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Flucythrinate. 1985 World Health Organization Review.


Note from FAN:
Comments on the references (below). Of the 18 studies referenced.

From: http://www.inchem.org/documents/jmpr/jmpmono/v85pr09.htm


    FLUCYTHRINATE

    EXPLANATION

         Flucythrinate is an insecticide related to synthetic pyrethroids.
    It was considered for the first time by the present Meeting.

    IDENTITY

    CHEMICAL NAME:      (RS)-alpha-cyano-3-phenoxybenzyl-(S)-2-
    (IUPAC)             [4-(difluoromethoxy)phenyl]-3-methylbutyrate

    SYNONYMS:           OMS 2007 (WHO); A13-29391 (USDA); AC 222,750; CL
                        222,705; PAY-OFF(R); FUCHING JUJR(R); CYBOLT(R)

    EMPIRICAL FORMULA:  C26H23F2NO4

   

    OTHER INFORMATION ON IDENTITY AND PROPERTIES

    MOLECULAR WEIGHT:   451.4

    PHYSICAL FORM:      Technical material is a viscous, dark amber liquid
                        with a very slight, ester-like odour, 80-88% pure.

    VAPOR PRESSURE
    (vapor saturation
     technique, mm Hg): 8.7 x 10-9 at 25C

    SOLUBILITY
    (g/100 ml solvent
    at 21C):           Acetone        82
                        Corn oil       56
                        Cottonseed oil 30
                        Hexane          9
                        Propanol       78
                        Soybean oil    30
                        Water           0.00005
                        Xylene         181

    PARTITION COEFFICIENT
    (n-octanol/water): 120

    HYDROLYSIS RATES
    (half-life in days) at:       27C  35C

         pH3                  ca. 40    ca. 40
         pH6                      52        31
         pH9                       6.3       2.6
         Distilled water          40        29

    FORMULATIONS AVAILABLE
    COMMERCIALLY:             3, 5, 10, and 30% emulsifiable concentrate;
                              5% wettable powder

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, excretion, and metabolism

         When C13/C14-alcohol labelled flucythrinate (19.7 mg/kg) was
    dosed orally to rats, about 30% of administered radioactivity was
    excreted in the urine and 70% in the faeces after 8 days. With
    C13/C14-acid labelled compound similar results were obtained, 22% and
    73%, respectively. Highest tissue residues were found in adipose
    tissue, but these declined with time (Table 1).

    Table 1.  Adipose tissue residues of flucythrinate (ppm)
                                                            

                                  24 hr.    192 hr
                                                            

    C13/C14-alcohol label         4.47      1.91
    C13/C14-acid label            0.69      0.26
                                                            

         Metabolites were qualitatively identified by thin layer
    chromatography and combined gas liquid chromatography/mass
    spectrometry. Principal metabolic pathways involved ester cleavage and
    oxidation at the para position of the alcohol moiety and at the gem-
    dimethyl groups of the acid moiety. The metabolite with the hydroxyl
    substitutent in the alcohol moiety was excreted as the sulphate
    conjugate in urine. A glycine conjugate was also formed. Alcohol
    radiolabelled flucythrinate yielded at least 29 urinary metabolites,
    the principal one being 3-(phenoxy)-hippuric acid. With the acid
    radiolabel the major urinary metabolite was 2-[4-(difluoromethoxy)
    phenyl]-3-methylbutyric acid, accounting for 60% of urinary radio
    activity (Zulalian, 1979).

    Toxicological studies

    Special studies on reproduction

    Rat

         Groups of 10 male COBS/CD rats (Sprague-Dawley) received
    technical flucythrinate (80% pure) at doses of 0, 2, 5, and 10 mg/kg
    in corn oil by gavage for 5 consecutive days and then were
    subjected to a standard dominant-lethal assay breeding program.
    Triethylenemelamine (0.05 mg/kg i.p.) was administered as a positive
    control. One male receiving 10 mg/kg flucythrinate died after the 3rd
    dose. Treatment with flucythrinate had no effect on pregnancy rate,
    number of implantation sites, number of live foetuses or the number of
    post implantation deaths. Flucythrinate was found to have no effect in
    the dominant-lethal assay (Harnois, 1979).

         In a three generation reproduction study, groups of 12 male and
    24 female COBS/CD (Sprague-Dawley derived) weanling rats received
    technical flucythrinate (80% pure) in the diet at concentrations of 0,
    30, 60, or 120 ppm for 10 weeks before mating (2 females/male) and
    then continuously. A similar dosing regimen was maintained throughout
    two successive generations resulting from the matings of the F1
    parents selected from the F1b generation and F2 parents selected
    from the F2b generation.

         Skin irritation, observed as hair loss, scabbing, and open
    lesions, was observed with low incidence in the F1 and F2 parental
    high-dose groups. No data were given for the F0 generation. In the
    F1 and F2 generations, weight gains were reduced at 60 and 120 ppm
    of both males and females for the duration of the study beyond
    weaning. There were no treatment-related effects on food consumption,
    fertility rate, gestation length or numbers of liveborn pups. Four-day
    survival was decreased at 120 ppm for the 1st and 3rd generations in
    both litters. Twenty-one day survival was decreased in both high-dose
    litters of the 1st generation.

         Pup body weights were reduced at 120 ppm and marginally reduced
    at 60 ppm for both sexes and in all generations. Alteration of the
    21-day sex ratio in favour of males was observed in the F2a litter at
    120 ppm. As this effect was not observed in any other litter, its
    toxicological significance can be discounted. A slight increase in the
    number of stillborn pups per litter was observed for the 1st litter of
    each generation at 60 and 120 ppm. Based on the findings of reduced
    weight gain and increased number of stillborn pups per litter, the no
    effect level established by this study was 30 ppm (Lang, 1981a).

    Special studies on teratogenicity

    Rat

         Groups of 30 mated Charles-River CD rats received technical
    flucythrinate (80% pure) in corn oil by gavage at 0, 2, 4, or 8 mg/kg
    on days 6-15 (inclusive) of gestation and were maintained without
    treatment until sacrificed at day 20.

         In an apparently treatment-related manner, 1 dam treated at
    4 mg/kg died, while 19 died at 8 mg/kg, but the cause of death was not
    determined. Absolute body weights were reduced at 4 and 8 mg/kg as
    were body-weight gains. Incomplete recovery of body weight had
    occurred by day 20 (termination).

         No treatment-related effects were observed for numbers of
    corpora lutea or live foetuses per dam, pre- or post-implantation
    losses, pregnancy rate, mean foetal body weight, foetal crown-rump
    length, or sex ratio.

         Increases in the incidence of 14th rudimentary ribs and
    incomplete ossification of sternebrae and other bones were observed at
    8 mg/kg. The results of this study indicate that daily treatment up to
    4 mg/kg was without effect, while daily treatment up to 8 mg/kg, which
    produced severe maternal toxicity in the rat, produced no teratogenic
    effect (Rodwell et al., 1979).

    Rabbit

         Groups of twenty female New Zealand white rabbits were
    artifically inseminated after induction of ovulation with chorionic
    gonadotropin on 2 consecutive days. Technical flucythrinate (80% pure)
    was administered in corn oil at 0, 10, 30, or 60 mg/kg daily from days
    6-18 (inclusive) of gestation and were maintained without treatment
    until sacrificed at day 29.

         One animal in the control group died prior to dosing, one rebbit
    fed 30 mg/kg died on day 17, and two fed 60 mg/kg died on days 16 and
    18. Mortality was probably not compound-related; it was attributed to
    peumonia.

         Depression of maternal body weight and faecal scouring were
    observed in the high-dose (60 mg/kg) group up to day 18. Maternal
    weight gain was significantly reduced in the mid- and high-dose groups
    and its recovery in the high-dose group was incomplete at day 29
    (termination).

         At autopsy one "dam" of the low-dose (10 mg/kg) group was found
    to be male. Mean uterine weight was decreased for the 60 mg/kg group.
    No treatment-related effects were seen for rates of pregnancy,
    corpora lutea or viable foetuses per dam, resorptions, sex ratio or
    foetal body weight. A slight decrease in the mumber of implants per
    dam was observed at 60 mg/kg. Post-implantation losses were decreased
    (50%) in all treated groups. The latter effect was not dose-related
    and was considered to be not compound-related. Increases in the
    incidence of bent hyoid arch and major-vessel variations were found in
    the high-dose group (60 mg/kg). No treatment-related terata were found
    at any dosage.

         The results of this study indicate a no-effect level at 30 mg/kg
    based on implantation rates and minor variations and no teratogenic
    effects at 60 mg/kg, although treatment at this level caused maternal
    toxicity (Janes et al., 1980).

    Special studies on mutagenicity

         Flucythrinate was without mutagenic activity in a number of
    assays with microorganisms and mammalian cells (Table 2).

    Acute toxicity

         Several acute toxicity studies are available on flucythrinate
    (Table 3). Signs of flucythrinate toxicity included decreased
    activity, salivation and tremors. Death usually occurred within two
    days and recovery among survivors was generally complete by six days.

        Table 2.  Results of mutagenicity assays on flucythrinate
                                                                                                           

    Test System              Test Object         Concentrations                               Reference
                                                 used                Purity(%)    Result
                                                                                                           

    Reverse mutation         S. typhimurium*     plate               84.8         -           Allen, 1979
                                                 incorporation
                             TA1535              0, 0.01,                         -
                             TA1537              0.1, 1 mg                        -
                             TA98                spot test                        -
                             TA100               0, 2 mg

    Reverse mutation         E coli**            spot test           84.8         -           Allen, 1979
                             wp2/uvr A-          0, 1 mg
                                                 plate
                                                 incorporation
                                                 0, 0.01,
                                                 0.1, 1 mg

    Unscheduled              primary-culture     0.001, 0.005,       85.4         -           Dulak, 1982
    DNA synthesis            rat-hepatocytes     0.01, 0.05,
                                                 0.1, 1.0 mg/ml

    CHO/HGPRT locus          Chinese             0, 0.001, 0.01,     85.4         -           Johnson &
    ribosyl transferase      Hamster             0.1, 0.25,                                   Allen, 1982
    (Chinese                 Ovary Cells         0.5, 1, 5 mg/ml
    Hamster Ovary/           (CHO-K1
    hypoxanthineguanine      -BH4)**
    phosphoribosyl
    transferase
    locus mutation
    induction)
                                                                                                           

    *    + S-9 metabolic activation
    **    S-9 metabolic activation
    
    Table 3.  Results of acute toxicity assays on flucythrinate
                                                                

                                  LD50
    Species   Sex    Route        (mg/kg b.w.)      Reference
                                                                

    Mouse     F      oral         76                Fischer, 1978a
    Rat       M      oral         81                "          "
              F      oral         67                "          "

    Rat       M,F    inhalation   LC50 = 65 g/1    Daly, 1985

    Rabbit    M      dermal       > 1000            Fischer, 1978a
              F      dermal       > 1000            "          "
                                                                

    Short-term studies

    Rat

         Groups of CD (Sprague-Dawley derived) rats received technical
    flucythrinate (86% pure) in the diet daily for 28 days at 0, 6, 30 ppm
    (8 male and 8 female rats per group) or at 150 or 300 ppm (12 male and
    12 female rats per group). Some survivors from the 150 and 300 ppm
    groups were used to study reversibility of toxicity. Animals receiving
    300 ppm exhibited severe hind limb ataxia, diuresis, hypersensitivity
    and salivation typical of pyrethroid intoxication. Animals receiving
    150 ppm were much less affected, while females generally exhibited
    greater sensitivity to flucythrinate than males. Five females of the
    300 ppm group died without apparent cause. Absolute weight and weight
    gain were markedly depressed for males and females in the groups
    receiving 150 and 300 ppm. All symptoms in the two highest-dose groups
    were reversed in 48 hours, while the weight loss, relative to
    controls, was regained within 4 weeks after cessation of exposure.
    Weight loss in the two highest-dosage groups was attributable to
    decreased food intake. Plasma urea nitrogen was elevated for females
    receiving 300 ppm. Absolute and relative liver weights were elevated
    in females receiving 300 ppm. Based on the findings of weight loss, a
    no-effect level of 30 ppm was determined (Fischer, 1979).

         Groups of 20 male and 20 female CD (Sprague-Dawley derived) rats
    received technical flucythrinate (80% purity) in the diet at 0, 15,
    30, 60, or 120 ppm daily for 90 days.

         No symptoms or mortality were observed and body weights in males
    and females receiving 120 ppm were only marginally depressed. No
    compound-related effect was noted on food intake, haematology,
    clinical chemistry or urinalysis.

         At autopsy, an increase in the total incidence of alopecia was
    noted. Females receiving 120 ppm had a slightly higher incidence of
    hydronephrosis than controls (4/20 vs 1/20 for 120 and 0 ppm,
    respectively). No compound-related effects on organ weights were
    found. Histology showed a slight increase in the incidence of skin
    disorders as attributable to irritation at 120 ppm. No pathological
    basis for the hydronephrosis was found, suggesting that this finding
    is without toxicological significance.

         Based on decreased body weight, a no-effect level of 60 ppm was
    determined (Jefferson & Jessup, 1979).

         Groups of 20 male and 20 female SPF (Sprague-Dawley derived) rats
    received 0, 30, 60, 120, or 240 ppm technical flucythrinate (85.4%
    pure) in the diet for 6 months.

         Males and females that received 240 ppm flucythrinate exhibited
    symptoms of decreased motor activity and ataxia, characterized by
    weakness in the extremities and gait disturbances. One control and 1
    male and 4 females of the 240-ppm group died during the study. Males
    receiving 240 ppm and females receiving 240 and 120 ppm flucythrinate
    exhibited weight loss attributable to decreased food consumption.
    Water intake was depressed in males and females receiving 240 ppm.
    Leucocyte counts were slightly depressed in males receiving 120 and
    240 ppm. Organ weights were in accord with body weights. An increased
    incidence of brown pigmentation in the spleen was observed in high-
    dose males and females.

         Based on the depression in body weight, the no-effect level for
    this study was 60 ppm (Shirasu, 1983).

    Dog

         Groups of 2 male and 2 female Beagle dogs received technical (80%
    pure) flucythrinate in the diet at 0, 30, 150, or 300 ppm daily for 14
    days. Symptoms were primarily vomiting at 150 and 300 ppm with some
    evidence of diarrhoea at the same dosages. After 14 days weight gain
    was markedly depressed at 300 ppm due to decreased food consumption.
    No other toxicological parameters were studied (Fischer, 1978b).

         Groups of 4 male and 4 female Beagle dogs received technical
    flucythrinate (80% pure) in the diet at 0, 30, 150, or 300 ppm daily
    for 90 days. Emesis occurred in the 150 and 300 ppm dose groups. Body
    weight was depressed in both males and females of the high-dose group
    and no unscheduled deaths occurred. Weight gain was slightly depressed
    at 150 ppm and markedly depressed at 300 ppm, although food
    consumption at this dose was not remarkably affected.

         Slight anaemia was observed in dogs of each sex receiving
    300 ppm, while males receiving this dosage also exhibited a decreased
    leucocyte count. Clinical chemistry showed no treatment-related
    effects while urinary pH was lower in males and females receiving
    300 ppm.

         At autopsy only slight changes in organ weights were observed,
    with males receiving 300 ppm having slightly lower relative heart
    weights than controls. Female heart weight, although depressed, was
    consistent with the decreased body weight at 300 ppm.

         At autopsy, 2/8 males receiving 300 ppm and 1/8 females receiving
    30 ppm flucythrinate were found to have oral papillomas. Only the
    latter lesion was confirmed histologically. There were no other
    significant histological findings (Mehring & Jessup, 1979).

         The results of this study indicate a no-effect level of 30 ppm
    based upon reduced weight gain.

    Long-term studies

    Mouse

         Groups of 50 male and 50 female CD-1 mice received technical
    flucythrinate (80% pure) in the diet at 0, 30, 60, or 120 ppm daily
    for 18 months.

         Skin lesions (abrasions, ulceration and scabs) were observed in
    high-dose males and females. No treatment-related symptoms or
    treatment-related changes in survival were found. No haematology,
    clinical chemistry or urinalysis were undertaken.

         At necropsy, hepatocellular adenomas were found in all control
    and treated groups. The incidence was variable and statistically-
    significant only in high-dose males. Hepatocellular adenocarcinoma and
    hepatocellular carcinoma were found in low incidence in all male
    groups, but only in control and low-dose female mice. The incidences
    of these neoplasms were similar to those previously found in mice and
    were apparently unrelated to treatment.

         Mild sciatic nerve degeneration occurred in all groups, but at
    slightly increased incidence in treated groups, especially high-dose
    males. There was no apparent dose-response relationship. The incidence
    of mild axonal degeneration was similar in all groups. The no-effect
    level for this study was therefore set at 30 ppm (Lang, 1981b).

    Rat

         Groups of 50 male and 50 female CD (Sprague-Dawley derived) rats
    received technical flucythrinate (80% pure) in the diet at 0, 30, 60
    or 120 ppm daily for 24 months.

         Skin lesions consistent with scratching of the head, neck and
    thorax were observed in all mid- and high-dose groups throughout the
    study. Mortality was decreased in high-dose males. Terminal body
    weights were decreased in treated animals, but especially in high-dose
    males and females. This was possibly related to a depression of food
    intake. A very mild anaemia was observed in the 3rd months for both
    high-dose males and females. Blood glucose was slightly, though
    consistently, depressed for high-dose males and females at months 3
    and 6. Urinalysis was normal at 3 and 6 months.

         At sacrifice, blood urea nitrogen was elevated in mid- and high-
    dose males. All other haematology, clinical chemistry and urinalysis
    parameters were unchanged by treatment. At autopsy, high-dose females
    exhibited an increased incidence of cystic uterus. Absolute and
    relative kidney weights were significantly elevated in mid- and high-
    dose males while only the relative kidney weight was elevated in high-
    dose females. A slight increase in relative heart weight was found in
    high-dose males.

         No increase in abnormal histopathology or neoplasia was observed
    in any group of treated males. The uterine cysts found at autopsy in
    the high-dose females were characterized as endometrial cysts. In the
    high-dose females, further slight increases in uterine pathology were
    described histologically, namely etritis/endometritis, cystic
    endometrial hyperplasia and uterine fibrovascular polyps.

         Mammary fibroadenomas occurred at similar incidences in all
    female groups. The incidence of mammary adenomas in treated females
    exceeded that of controls, but not in a dose-related manner. Mammary
    adenocarcinomas occurred at higher incidence at 60 and 120 ppm, but
    not in a dose-related manner. The latter incidences remained within
    the range of historical control data. The variable incidences and lack
    of dose-response relationships contraindicate a neoplastic response,
    but in view of the observed weight losses, especially in high-dose
    groups, these findings cannot be discounted entirely. Based on these
    findings, the increased blood urea nitrogen found in males treated at
    60 and 120 ppm and slight changes in organ weights, the no-effect
    level of this study was set at 30 ppm (Brewer et al., 1981).

    Dog

         Groups of 6 male and 6 female Beagle dogs received technical
    flucythrinate (87.3% pure) in the diet at 0, 30, 100, or 300 ppm daily
    for 24 months.

         Male dogs receiving 300 ppm flucythrinate in the diet appeared
    thin and exhibited alopecia and dermal scaling; one dog died. Food
    consumption was reduced in both males and females fed at this level
    and there was a marked decrease in the body weights of both sexes.
    These changes may have related to increased emesis observed in these
    dogs. A statistically-significant but transient anaemia was observed

    in high-dose males at month 18. This was attributable to a persistent
    but fluctuating anaemia in one of the high-dose male dogs present
    throughout the study. This same animal also had depression of serum
    calcium and albumin and was later diagnosed at autopsy as one of two
    males suffering nematode infestation. Urinalysis and gross pathology
    exhibited no treatment-related changes.

         At sacrifice, the relative liver, kidney, and pituitary weights
    were increased in both high-dose males and females, while increases in
    relative spleen, testis and lung weights were noted for high-dose
    males only. Upon histological examination, mid- and high-dose groups
    exhibited increased evidence of interstitial pneumonia, compared to
    controls. As it is likely that the nutritional status of the dogs was
    compromised by compound-induced emesis, these findings were considered
    not directly attributable to treatment.

         The results of this study indicate a no-effect level of 100 ppm
    based upon changes in relative organ weights and body weight (Spicer
    et al., 1984).

    COMMENTS

         The principal mechanism of flucythrinate metabolism involves
    ester cleavage and oxidation at the para-position of the alcohol
    moiety and at the gem-dimethyl group of the acid moiety. Flucythrinate
    does not bioaccumulate and the metabolites are mostly excreted in the
    urine and do not accumulate in the tissues.

         The toxicological profile of flucythrinate is similar to that of
    related pyrethroids, although the acute oral toxicity is relatively
    high. The production of hepatocellular tumours in the mouse is not
    considered to be of biological significance, considering the known
    susceptibility of the mouse to this effect.

         Flucythrinate is not teratogenic in the rat or rabbit. The
    compound was observed to cause mild maternal weight reduction in a
    reproduction study, but not at levels causing concern.

         Flucythrinate has no dominant lethal effect in rats and was not
    mutagenic in several assays.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:     30 ppm in the diet, equal to 4.0 mg/kg b.w.
         Rat:       30 ppm in the diet, equal to 1.6 mg/kg b.w.
         Dog:      100 ppm in the diet, equal to 2.5 mg/kg b.w.

    ESTIMATE OF ACCEPTABLE DAILY TAKE FOR MAN

         0 - 0.02 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    DESIRED

    1.   Further studies on the biological activity of flucythrinate
         relevant to the mild nerve demyelination observed in the mouse
         and on possible effects on neurotransmitters.

    2.   Observations in man.

    REFERENCES

    Allen, J.S. Mutagenicity testing of CL 222,705; (+) Butyric acid, 2-
    (1979)    (phi-(difluromethoxy)phenyl)-cyano-m-phenoxybenzyl ester, in
              the Ames bacterial test. Unpublished report Project No. 0-
              796 by the Agricultural Research Division, American Cyanamid
              Co. Submitted to WHO by the American Cyanamid Co.,
              Princeton, NJ, USA.

    Brewer, L., Jefferson, N.D., & Blair, M. 24-Month feeding study in
    (1981)    rats. Unpublished report No.141-005 from International
              Research and Development Corporation, submitted to WHO by
              the American Cyanamid Co., Princeton, NJ, USA.

    Daly, I.W. An acute inhalation study of AC 222,705 in the rat.
    (1985)    Unpublished report No. 78-7226 from Bio/dynamics Inc.,
              submitted to WHO by American Cyanamid Co., Princeton, NJ,
              USA.

    Dulak, L. The unscheduled DNA synthesis (UDS) test on CL 222,705 using
    (1982)    primary rat hepatocytes in culture. Unpublished report No.
              81319 by the Experimental Pathology Department, American
              Cyanamid Co., submitted to WHO by the American Cyanimid Co.,
              Princeton, NJ, USA.

    Fischer, J.E. Toxicity data report. Unpublished report No. A78-88 by
    (1978a)   the Agricultural Division, American Cyanamid Co., submitted
              to WHO by the American Cyanimid Co., Princeton, NJ, USA.

    Fischer, J.E. Experiment L-1715: 14 Day feeding to dogs of CL 222,705.
    (1978b)   Unpublished report No. A78-77 from the American Cyanamid
              Co., submitted to WHO by the American Cyanimid Co.,
              Princeton, NJ, USA.

    Fischer, J.E. Experiment L-1705: 28-day feeding to rats of CL 222,705.
    (1979)    Unpublished report No. AX-79-1 by the American Cyanamid Co.,
              submitted to WHO by the American Cyanimid Co., Princeton,
              NJ, USA.

    Harnois, M. A dominant lethal test in male rats treated with CL
    (1979)    222,705 by gavage for 5 days. Unpublished report No. 79072
              by the Medical Research Division, American Cyanamid Co.
              Submitted to WHO by the American Cyanimid Co., Princeton,
              NJ, USA.

    Janes, J.M., Rodwell, D.E., & Jessup, D.C. Teratology study with AC
    (1980)    222,705 in rabbits. Unpublished report from International
            Research and Development Corporation. Submitted to WHO by
              the American Cyanimid Co., Princeton, NJ, USA.

    Jefferson, N.D. & Jessup, D.C. 90-Day feeding study in rats.
    (1979)    Unpublished report No. 141-003 from International Research
            and Development Corporation. Submitted to WHO by the
              American Cyanimid Co., Princeton, NJ, USA.

    Johnson, E. & Allen, J.S. Mutagenicity testing of CL 222,705 in the
    (1982)    in vitro CHO/HGPRT mutation assay. Unpublished report No.
              0414 by the Discovery Department, American Cyanamid Co.
              Submitted to WHO by the American Cyanimid Co., Princeton,
              NJ, USA.

    Lang, P. Three generation reproduction study of AC 222,705 to rats.
    (1981a)   Unpublished report No. 141-008 from International Research
            and Development Corporation, submitted to WHO by the
              American Cyanimid Co., Princeton, NJ, USA.

    Lang, P. 18-Month feeding study of AC 222,705 to mice. Unpublished
    (1981b)   report No. 141-009 from International Research and
            Development Corporation. Submitted to WHO by the American
              Cyanimid Co., Princeton, NJ, USA.

    Mehring, J. & Jessup, D.C. 90-Day feeding study in dogs. Unpublished
    (1979)    report No. 141-004 from International Research and
              Development Corporation. Submitted to WHO by the American
              Cyanimid Go., Princeton, NJ, USA.

    Rodwell, D.E., Benson, B.W., & Jessup, D.C. Teratology study of AC
    (1979)    222,705 in rats. Unpublished report from International
              Research and Development corporation. Submitted to WHO by
              the American Cyanimid Co., Princeton, NJ, USA.

    Shirasu, Y. AC 222,705: 6-month oral sub-chronic toxicity study in
    (1983)    rats. Unpublished report from the Institute of Environmental
              Toxicology. Submitted to WHO by the American Cyanimid Co.,
              Princeton, NJ, USA.

    Spicer, E.J.F., Jefferson, N.D., & Blair, M. Chronic dietary toxicity
    (1984)    study in dogs. Unpublished report No. 141-025 from
              International Research and Development Corporation.
              Submitted to WHO by the American Cyanimid Co., Princeton,
              NJ, USA.

    Zulalian, J. Pyrethroids, I. A study of the disposition of
    (1979)    carbon-14 labelled CL 222,705 [butyric acid, 2-(4-
              difluoromethoxy)phenyl)-3-methyl-alpha-cyano-m-phenoxybenzyl
              ester] in rats. Unpublished report by the American Cyanamid
              Co., Agricultural Research Division. Submitted to WHO by the
              American Cyanimid Co., Princeton, NJ, USA.