

    a figure that could possibly be photocopied is on p. 9 of the summary
    submitted by FBC Ltd.

    CHEMICAL STRUCTURE 2

    Figure 1. The metabolism of clofentizine in animals.

         Metabolites were also identified in a study with baboons.
    4-Hydroxy-clofentezine in free and conjugated (beta-glucuronide
    conjugate) forms accounted for over 70% of the urinary metabolites.
    Other minor metabolites included 3-hydroxy-clofentezine (present as
    phenol and glucuronide conjugates) and a mono-chloro sulfur-containing
    compound, each accounting for less than 1% of the extractable
    radioactivity (Sortwell et al., 1983).

         The metabolism of clofentezine in rats, mice, rabbits, calves,
    goats, dogs, and baboons was qualitatively similar, with hydroxylation
    and replacement of chlorine with a methylthio group being the major
    pathways (see Figure 1). In calves and baboons, hydroxylation and
    subsequent conjugation were the most important pathways, while
    methylthiolation was more prominent in rodents and rabbits (Challis,
    1985).

         The chromatographic profiles of liver extracts from rats, goats,
    and calves following oral administration of 14C-clofentezine were
    qualitatively similar to that of rat urine, with conjugates of 3-, 4-,
    and 5-hydroxylated clofentezine and a 3-(methylthio-hydroxyphenyl)-6-
    (2'-chlorophenyl)-1,2,4,5-tetrazine isomer (Needham & Challis, 1985).

    Toxicological studies

    Special studies on the endocrine system

         After treatment of male rats with 0 or 3% clofentezine for
    1 month, a slight decrease in thyroxine (T4) half-life was observed
    in dosed rats compared to control animals (a slight increase occurred
    over this time period in the controls). A comparison of the effect of
    clofentezine treatment (0 and 3% for 4 weeks) in rats and mice (both
    sexes) showed that in rats there was a significant and rapid increase
    in thyroid uptake of iodine (compared to control animals) following
    i.p. dosing with [131I]-sodium iodide. This effect was not observed
    in mice (Challis & Creedy, 1985).

         Groups of 10 rats/sex were fed diets containing 0, 400, or
    30,000 ppm technical clofentezine for 6 weeks. At 30,000 ppm
    clofentezine, T4, free T4 index, thyrotropin (TSH), progesterone,
    dehydroepiandrosterone, and liver weights were significantly increased
    in both sexes. Triiodothyronine (T3) was significantly increased in
    males only. Body weights and thyroxine binding capacity were
    significantly reduced in females. At 400 ppm clofentezine, T4 and
    liver weight were significantly increased in males and dehydroepi-
    androsterone was significantly increased in females (Saunders & Mallyon,
    1986).

    Special studies on enzyme induction

    Mice

         Groups of 9 - 10 male Charles River CD1 mice received
    clofentezine at dietary levels of 0, 40, or 27,000 ppm for 8 weeks
    prior to examination of their livers for aniline hydroxylase and
    aminopyrine demethylase activities, for levels of cytochromes P-450
    and b5, and for microsomal protein concentration. At 27,000 ppm the
    levels of cytochrome P-450 and b5 were increased 3-fold. The activity
    of aminopyrine demethylase rose by a factor of 2.2 and the mean liver
    weights increased by 35%. There was a marginal effect on the enzyme
    induction system at 40 ppm (Needham et al., 1984).

    Rats

         Groups of 6 male Charles River CD rats were fed diets containing
    clofentezine at levels of 0, 40, or 27,000 ppm for 8 weeks.
    Twenty-four hours after the final dose, their livers were examined for
    aniline hydroxylase activity, for levels of cytochromes P-450 and b5,
    and for microsomal protein concentration. At 27,000 ppm a 50% increase
    in the level of cytochrome P-450 and 2-fold increases in the level of
    cytochrome b5 and in the activity of aniline hydroxylase were found.
    In a subsequent study it was discovered that the effect could be
    reversed after a 2-week withdrawal period. No induction was observed
    at 40 ppm (Needham et al., 1983a,b).

         In a more extensive study, male and female rats were given diets
    with 0, 10, 40, or 400 ppm clofentezine for 2 weeks. At 400 ppm there
    was an increase in the level of liver protein (+ 12%), aldrin
    epoxidase (22 - 32%), ethoxycoumarin deethylase (20 - 49%), and
    cytochrome P-450 (24 - 26%) in both sexes. Liver weights and
    cytochrome b5 were increased in males only. At 40 ppm, liver
    ethoxycoumarin deethylase was slightly increased in males only
    (Creedy et al., 1985).

    Special studies on mutagenicity

         Clofentezine was negative in various mutagenicity assays
    (Table 1).

        Table 1:  Results of mutagenicity assays on clofentezine
                                                                                                

                         Test                  Concentration
    Test system          Object                of clofentezine      Results        Reference
                                                                                                

    Ames testa           Salmonella            10 - 3300            negative       McConville,
                         typhimurium           g/plate                            1980
                         TA98, TA100,
                         TA1535, TA1537,
                         and TA1538

    Yeast testa,b        Saccharomyces         12.5 - 200           negative       Riach &
                         cerevisiae D7         g/ml                               McGregor, 1983

    Mouse lymphoma       Mouse L 5178Y         0 - 128              negative       Bootman &
       assaya            TK +/- cells          g/ml                               Rees, 1982

    Micronucleus         Mouse                 2  0 to             negative       Hounsell, 1982
       assay (bone                             3200 mg/kg
       marrow)                                 in 0.5%
                                               aqueous gum,
                                               orally

    Dominant             Rat (males)           0 to 400             negative       Jackson, 1983
       lethal test                             mg/kg in
                                               the diet
                                               for 10 weeks
                                                                                                
    a  with and without metabolic activation
    b  gene conversion and mitotic recombination
        Special study on reproduction

    Rats

         Groups of 6-week old Charles River rats (30 - 40/sex) were fed
    diets containing 0, 4, 40, or 400 ppm clofentezine. After 74 days of
    treatment the rats were paired for 20 days to start a 2-generation
    (2 litters/generation) study. Diets were maintained during mating,
    gestation, and lactation. Weanlings from the second litter were
    selected to become parents of the next generation. The F2a litters
    were grown to maturity.

         In the parental generations clinical signs and food consumption
    of treated rats were comparable to those of the control rats. Mating
    performance, pregnancy rate, fertility, and the duration of gestation
    and parturation were unaffected by clofentezine treatment. Parental
    toxicity was observed at 400 ppm, which included reduced body-weight
    gain of F1- and F2-generation females (maturation) and
    F1-generation females (post-coitum and post-partum), as well as
    significantly increased liver weights in F1- and F2-generation
    males. The increased liver weight was associated with minimal
    centrilobular hepatocyte enlargement and a slight reduction in
    periportal fat deposition. Toxic effects on litters included
    significantly reduced F1a and F2a pup weights and significantly
    smaller F2b litter sizes. The only toxic effect at 40 ppm was a
    significant increase in liver weights of F2a males. No adverse
    effects on fertility or reproductive performance were observed at 4 or
    40 ppm clofentezine (Jackson & Chambers, 1984).

    Special studies on skin and eye irritation

         Application of clofentezine (0.2 ml of 333 mg/ml suspension) to
    the intact and abraded skin of 6 guinea pigs showed pink staining and
    very slight edema (in 2 out of 12 treated areas), both receding during
    observation (Crome et al., 1980b).

         A dermal irritation study with 6 guinea pigs was conducted with
    clofentezine using the 50% wettable powder formulation (0.2 ml of 6 or
    947 mg/ml suspension). Observations were carried out at 24 hours and
    then daily for one week. Pink staining and erythema (between moderate
    and severe) were observed in all animals treated with 947 mg/ml
    suspension, and slight erythema was observed in 3/6 guinea pigs
    treated with 6 mg/ml suspension. The erythema regressed in one week.
    In 2/6 guinea pigs treated with 947 mg/ml suspension, very slight
    erythema was present when the animals were subjected to post-mortem
    examination (no abnormalities were observed) (Crome & Sanderson,
    1981b).

         Treatment of the intact and abraded skin of 6 New Zealand white
    rabbits with clofentezine in 50% aqueous suspension produced very
    slight edema in 1/6 animals after 24 hours, with full recovery after
    72 hours. Erythemal response could not be scored because of the bright
    pink color of the test substance (Cuthbert et al., 1983).

         Undiluted clofentezine (50% aqueous suspension) caused mild
    conjunctival irritation 24 hours after installation; it had
    disappeared at 48 hours (Cuthbert & Carr, 1983).

    Special study on skin sensitization

         Clofentezine had no sensitizing potential in guinea pigs when
    tested by the Magnusson & Kligman method (Teale, 1982).

    Special studies on teratogenicity

    Rats

         Groups of 34 - 35 pregnant female Sprague-Dawley CD rats received
    0, 320, 1280, or 3200 mg clofentezine/kg b.w. by gavage from days 7 to
    20 post-coitum (p.c.). The dams were examined twice daily for
    mortality, appearance, and behaviour. Body weights were recorded on
    days 1 and 4 and on days 7 to 21 p.c. The dams were killed on day 21
    of pregnancy. The number of implantations, resorptions (early and
    late), corpora lutea, and uteri were determined, as well as placental
    weight, weight and histopathology of the liver of the dams, number of
    live and dead fetuses, litter and pup weights, sex ratios, gross
    pathology, and histopathology (skeletal and visceral) of the fetuses.

         Maternal toxicity was observed at 1280 and 3200 mg/kg b.w. At the
    highest dose, body weights were significantly decreased (also when
    corrected for uterine content). Dose-related and significantly
    increased relative liver weights were observed at all dose levels;
    when corrected for the uterine contents, the increase was significant
    only at 1280 and 3200 mg/kg b.w. At histopathology, slight
    differential staining and enlargement of centrilobular hepatocytes
    were seen at 3200 mg/kg b.w. Litter size, litter weight, mean
    placental weight, and post-implantation losses were not affected at
    any of the treatment levels, although mean fetal weight was increased
    at 3200 mg/kg b.w.

         Embryonic and fetal development were unaffected by treatment
    (Jackson, 1982).

    Rabbits

         Groups of 14 - 15 pregnant New Zealand white rabbits were
    administered daily doses of 0, 250, 1000, or 3000 mg clofentezine/kg
    b.w. by gavage on days 7 to 28 of gestation. All animals were killed
    on day 29 of pregnancy. The dams were examined for mortality,

    appearance, behaviour, body weight, food consumption, serum
    cholesterol and serum triglyceride (day 29), weight of uterus, number
    of implantations, resorptions (early and late), and corpora lutea. The
    fetuses, delivered by caeserean section, were examined for the number
    alive and dead, litter and pup weight, gross pathology, and
    histopathology (skeletal and visceral).

         Maternal body-weight gain was significantly reduced at
    3000 mg/kg b.w. (and to a lesser extent at 1000 mg/kg b.w.) initially
    during treatment, which was associated with reduced food intake. Mean
    litter and fetal weights were significantly reduced at 3000 mg/kg b.w.
    No visceral or skeletal anomalies were reported (Cozens et al.,
    1983).

    Acute toxicity

         The acute toxicity of clofentezine to several animal species is
    given in Table 2. Signs of clofentezine toxicity in rats after oral
    administration were confined to very slight salivation and slight
    urinary incontinence. No clinical symptoms after oral administration
    were observed in hamsters, mice, guinea pigs, or dogs, except for skin
    reddening in dogs at the highest dose.

    Short-term studies

    Mice

         Groups of mice (20 males and 20 females per group) were
    administered clofentezine (technical grade) in the diet for 90 days at
    dose levels of 0, 200, 1000, or 5000 ppm. All animals were observed
    daily for mortality and signs of toxicity while body weights and food
    consumption were recorded weekly. Haematology and clinical chemistry
    were performed at weeks 4 and 12 on 10 mice/sex/group, and urinalysis
    was performed at weeks 4 and 12 on 20 mice/sex/group. At termination
    of the study all animals were killed, selected organs were weighed,
    and complete gross and histopathological examinations were performed.

         There were no effects on mortality, appearance, body weight, food
    consumption, or haematology. Significantly increased plasma levels of
    triglycerides, calcium, and phosphate were observed in mice in the
    5000- and 1000-ppm groups. Urinanalysis investigations revealed red
    stellar crystals in high-dose males. A dose-related urinary colour
    change from yellow, through orange, to red was observed in female
    mice. A treatment-related significant increase in liver weight was
    observed in both sexes of the mid- and high-dose groups, which was
    associated in males at 5000 ppm with centrilobular hepatocyte
    enlargement (5/20). The NOEL in this study was 200 ppm (Hounsell
    et al., 1982).

        Table 2.  Results of acute toxicity assays on clofentezine
                                                                                               

                                              LD501            LC502
    Species         Sex       Route           (mg/kg b.w.)     (mg/l)      Reference
                                                                                               

    Mouse           M+F       oral            > 3200                -      Crome et al., 1980a

    Rat             M+F       oral            > 3200                -      Mallyon &
                                                                           Sanderson, 1980

    Rat             M+F       dermal          > > 1332              -      Crome et al., 1980c

    Rat             M+F       i.p.            > 800                 -      Crome et al., 1981

    Rat             M         inhalation      -                > 9.08      Mallyon et al.,
                                                                           1981

    Hamster         M+F       oral            > 3200                -      Crome & Sanderson,
                                                                           1980

    Beagle dog      M+F       oral            > 2000                -      Chambers et al.,
                                                                           1981

    Guinea pig      F         oral            > 1500                -      Crome & Sanderson,
                                                                           1981a
                                                                                               

    1  given as a 33% suspension in 0.5% gum tragacanth.
    2  6 hours exposure with 80% wettable powder.
    
    Rats

         Groups of Charles River CD rats (20 males and 20 females/group)
    were fed diets containing 0, 3000, 9000, or 27,000 ppm clofentezine
    for 90 days. Five rats/sex/group were interim-sacrificed after 64 days
    and 5 rats/sex/group were maintained untreated for a 28-day recovery
    period. All animals were observed daily for mortality and physical
    signs. Body weights, food consumption, and water consumption were
    recorded weekly. Haematology, clinical chemistry, and urinalysis were
    performed at weeks 4 and 12 on 10 rats/sex/group. Cholesterol,
    triglycerides, and alanine aminotransferase were also measured after
    6 weeks of treatment and at the end of the 4-week recovery period.
    Detailed gross and histopathological examinations were performed and
    selected organs were weighed.

         Dose-related hair loss was observed in 50% and 40% of the animals
    of the high- and mid-dose groups, respectively. Six animals died
    throughout the study, 2/6 of the 27,000 ppm group, probably because of
    the test substance. Body-weight gain was significantly reduced in
    males and females of the mid- and high-dose groups. In all dose groups
    some haematological and clinical chemistry values changed in a dose-
    related manner (e.g., haemoglobin and packed cell volume decreased,
    protein and cholesterol increased, and alkaline phosphatase and
    albumin/globulin ratios decreased in treated groups compared to
    controls. After the 4-week recovery period, low- and mid-dose values
    were comparable to controls. Relative liver, kidney, heart, and brain
    weights were significantly increased at all dose levels. Hepatocyte
    enlargement was noted at all dose levels. These effects had
    disappeared after the 4-week recovery period. In this experiment a
    NOEL could not be established (Ginocchio & Brooks, 1981).

         In a second 90-day study, groups of Charles River CD rats
    (25 males and 25 females per group) were fed diets containing 0, 40,
    400, or 4000 ppm clofentezine for 90 days. Five males and 5 females
    per group were maintained untreated for a 6-week recovery period. All
    animals were observed daily for mortality and clinical signs, while
    body weights, food consumption, and water consumption were measured
    weekly. Haematology, clinical chemistry, and urinalysis were performed
    at 4, 8, and 12 weeks of treatment on 10 rats/sex/group, with
    subsequent monitoring of the regression of treatment-related effects.
    Organ weights and detailed gross and histopathological examinations
    were performed on 20 male and 20 female rats after 90 days of
    treatment and on the remaining animals at the end of the 6-week
    regression period.

         There were no effects on mortality or clinical signs. Body-weight
    gain was significantly decreased in females of the 4000 ppm group. A
    statistically-significant decrease in the haemoglobin concentration in
    the 4000 ppm group was observed after 4 (females only), 8, and
    12 weeks of treatment. This decrease was also observed in the 400 ppm
    group after 12 weeks. Plasma cholesterol was significantly increased
    in both sexes in the high- and mid-dose groups after 4, 8, and
    12 weeks of treatment; protein and albumin levels were increased in
    the same dose groups at the same times in males. All these effects had
    regressed after the recovery period. A dose-related colouration from
    orange to red in the urine was observed at all dose levels. Relative
    liver, kidney, and spleen weights were significantly increased in both
    sexes of the high-dose group and the relative liver weight was also
    increased at 400 ppm. Centrilobular hepatocyte enlargement was
    observed among male rats receiving 400 and 4000 ppm and among female
    rats receiving 4000 ppm clofentezine. There was evidence of slight,
    localized hepatocyte enlargement in males at 40 ppm. Retrospective

    examination of liver tissue by electron microscopy indicated moderate
    proliferation of smooth endoplasmic reticulum in centrilobular
    hepatocytes of males and females treated at 4000, but not at 40 ppm,
    clofentezine. These changes (but not the increase in liver weight)
    were completely reversible during the 6-week recovery period. The
    authors concluded that the NOEL in this study was 40 ppm clofentezine
    (Brooks & Turnbull, 1983).

    Dogs

         Beagle dogs (4/sex/group) were fed diets containing 0, 3200,
    8000, or 20,000 ppm clofentezine for 90 days. Two dogs were killed for
    humane reasons in week 6 of the study (no relation to treatment:
    polyarteritis). Except for pink coloration of the faeces and an
    increased liver weight in all treated groups, no compound-related
    effects were reported on any of the tested parameters measured: body
    weight, food and water consumption, haematology, clinical chemistry,
    urinalysis, ophthalmoscopy, electrocardiography, organ weights, gross
    pathology, or histopathology (Hounsell et al., 1981).

         Beagle dogs (6/sex/group) were fed diets containing 0, 50, 1000,
    or 20,000 ppm clofentezine for 52 weeks. No mortality occurred. Apart
    from reddish-pink coloured faeces in high-dose dogs, no effects of
    treatment were observed on clinical signs, body weight, food and water
    consumption, ophthalmoscopy, electrocardiography, blood pressure
    measurements, or urinalysis. The highest dose was associated with
    moderate hepatotoxicity consisting of significantly-increased relative
    liver weights, enlargement of periportal hepatocytes with cytoplasmic
    eosinophilia, hepatomegaly, and increased plasma cholesterol
    triglycerides and alkaline phosphatase. Adrenal and thyroid weights
    were also significantly increased in males and females, respectively.
    At 1000 ppm clofentezine, minimal hepatotoxicity was observed, with
    increased liver weights in females only. The authors concluded that
    the NOEL was 50 ppm clofentezine in the diet (equal to 1.72 mg/kg
    b.w./day) (Chesterman et al., 1984).

    Long term studies

    Mice

         Groups of 52 male and 52 female CD mice were fed diets containing
    0, 50, 500, or 5000 ppm clofentezine for 105 weeks. Observations
    included clinical signs, mortality, body weight, food consumption,
    haematological determinations (weeks 52 and 104) and organ weights and
    comprehensive histopathological examinations at the end of the
    experiment.

         At 5000 ppm clofentezine, increased mortality attributed to
    amyloidosis was observed in females. Growth was decreased during the
    first 52 weeks in males at the high-dose level and after 52 weeks
    decreases were also found in haemoglobin, haematocrit, and the number
    of red blood cells, especially in males. Total white blood cells were
    decreased in males after 52 and 105 weeks. Liver weights were
    increased in both sexes (significantly in females) at the high-dose
    level. Testes weights were significantly increased in males and an
    increased incidence of magenta-discoloured forestomach epithelium was
    noted in both sexes of the high-dose group. A higher number of benign
    liver cell tumours was observed in female mice dosed with 5000 ppm
    clofentezine, but the incidence was not significantly above that of
    the controls. At 5000 and 500 ppm an increased incidence of focal
    eosinophilic/basophilic hepatocytes was observed in females. The
    authors concluded that the NOEL was 50 ppm clofentezine (equivalent to
    5 mg/kg b.w./day) (Lloyd et al., 1985).

    Rats

         Groups of 50 male and 50 female CD rats were fed diets containing
    0, 10, 40, or 400 ppm clofentezine (technical) for 118 weeks
    (27 months). Additional supplementary groups of 20 male and 20 female
    rats were fed diets containing clofentezine at the same dietary levels
    and sacrificed after 12 months of treatment. Observations included
    clinical signs, mortality, body weight, food consumption, water
    consumption, haematology, clinical chemistry, urinalysis, ophthal-
    moscopy, and assays for thyroid function and sex hormones. At
    termination all surviving rats were killed, organs were weighed, and
    comprehensive histopathological examinations were made of tissues from
    each of these animals as well as from those dying during the study.

         The only treatment-related effects found after haematology and
    clinical chemistry analyses were decreased haemoglobin in females
    after 18 and 27 months and an increase in free T4 in males at
    400 ppm. However, other parameters of thyroid function were not
    affected. There was no evidence of chronic toxicity in any tissues
    other than the liver and the thyroid. Increased relative liver weights
    and liver cell hypertrophy, characterized by centrilobular hepatocyte
    enlargement and by vacuolisation and fat deposits, were observed at
    400 ppm in males (in females in a few cases). There was a slight
    increase in the number of follicular cell tumours in the thyroid at
    400 ppm in males. This is considered of doubtful biological
    significance since a comparable incidence was observed in control
    males in a parallel study. The authors concluded that the NOEL was
    40 ppm clofentezine in the diet (equivalent to 2 mg/kg b.w./day)
    (Ginocchio & Mallyon, 1985).

    Observations in humans

         Information useful for evaluation is not available.

    COMMENTS

         Clofentezine is an acaricide with low mammalian toxicity. Its
    mode of action is not understood. At high doses clofentezine exerts an
    effect on the liver (enzyme induction). Pretreatment with high dietary
    levels of clofentezine increases the rate of metabolism. It also
    affects thyroid function and impairs steroid hormone regulation.

         After oral administration of clofentezine to rats, it was
    excreted predominantly in the faeces. Low levels of residues were
    found in organs and tissues. The levels in plasma reached a maximum 4
    to 6 hours after an oral dose of 10 mg/kg b.w. after which the level
    decreased, with a half-life of 2 - 3 hours.

         When clofentezine was given to rats during 25 days, a plateau was
    reached after 5 - 10 days in various organs, with the highest residues
    in the liver. The concentration in the liver after 25 days was 2 - 4
    times higher than after 1 day, while fat residues were about 8 times
    higher.

         The material excreted in rat urine consisted mainly of
    metabolites. The two major pathways were hydroxylation of clofentezine
    and formation of a monochlorosulfur derivative. In the faeces 50% was
    excreted unchanged; the rest was metabolized to more that 20 minor
    metabolites.

         The metabolic pattern in other species (rabbits, dogs, baboons)
    was similar to the rat, with a higher excretion in the faeces than in
    the urine. The same metabolites were formed in rats, mice, calves,
    dogs, goats, and baboons, with methylthiolation being more prominent
    in rodents. In calves and baboons, hydroxylation was more prominent.

         Clofentezine has a low acute toxicity in rats, mice, hamsters,
    guinea pigs, and dogs.

         Clofentezine did not affect fertility or reproductive
    performance. Maternal effects (decreased growth, liver enlargement)
    were seen in all generations at 400 ppm. There were no indications of
    a teratogenic effect in rats or rabbits.

         A battery of mutagenicity tests did not indicate mutagenic
    potential.

         Short-term oral administration to mice, rats, and dogs produced
    liver enlargement as the main toxicological effect. In rats, decreased
    growth and decreased haemoglobin were observed at high-dose levels, as
    well as effects on biochemical parameters. Histopathological liver
    changes were in all cases associated with liver enlargement and liver
    enzyme induction. In addition, changes in thyroid function and steroid
    hormone regulation were observed (tested in special studies with
    rats).

         In long-term studies the same effects were found as in short-term
    studies. In mice a non-significant increase in benign liver tumours
    was found in females. In the rat study with relatively low dose levels
    a slight increase of thyroid follicular cell tumours was observed.
    Neither effect was considered to be an indication of carcinogenicity.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:    50 ppm in the diet, equal to 5 mg/kg b.w./day.
         Rat:      40 ppm in the diet, equivalent to 2 mg/kg b.w./day.
         Dog:      50 ppm in the diet, equal to 1.72 mg/kg b.w./day.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.02 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         1.  Observations in man.
         2.  Studies on the possible mode of action on the thyroid.
         3.  Information on possible enterohepatic recirculation.

    REFERENCES

    Bootman, J. & Rees, R. Technical NC 21314: Investigation of mutagenic
    1982      activity in the TK +/- mouse lymphoma cell mutation system.
              Unpublished report No. TOX/82/167-38 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Brooks, P.M. & Turnbull, G.J. Technical NC 21314: 90-Day dietary
    1983      toxicity study in the rat - additional examination of the
              liver histology. Unpublished report No. TOX/83/167-44 from
              FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Campbell, J.K. & Needham, D. Excretion and tissue residues of
    1981      (14C) NC 21314 in male and female dogs following a single
              intravenous dose at 0.1 mg/kg. Unpublished report
              No. METAB/81/37 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Campbell, J.K. & Challis, I.R. Concentration of (14C) NC 21314 and
    1982      its metabolites in the plasma of rats doses orally with NC
              21314 at the rate of 10 mg/kg body weight. Unpublished
              report No. METAB/82/39 from FBC Ltd. Submitted to WHO by FBC
              Ltd., Hauxton, Cambridge, England.

    Campbell, J.K. & Needham, D. Excretion and residues of (14C)
    1982a     NC 21314 in male and female mice given a single oral dose of
              10 mg/kg. Unpublished report No. METAB/82/11 from FBC Ltd.
              Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Campbell, J.K. & Needham, D. Excretion and residues of (14C)
    1982b     NC 21314 in male and female rabbits following a single oral
              dose of 10 mg/kg. Unpublished report No. METAB/82/21 from
              FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Campbell, J.K. & Needham, D. Excretion and residues of (14C)
    1982c     NC 21314 in male and female dogs following a single oral
              dose of 10 mg/kg. Unpublished report No. METAB/82/6 from FBC
              Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Campbell, J.K. & Needham, D. Concentration of (14C)-clofentezine and
    1985a     its metabolites in the plasma of rats given fourteen daily
              doses of clofentezine followed by a single oral dose of
              (14C)-clofentezine at 14 mg/kg bodyweight. Unpublished
              report No. METAB/85/6 from FBC Ltd. Submitted to WHO by FBC
              Ltd., Hauxton, Cambridge, England.

    Campbell, J.K. & Needham, D. Concentration of (14C)-Clofentezine and
    1985b     its metabolites in the plasma of rats dosed orally with
              clofentezine at the rate of 1000 mg/kg bodyweight.
              Unpublished report No. METAB/85/2 from FBC Ltd. Submitted to
              WHO by FBC Ltd., Hauxton, Cambridge, England.

    Challis, I.R. & Needham, D. The excretion and distribution of
    1981a     radiolabelled residues in male and female rats dosed orally
              at 0.1 mg/kg with NC 21314. Unpublished report
              No. METAB/81/26 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Challis, I.R. & Needham, D. The excretion and distribution of
    1981b     radiolabelled residues following a single intravenous dose
              of 0.1 mg/kg (14C)-NC 21314. Unpublished report
              No. METAB/81/38 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Challis, I.R. & Needham, D. The distribution and level of
    1981c     radiolabelled residues in rats following repeat oral dosing
              with (14C)-NC 21314 at 20 mg/kg/day. Unpublished report
              No. METAB/81/32 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Challis, I.R. & Needham, D. The excretion and distribution of
    1982a     radiolabelled residues in male and female rats dosed orally
              at 10 mg/kg with NC 21314. Unpublished report No. METAB/82/1
              from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.

    Challis, I.R. & Needham, D. The excretion and distribution of
    1982b     radiolabelled residues in male and female rats dosed orally
              at 1000 mg/kg with NC 21314. Unpublished report
              No. METAB/82/22 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Challis, I.R. & Needham, D. The excretion and distribution of
    1982c     radiolabelled residues in male and female rats dosed orally
              at 10 mg/kg with (14C)-NC 21314 following 14 days
              pre-treatment by dosing with unlabelled NC 21314 at
              10 mg/kg/day. Unpublished report No. METAB/82/37 from FBC
              Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Challis, I.R. & Needham, D. The excretion and distribution of
    1983      radiolabelled residues in male and female rats dosed
              intravenously at 0.1 mg/kg with (14C)-NC 21314.
              Unpublished report No. METAB/83/14 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Challis, I.R. A comparison of the metabolism of clofentezine in rat,
    1985      mouse, rabbit, calf, dog and baboon. Unpublished report
              No. METAB/85/9 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Challis, I.R. & Creedy, C.L. The effects of clofentezine on thyroid
    1985      function. Unpublished report No. METAB/85/36 from FBC Ltd.
              Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Challis, I.R. & Needham, D. The metabolism of clofentezine in the rat.
    1985      Unpublished report No. METAB/85/5 from FBC Ltd. Submitted to
              WHO by FBC Ltd., Hauxton, Cambridge, England.

    Chambers, P.R., Sanderson, D.M., & Brooks, P.N. The acute oral
    1981      toxicity of technical (pilot plant) NC 21314 to the male and
              female beagle dog. Unpublished report No. TOX/80/167-10 from
              FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Chesterman, H., Massey, J.E., Heywood, R., Buist, D., Street, A.E.,
    1984      Gopinath, C., & Rupanagudi, S. Rao. NC 21314 oral toxicity
              study in dogs (final report: repeated dietary administration
              for 52 weeks). Unpublished report No. TOX/84/167-68 from
              Huntingdon Research Centre, Huntingdon, Cambridgeshire,
              England, and FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.

    Cozens, D.D., Perkin, C.J., Barton, S.J., Clark, R., Offer, J.M.,
    1983      Gibson, W.A., & Street, A.E. Effect of technical NC 21314 on
              pregnancy of the rabbit (teratology study). Unpublished
              report No. FBC TOX/83/167-42 from Huntingdon Research
              Centre, Huntingdon, Cambridgeshire, England and from FBC
              Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Creedy, C.L., Hemmings, P.A., & Needham, D. The effect of clofentezine
    1985      on the hepatic mixed-function oxidase system of the male and
              female rat following dietary administration at 10, 40, or
              400 ppm diet for two weeks. Unpublished report No. METAB/
              85/34 from FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Crome, S.J. & Sanderson, D.M. The acute oral toxicity of unformulated
    1980      NC 21314 (CR 20099) to the hamster. Unpublished report
              No. TOX/80/167-8 from Fisons Ltd, Saffron Walden, Essex,
              England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Crome, S.J., Sanderson, D.M., & Brooks, P.N. The acute oral toxicity
    1980a     of unformulated (CR 20099/4) to the male & female mouse.
              Unpublished report No. TOX/80/167-7 from Fisons Ltd, Saffron
              Walden, Essex, England. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Crome, S.J., Sanderson, D.M., & Brooks, P.N. The primary skin
    1980b     irritancy of unformulated NC 21314 (CR 20099/5) to the
              guinea pig. Unpublished report No. TOX/80/167-6 from Fisons
              Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC
              Ltd., Hauxton, Cambridge, England.

    Crome, S.J., Sanderson, D.M., & Brooks, P.N. The acute dermal toxicity
    1980c     of unformulated NC 21314 (CR 20099/5) to the male and female
              rat. Unpublished report No. TOX/80/167-4 from Fisons Ltd,
              Saffron Walden, Essex, England. Submitted to WHO by FBC
              Ltd., Hauxton, Cambridge, England.

    Crome, S.J. & Sanderson, D.M. The acute oral toxicity of technical
    1981a     (pilot plant) NC 21314 to the guinea pig (CR 20099).
              Unpublished report No. TOX/81/167-16 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Crome, S.J. & Sanderson, D.M. The primary skin irritancy of NC 21314
    1981b     50WP to the guinea pig. Unpublished report No. TOX/81/167-13
              from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.

    Crome, S.J., Sanderson, D.M., & Brooks, P.N. Acute intraperitoneal
    1981      toxicity of pilot plant technical NC 21314 to the rat.
              Unpublished report No. TOX/80/167-5 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Cuthbert, J.A. & Carr, S.M.A. NC 21314 50 SC formulation primary eye
    1983      irritancy study in rabbits. Unpublished report No. TOX/83/
              167-46 from Inveresk Research International, Musselburgh,
              Scotland, and from FBC, Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Cuthbert, J.A., Carr, S.M.A., & D'Arcy-Burt, K.J. NC 21314 50 SC
    1983      formulation primary skin irritancy study in rabbits.
              Unpublished report No. TOX/83/167-47 from Inveresk Research
              International, Musselburgh, Scotland, and from FBC, Ltd.
              Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Ginocchio, A.V. & Brooks, P.N. Technical NC 21314 (pilot plant, CR
    1981      20099/5): the 90-day dietary toxicity study in the rat.
              Unpublished report No. TOX/81/167-23/1 from FBC Ltd.
              Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Ginocchio, A.V. & Mallyon, B.A. The oncogenicity and chronic toxicity
    1985      of technical NC 21314 (clofentezine) in the diet to the rat.
              Unpublished report No. TOX/84/167-70 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Hounsell, I.A., Chambers, P.R., & Brooks, P.N. The 90-day subchronic
    1981      oral toxicity of technical (CR 20099/8) NC 21314 in the diet
              to the dog. Unpublished report No. TOX/81/167-21/1 from FBC
              Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Hounsell, I.A. A micronucleus study in mice using technical NC 21314.
    1982      Unpublished report No. TOX/82/167-32 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Hounsell, I.A., Chambers, P.R., & Brooks, P.N. The 90-day subchronic
    1982      oral toxicity of technical (pilot plant) NC 21314 in the
              diet to the mouse. Unpublished report NO. TOX/82/167-33 from
              FBC Ltd. Submitted to WHO by FBC Ltd.,
              Hauxton, Cambridge, England.

    Jackson, C.M. Technical NC 21314: Teratogenicity study in the rat
    1982      (plus addendum). Unpublished report No. TOX/82/167-34 from
              FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Jackson, C.M. Technical NC 21314: dominant lethal mustation assay in
    1983      male rats. Unpublished report No. TOX/83/167-45 from FBC
              Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge,
              England.

    Jackson, C.M. & Chambers, P.R. Technical clofentezine: a dietary
    1984      multigeneration study in the rat. Unpublished report
              No. TOX/84/167-66 from FBC Ltd. Submitted to WHO by FBC
              Ltd., Hauxton, Cambridge, England.

    Lloyd, G.K., Spencer-Briggs, D.J., Heywood, R., Gopinath, C., &
    1985      Cherry, C.P. Technical NC 21314: oncogenicity in the diet to
              the mouse (final report). Unpublished report No. TOX/85/
              167-80 from Huntingdon Research Centre, Huntingdon,
              Cambridgeshire, England, and from FBC Ltd. Submitted to WHO
              by FBC Ltd., Hauxton, Cambridge, England.

    Mallyon, B.A. & Sanderson, D.M. The acute oral toxicity of
    1980      unformulated NC 21314 (NC 21314/4, 99% pure) to the male and
              female rat. Unpublished report No. TOX/80/167-2 from Fisons
              Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC
              Ltd., Hauxton, Cambridge, England.

    Mallyon, B.A., Sanderson, D.M., & Brooks, P.N. The acute inhalational
    1982      toxicity of NC 21314 80WP CR 15569, to the rat. Unpublished
              report No. TOX/81/167-24 from FBC Ltd. Submitted to WHO by
              FBC Ltd., Hauxton, Cambridge, England.

    McConville, M. Ames test for mutagenic activity carried out with
    1980      technical NC 21314 (CR 20099/4). Unpublished report
              No. TOX/80/167-3 from Inveresk Research International,
              Musselburgh, Scotland, and from Fisons Ltd, Saffron Walden,
              Essex, England. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.

    Needham, D. The distribution of radioactivity in the maternal tissues
    1981      and foetuses of rats after an oral dose of (14C)-NC 21314.
              Unpublished report No. METAB/81/19 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Needham, D. The whole-body autography of (14C)-NC 21314 in rats
    1982      following oral administration at 10 mg/kg body weight.
              Unpublished report No. METAB/82/23 from FBC Ltd. Submitted
              to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Needham, D., Challis, I., & Campbell, J. The effect of eight weeks
    1983a     dietary administration of NC 21314 at 40 and 27,000 mg/kg on
              the hepatic mixed function oxidase system of the male rat.
              Unpublished report No. METAB/81/31 (2nd Edn.) from FBC Ltd.
              Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Needham, D., Challis, I., & Campbell, J. The effect of a two week
    1983b     withdrawal period on the induction of hepatic microsomal
              mixed function oxidases caused by dietary administration of
              NC 21314 at 27,000 mg/kg diet. Unpublished report
              No. METAB/82/2 (2nd Edn.) from FBC Ltd. Submitted to WHO by
              FBC Ltd., Hauxton, Cambridge, England.

    Needham, D., Campbell, J., & Challis, I. The effect of eight weeks
    1984      dietary administration of NC 21314 at 27,000 and 400 mg/kg
              diet on the hepatic mixed-function oxidase system of the
              male mouse. Unpublished report No. METAB/82/20 (2nd Edn.)
              from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.

    Needham, D. & Challis, I.R. An investigation into the nature of the
    1985      residues present in the liver of the rat, goat and calf
              following the oral administration of clofentezine.
              Unpublished report No. METAB/85/8 from FBC Ltd. Submitted to
              WHO by FBC Ltd., Hauxton, Cambridge, England.

    Riach, C.G. & McGregor, D.B. Technical NC 21314: induction of gene
    1983      conversion and mitotic recombination in yeast. Unpublished
              report No. TOX/83/167-56 from Inveresk Research
              International, Musselburgh, Scotland, and from FBC Ltd.
              Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.

    Saunders, P.C. & Mallyon, B.A. Technical clofentezine: 6 week dietary
    1986      investigation of thyroid function in the rat. Unpublished
              report No. TOX/85/167-77 from FBC Ltd. Submitted to WHO by
              FBC Ltd., Hauxton, Cambridge, England.

    Sortwell, R.J., Richmond, G.P., Kirkpatrick, D., Finn, C.M., & Conway,
    1983      B. Excretion and tissue distribution of radioactivity after
              oral administration of (14C)-NC 21314 to a male and female
              baboon. Unpublished report No. METAB/83/26 from Huntingdon
              Research Centre, Huntingdon, Cambridgeshire, England, and
              from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.

    Teale, H.J. Delayed dermal sensitisation study in the guinea pig,
    1982      NC 21314 technical. Unpublished report No. TOX/82/167-36
              from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton,
              Cambridge, England.
    


    See Also:
       Toxicological Abbreviations
       Clofentezine (JMPR Evaluations 2005 Part II Toxicological)