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    FENPYROXIMATE

    First draft prepared by
    K. Fujimori

    Division of Pharmacology, Biological Safety Research Center, National
    Institute of Health Sciences, Ministry of Health and Welfare, Tokyo,
    Japan

    Explanation
    Evaluation for acceptable daily intake
         Biochemical aspects
              Absorption, distribution, and excretion
              Biotransformation
         Toxicological studies
              Acute toxicity
              Short-term toxicity
              Long-term toxicity and carcinogenicity
              Reproductive toxicity
              Developmental toxicity
              Genotoxicity
              Special studies
                   Dermal and ocular irritation and dermal sensitization
                   Acute delayed neurotoxicity
                   Observations in humans
         Comments
         Toxicological evaluation
    References

    Explanation

         Fenpyroximate,  tert-butyl (E)-alpha-(1,3)-dimethyl-5-
    phenoxy-1 H -pyrazol-4-yl methyleneamino-oxy)- para-toluate, is a
    phenoxypyrazole acaricide for application to leaves. It is very active
    against phytophagous mites, relatively less active against predacious
    mites, and inactive against animal parasitic and soil mites. The only
    insect against which it is active is  Empoasca onukii (tea green
    leafhopper) (Taninaka, 1993). Fenpyroximate inhibits mitochondrial
    NADH-coenzyme Q reductase on the electron transport chain in
     Tetrachynus urticae (two-spotted spider mite) and in rats (Motoba
     et al., 1992).

         Fenpyroximate was evaluated for the first time by the present
    Meeting.

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

    (a)  Absorption, distribution, and excretion

         Groups of six male and six female Sprague-Dawley (Crl;CD)
    rats were given single doses by gavage of 2 or 400 mg/kg bw of
    [3-14C]-pyrazole-(radiochemical purity, 96.4-99.9%) or
    [U-14C]-benzyl-fenpyroximate (radiochemical purity, 99.2-99.5%)
    suspended in 1% aqueous Tween 80. Blood was collected from the tail
    vein of five rats per group at various times up to 168 h after dosing.
    In rats given 2 mg/kg bw, the concentration of radiolabel in blood
    peaked within 1 h after dosing and reached a plateau, which was
    sustained for about 18 h and was followed by a slow elimination phase
    with a half-life of 6-9 h. In the group given 400 mg/kg bw, absorption
    was delayed, and radiolabel was not detectable in blood within the
    first 12 h after dosing. A nearly maximal level was achieved 12-24 h
    after dosing, the plateau was sustained for 80-100 h and was followed
    by an elimination phase with a half-life of 35-49 h (Table 1; Sharp,
    1990a,b)

         Groups of five male and five female Sprague-Dawley CD rats
    received a single oral dose of 2 or 400 mg/kg bw 14C-pyrazole- or
    14C-benzyl-labelled fenpyroximate. The recoveries of total radiolabel
    within 168 h were 93-108%. The major route of excretion was the
    faeces; 70-91% of the low dose and 75-80% of the high dose were found
    in faeces, and 9-18% of the low dose and 10-12% of the high dose were
    excreted in urine within 168 h. Excretion by both routes after the
    high dose was time-dependent. There was little residual radiolabel
    in tissues 168 h after treatment with 2 mg/kg bw; the highest
    concentration was found in fat, which contained 0.01-0.03 g/g
    pyrazole- and 0.06-0.1 g/g benzyl-labelled fenpyroximate. After
    treatment with 400 mg/kg bw, the highest residual tissue
    concentrations after 168 h were found in fat (3-21 g/g), liver
    (2-8 g/g), and kidney (1-3 g/g). Less than 0.1% of the low dose was
    found in the gastric contents 24 h after treatment, but 53-64% of the
    high dose remained after 24 h, and 0.3-2.6% was still observed at
    168 h. The concentrations in blood 168 h after treatment with
    400 mg/kg bw were very low (0.5 g/g) for pyrazole-labelled
    fenpyroximate and were not detectable for that labelled with benzyl.
    There were no obvious changes in the tissue distributions of labelled
    compound after pretreatment with unlabelled fenpyroximate, and there
    was no significant sex-related difference. Further groups of five
    males and five females received 14 consecutive daily doses of 2 mg/kg
    bw unlabelled compound followed by a single dose of 14C-pyrazole- or
    14C-benzyl-labelled compound. No significant difference in the
    excretion pattern was observed between singly and repeatedly dosed
    groups, and there was no significant difference between males and
    females or with the pyrazole- and benzyl-labelled compounds (Sharp
    1991a,b).

        Table 1.  Toxicokinetic parameters for radioactivity in blood of rats dosed with [14C-pyrazole]-
              or [14C-benzyl]-fenpyroximate
                                                                                                            

    Label     Dose           Sex         Toxicokinetic parameter (mean + SD)
              (mg/kg bw)                                                                                    

                                         Cmax (g/g)       Tmax (h)        Half-life (h)     AUC (g  h/ml)
                                                                                                            

    Pyrazole  2              Male        0.15  0.06       11.0  8.3           8.9          3.49  0.64
                             Female      0.18  0.04       11.4  4.5           8.9          3.82  0.57
              400            Male        4.67  1.69       100.8  26.3        48.7          377  190
                             Female      4.69  0.66       90.0  12.0         45.3          411  134
    Benzyl    2              Male        0.10  0.16       7.8  1.6            6.1          1.80  0.34
                             Female      0.18  0.05       7.2  3.4            7.9          3.01  0.60
              400            Male        5.10  1.21       28.8  10.7         47.0          425  132
                             Female      8.88  2.73       86.4  27.4         35.4          728  211
                                                                                                            

    Total radioactivity, expressed as micrograms equivalent fenpyroximate; AUC, area under the
    concentration-time curve
             Groups of six male and six female Sprague-Dawley rats with
    bile duct cannulae were given a single oral dose of 2 mg/kg of
    14C-pyrazole- or 14C-benzyl-fenpyroximate. Within 48 h after
    treatment with pyrazole-labelled fenpyroximate, 47% (females) to 55%
    (males) of the radiolabel had been excreted in the bile, 5%, (males)
    to 10% (females) in urine, and 17% (females) to 28% (males) in faeces.
    Total excretion 48 h after treatment was about 88% for males and 73%
    for females. The Tmax, Cmax, and half-lives of the radiolabel in the
    blood of cannulated rats were similar to those of rats with no
    cannulae. Within 48 h after oral administration of benzyl-labelled
    fenpyroximate, 47% (females) to 51% (males) of the radiolabel had been
    excreted in the bile, 6% (males) to 8% (females) in urine, and 28%
    (females) to 40% (males) in faeces (Tsu-Han Li, 1991a,b).

         Groups of four male Sprague-Dawley CD rats received single dermal
    applications of 14C-pyrazole-fenpyroximate suspended in water at doses
    of 0.1, 1.0, or 5.2 mg in 1 ml on a 10-cm2 area of skin for 0.5, 1,
    2, 4, 10, or 24 h and were sacrificed at the end of the exposure
    period, The concentration of radiolabel in blood was very low after
    all applications. Excretion in urine was slight but increased with
    duration of exposure; after 24 h of exposure, 0.7-0.9% of the applied
    dose had been excreted. Radiolabel was found in faeces after 10 and
    24 h of treatment, and faecal excretion was 1.4% at a dose of 1 mg,
    0.5% at 10 mg, and 0.2% at 52 mg. These results suggest that
    fenpyroximate is barely absorbed from the skin and is excreted via the
    biliary-faecal and urinary routes (Mahon, 1993).

    (b)  Biotransformation

         The proposed metabolic pathways for fenpyroximate in rats are
    shown in Figure 1. Fenpyroximate is metabolized extensively by
    hydrolytic cleavage of the oxime ether bond, hydrolysis of the
     tert-butyl ester, oxidation of the  tert-butyl, hydroxylation of
    the phenoxy ring and 3-methyl, isomerization, N-demethylation, and
    conjugation, producing a large number of metabolites. The major
    metabolites identified are ( E)-4-[(1,3-dimethyl-5-phenoxypyrazol-
    4-yl) methyleneaminooxymethyl] benzoic acid (C), (Z)-4-[(1,3-dimethyl-
    5-phenoxypyrazol-4yl) methyleneaminooxymethyl] benzoic acid (D),
    ( E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl]
    methyleneaminooxymethyl} benzoic acid ( E), 1,3-dimethyl-5-
    phenoxypyrazole-4-carboxylic acid (H), 4-hydroxymethyl benzoic acid
    (P), terephthalic acid (R), 4-cyano-1-methyl-5-phenoxypyrazole-
    3-carboxylic acid (S), ( E)-2-{4-[(1,3-dimethyl-5-phenoxypyrazol-
    4-yl) methyleneaminooxymethyl] benzoyloxy}-2-methylpropanoic acid (F),
    ( E)-2-{4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl]
    methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid (W), and
    ( E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl]
    methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid (X).

    CHEMICAL STRUCTURE 1

         Groups of five male and five female Sprague-Dawley CD rats were
    treated with single oral doses of 2 or 400 mg/kg bw 14C-pyrazole- or
    14C-benzyl-labelled fenpyroximate, and urinary and faecal samples
    were collected at 0-24, 24-48, 48-120, and 120-168 h. The samples from
    each group were pooled for each time period. Radiolabel in faeces
    after 0-48 h represented 80-87% of the dose of 2 mg/kg and 80% of the
    dose of 400 mg/kg; parent fenpyroximate was found at 6-8% after
    2 mg/kg and 50-52% after 400 mg/kg. No parent compound was found in
    urine. Eleven urinary and 19 faecal metabolites were identified by
    thin-layer co-chromatography with authentic samples. The major urinary
    metabolites were H, S, and R (Figure 1), produced by hydrolytic
    cleavage of the oxime ether bond between the benzyl moiety and the
    pyrazole ring. The major faecal metabolites were C, D, and E, produced
    by hydrolysis of the  tert-butyl ester, and T, produced by oxidation
    of the  tert-butyl group. A Z isomer of fenpyroximate, A, was found
    in faeces of rats treated with the high dose. The concentrations of
    urinary metabolite H and faecal metabolites H and T were increased by
    enzymatic hydrolysis of the excreta with -glucuronidase or sulfatase
    (Sharp 1991a,b).

         Groups of four male Sprague-Dawley (SLC) rats were treated with a
    single oral dose of 1.5 mg/kg bw 14C-pyrazole- or 14C-benzoyl-
    labelled fenpyroximate (radioactive purity, > 99%), and urinary and
    faecal samples were collected for 0-72 h. Six urinary and 17 faecal
    metabolites were identified by thin-layer co-chromatography with
    authentic samples. Three of them, W, X, and V, were isolated from
    faeces and identified by mass spectrometry and nuclear magnetic
    resonance. The major urinary metabolites were H (7.3% of the dose),
    S (2.5%), and R (3.8%). The major faecal metabolites were C (4.1-11.0%
    of the dose), E (2.9-4.2%), and T (3.5-4.3%); P (7.5%) was found as a
    precursor of R and W (2.0-9.7%) and X (3.3-4.5%) as hydroxylated
    bodies of T. The concentrations of the urinary metabolites J and N and
    the faecal metabolites B, T, W, X, and V were increased by enzymatic
    hydrolysis of the excreta with -glucuronidase or sulfatase (Nishizawa
     et al., 1993).

         Groups of six male and six female Sprague-Dawley rats with
    bile-duct cannulae were given a single oral dose of 2 mg/kg
    14C-pyrazole-labelled fenpyroximate. No parent fenpyroximate was
    found in bile, but metabolites C, D, E, F, G, H, I, J, M, N, and T and
    conjugates of C, D, E, and H were found. Total radiolabel represented
    less than 2% of the dose. The metabolic pathway proposed for
    fenpyroximate in rats is cleavage of the ester bond, hydroxylation at
    the phenoxypyrazole group, oxidation at the  tert-butyl group, and
    conjugation with sulfate and glucuronide (Tsu-Han Li, 1991a,b).

    3.  Toxicological studies

    (a)  Acute toxicity

         Studies of the acute toxicity of technical-grade (> 98%)
    fenpyroximate and of a 5% suspension concentrate are summarized in
    Table 2. Moderate oral toxicity was observed in rats and mice, with
    LD50 values ranging from 245 to 520 mg/kg bw. Fenpyroximate was more
    toxic to rats when administered by inhalation, with LC50 values
    ranging from 0.21 to 0.36 mg/litre air. Signs of acute toxicity in
    mice and rats included urinary and faecal staining, hypoactivity, and
    hypopnoea. Decreased food consumption was observed in surviving
    animals one week after dosing. Necropsy of animals found dead revealed
    irritation and/or corrosive effects in the gastointestinal tract.
    There were no signs of acute toxicity or dermal irritation after
    dermal application of either formulation. Inhalation of active
    ingredient or the formulation resulted in signs of respiratory
    irritation (laboured breathing, rale, and gasping). The findings at
    necropsy were unremarkable in groups exposed by whole-body inhalation,
    but those in groups exposed by nose only included oedematous,
    reddened, firm lungs and frothy fluid in the trachea.

    (b)  Short-term toxicity

    Mice

         In a preliminary study to establish the dose range for a
    carcinogenicity study, groups of nine male and nine female ICR
    (Crj:CD-1) mice were given fenpyroximate (purity, 97.9%) mixed into
    the diet at concentrations of 80, 400, or 2000 ppm, equal to 0, 10.8,
    48.4, and 181.6 mg/kg bw per day in males and 0, 11.7, 50.4, and
    170.0 mg/kg bw per day in females, for four weeks. There were no
    deaths and no abnormal behavioural signs in any treated group.
    Decreased body-weight gain was observed in males at 400 ppm and in
    animals of each sex at 2000 ppm; food consumption and food efficiency
    were reduced in animals at 2000 ppm. Haematological examination
    revealed significant decreases in haemoglobin in animals of each sex,
    of the haematocrit in males, and of the erythrocyte count in females,
    and a significant decrease in total plasma protein and a significant
    increase in aspartate aminotransferase in animals of each sex at
    2000 ppm. The NOAEL in this study was 80 ppm, equal to 10.8 mg/kg bw
    per day in males and 11.7 mg/kg bw per day in females (Takahashi,
    1988).

         In a four-week study to find the dose range for the
    carcinogenicity study, groups of nine male and nine female ICR
    (Crj:CD-1) mice received fenpyroximate (purity, 97.9%) mixed into the
    diet at a concentration of 0, 20, 100, or 500 ppm, equal to 0, 2.58,
    12.9, and 53.2 mg/kg bw per day in males and 0, 3.07, 14.5, and
    66.7 mg/kg bw per day in females. Slight reductions in body-weight

        Table 2.  Acute toxicity of fenpyroximate
                                                                                                           

    Species             Sex         Route             LD50 or LC50             Purity    Reference
                                                      (mg/kg bw or             (%)
                                                      mg/litre air)
                                                      (confidence interval)
                                                                                                           

     Fenpyroximate
    ICR CD-1 mouse      Male        Orala             520 (334-706)            98        Blaszcak (1989a)
                        Female                        440 (281-599)

    Sprague-Dawley      Male        Orala             480 (298-662)            98        Blaszcak (1989b)
    CD rat              Female                        245 (167-323)

    Sprague-Dawley      Male        Dermalb           > 2000                   98        Blaszcak (1989c)
    CD rat              Female                        > 2000

    Sprague-Dawley      Male        Inhalation        0.33 (0.16-0.68)         99        Hoffman (1989)
    CD rat              Female      (whole-body)c     0.36 (0.24-0.54)

    Sprague-Dawley      Male        Inhalation        0.21 (0.04-1.20)         98        Hoffman (1991a)
    CD rat              Female      (nose-only)d      0.33 (0.20--0.55)

     5% suspension concentrate
    Sprague-Dawley      Male        Oral              7193 (2989-17 308)                 Mitchell (1990)
    CD rat              Female                        6789 (4704-9797)

    Sprague-Dawley      Male        Dermal            > 4000                             Mitchell (1991)
    CD rat              Female                        > 4000

    Sprague-Dawley      Male        Inhalation        1.9 (1.2-3.1)                      Hoffman (1990)
    CD rat              Female      (whole-body)e     2.4 (2.0-2.9)
                                                                                                           

    Table 2.  (con't)
                                                                                                           

    Species             Sex         Route             LD50 or LC50             Purity    Reference
                                                      (mg/kg bw or             (%)
                                                      mg/litre air)
                                                      (confidence interval)
                                                                                                           

    Sprague-Dawley      Male        Inhalation        5.1 (0.0-17.1)                     Hoffman (1991b)
    CD rat              Female      (nose-only)f      3.4 (1 9-4.9)
                                                                                                           

    a  In Tween 80 and a 1% solution of Methocel (A4C)
    b  Applied on a gauze moistened with 0.9% saline
    c  Fenpyroximate containing white carbon (9:1); mean particle size, 4.2 m; exposure time, 4 h
    d  Fenpyroximate containing white carbon (9:1); mean particle size, 2.8 m; exposure time, 4 h
    e  Mean particle size, 3.3 m; exposure time, 4 h
    f  Mean particle size, 5.1 m; exposure time, 4 h
    
    gain and in food consumption were observed in males at 500 ppm. There
    were no abnormal clinical signs, no changes in haematological
    parameters, and no changes in organ weights. The NOAEL in this study
    was 100 ppm, equal to 12.9 mg/kg bw per day in males and > 500 ppm in
    females (Takahashi, 1987).

    Rats

         Groups of 10 male and 10 female Sprague-Dawley CD rats received
    fenpyroximate (purity, 99.0%) in the diet at concentrations of 0, 20,
    100, or 500 ppm, equal to 0, 1.3, 6.6, or 35.2 mg/kg bw per day for
    males and 0, 1.7, 8.3, or 38.6 mg/kg bw per day for females, for 13
    weeks. There were no overt changes in physical condition or behaviour
    and no abnormal ophthalmoscopic findings. Increased encrustations
    of the muzzle in males and an increased incidence of hair loss
    accompanied by encrustation of the skin in females were observed at
    500 ppm, Significant reductions in body-weight gain at 100 and 500 ppm
    and significant reductions in food consumption at 500 ppm were
    observed in animals of each sex. A significant lowering of total
    plasma protein level was observed in females at 100 ppm and in animals
    of each sex at 500 ppm. A significant increase in relative liver body
    weights and slight hypertrophy of hepatic cells were observed in
    animals of each sex and a significant increase in alkaline phosphatase
    activity in females at 500 ppm; a significantly lower volume and pH
    value of urine were also observed at this dose. Erythrocyte
    cholinesterase activity was significantly lowered in animals at
    500 ppm, but the inhibition was less than 20% of control. The NOAEL in
    this study was 20 ppm, equal to 1.30 mg/kg bw per day in males and
    1.65 mg/kg bw per day in females, based on the lowered body-weight
    gain in animals of each sex and a lowered plasma protein level in
    females at 100 ppm (Aughton, 1987).

         Fenpyroximate (purity, 99%) was applied to the dorsal skin of
    groups of five male and five female Sprague-Dawley rats in a uniform
    layer moistened with water at 0, 100, 300, or 1000 mg/kg bw for 6 h
    per day for 21 consecutive days. Minor acanthosis was observed in all
    treated and one control animal. All rats survived, and there were
    no compound-related clinical abnormalities. Reductions in food
    consumption and body-weight gain in animals of each sex and increases
    in absolute liver weight in females were observed at 1000 mg/kg bw.
    There were no compound-related changes in haematological or blood
    chemical parameters. The NOAEL in this study was 300 mg/kg bw per day,
    based on the reduction in body-weight gain in animals of each sex and
    the increase in absolute liver weight in female at 1000 mg/kg bw
    (Wilkinson  et al., 1992).

         Groups of four male and four female Sprague-Dawley CD rats were
    exposed by nose-only inhalation to fenpyroximate (purity, 98.6%; mean
    particle size, 3 m) at a target concentration of 0, 2, 10, or
    50 mg/m3 for 6 h per day, five days per week for four weeks. All

    animals survived. The only treatment-related physical or behavioural
    change was an increased incidence of laboured breathing during the
    last three weeks of exposure to 50 mg/m3. Increase in absolute and
    relative lung weight were observed in animals of each sex after four
    weeks' exposure to 10 or 50 mg/m3, but these effects were not seen
    two weeks after exposure. A higher incidence of mucosal changes in
    the nasal passages (atrophy and metaplasia) were observed at
    concentrations of 10 (in males) and 50 mg/m3 (males and females). The
    NOAEL in this study was 2 mg/m3, based on an increase in lung weight
    and an increased incidence of mucosal changes in the nasal passages
    (Hoffman, 1991c).

    Dogs

         Groups of four male and four female beagle dogs received
    fenpyroximate (purity, 98.4%) in gelatin capsules at 0, 2, 10, or
    50 mg/kg bw per day for 13 weeks. Two females given 50 mg/kg bw were
    found moribund and were killed after five weeks of treatment.
    Increased incidences of diarrhoea and emaciation were observed in
    females at 10 mg/kg bw per day and in males at 50 mg/kg bw per day.
    Electrocardiograms examined 2 and 24 h after treatment showed
    bradycardia in males after six weeks of treatment at 10 or 50 mg/kg bw
    per day and after 12 weeks of treatment at 50 mg/kg bw per day. There
    were no treatment-related ocular lesions. Significant decreases in
    total body-weight gain were observed in females at 10 mg/kg bw per
    day and in animals of each sex at 50 mg/kg bw per day. The only
    significant haematological change was a reduction in the total number
    of leukocytes in females at 50 mg/kg bw per day after 6 and 12 weeks
    of treatment. Histopathological examination showed fine cytoplasmic
    vacuolation of cells in the renal medullary rays in two females at
    50 mg/kg bw per day sacrificed before the end of treatment and in one
    female killed at termination. There were no significant changes in
    cholinesterase activity in plasma or erythrocytes. The NOAEL in this
    study was 2 mg/kg bw per day, based on the reduction in body-weight
    gain and clinical signs at 10 mg/kg bw per day (Broadmeadow, 1988).

         Groups of four male and four female beagle dogs received
    fenpyroximate (purity, 98.0%) in gelatin capsules at 0, 0.5, 1.5, 5,
    or 15 mg/kg bw per day on seven days per week for 52 weeks. Clinical
    observations were made daily, electrocardiograms were perfomed after
    11, 24, and 50 weeks, haematological examinations were done after
    12, 24, and 50 weeks, blood chemistry after 24 and 50 weeks, and
    ophthalmoscopy after 49 weeks of treatment. There were no deaths.
    Increased incidences of diarrhoea were observed during treatment in
    males at 5 or 15 mg/kg bw per day and in females at 15 mg/kg bw per
    day. Increased salivation was observed in females at 15 mg/kg bw per
    day. Slight bradycardia was observed in animals of each sex at
    15 mg/kg bw per day, which was significant in males at 11 and 50 weeks
    of treatment. The overall body-weight gain throughout treatment was
    significantly lower in males at 15 mg/kg bw per day, and a slightly

    reduced total food consumption was observed. There were no treatment-
    related haematological or ophthalmological findings. A slight but
    significant lowering of total plasma protein level was observed in
    males at 15 mg/kg bw per day after 50 weeks of treatment. There was no
    change in erythrocyte acetylcholinesterase activity. The absolute and
    relative prostatic weights were significantly increased in all treated
    groups, but no histopathological changes were observed in the prostate
    or in any other tissue examined. The NOAEL was 1.5 mg/kg bw per day,
    based on the increased incidence of diarrhoea at 5 mg/kg bw per day
    (Broadmeadow, 1989).

    (c)  Long-term toxicity and carcinogenicity

    Mice

         Groups of 50 male and 50 female ICR (Crj;CD) mice received
    fenpyroximate (purity, 97.9-98.4%) mixed into the diet at
    concentrations of 0, 25, 100, 400, or 800 ppm (overall mean
    concentrations: 0, 24, 98, 388, and 776 ppm) for 18 months (78 weeks),
    equal to 0, 2.4, 9.5, 38.0, or 69.6 mg/kg bw per day for males and 0,
    2.5, 10.2, 41.5, or 73.1 mg/kg bw per day for females. There were no
    treatment-related alterations in clinical signs. Body-weight gain and
    food consumption were significantly lower than those of controls in
    animals of each sex at 400 and 800 ppm. The only significant change in
    haematological parameters was a decrease in the number of segmented
    neutrophils at 500 ppm. A significant increase in the incidence of
    emaciation was observed in males a t 500 ppm at the termination of
    treatment. Histopathological examination revealed significant
    increases in the incidence of ovarian atrophy in females at 400 and
    800 ppm (25/50 in controls, 35/50 at 400 ppm, 35/50 at 800 ppm), but
    these changes were morphologically similar to age-related changes seen
    in female mice of this strain. There was no treatment-related increase
    in the incidence of neoplasia. The NOAEL in this study was 100 ppm,
    equal to 9.5 mg/kg bw per day in males and 10.2 mg/kg bw per day in
    females, based on decreased body-weight gain and food consumption at
    400 ppm (Takahashi, 1990).

    Rats

         Groups of 80 male and 80 female Sprague-Dawley CD rats
    received fenpyroximate (purity, 97.1-97.2%) mixed into the diet at
    concentrations of 0, 10, 25, 75, or 150 ppm for 104 weeks. The overall
    doses achieved by the groups in which toxicity was assessed were 0,
    0.40, 0.97, 3.08, and 6.18 mg/kg bw per day in males and 0, 0.48,
    1.16, 3.79, and 7.57 mg/kg bw per day in females; those in the groups
    for assessment of carcinogenicity were 0, 0.40, 0.97, 3.00, and
    6.20 mg/kg bw per day in males and 0, 0.49, 1.21, 3.81, and 8.01 mg/kg
    bw per day in females. Fifty rats of each sex per dose were assigned
    for assessment of carcinogenicity and 30 of each sex per dose for
    toxicity; 10 rats of each sex per dose were sacrificed at week 52 for

    interim assessment. Blood samples were collected in weeks 24, 49, 76,
    and 102 of treatment and urine samples in weeks 23, 49, 77, and 101.
    Mortality after 104 weeks was 70, 72, 54, 60, and 52% among males and
    58, 60, 50, 30, and 46% among females at 0,10, 25, 75, and 150 ppm,
    respectively. There were no treatment-related adverse effects on
    behaviour, appearance, or ophthalmoscopic parameters during treatment
    or at termination. Absolute body weight was reduced after 104 weeks of
    treatment, by 1-15% in males and 6-12% in females at 75 mg/kg bw per
    day and by 11-28% in males and 17-22% in females at 150 mg/kg bw per
    day. These changes were not statistically significant; however,
    body-weight gains were significantly decreased in males at 75 ppm
    and in animals of each sex at 150 ppm. Blood chemical analysis,
    haematological examination, and urinalysis showed no treatment-related
    findings. Macroscopic examination of animals used for toxicity
    assessment revealed a significantly increased incidence of dark
    popliteal lymph nodes in females at 150 ppm. Macroscopic examination
    of animals for carcinogenicity revealed significantly increased
    incidences of pituitary masses, masses that compressed the ventral
    surface of the brain, and masses in the abdominal fat in males at
    150 ppm, and increased incidences of uterine masses and distension of
    the uterus in females at this dose. Histopathological examination
    revealed higher incidences of non-neoplastic changes, which included
    syncytial macrophages in the mesenteric lymph nodes of females in
    the toxicity assessment group, and lesions associated with gastric
    ulceration, compression of the brain due to pituitary neoplasia,
    and pancreatic lobular degeneration in males and interstitial
    proliferation of the ovary in females in the carcinogenicity
    assessment groups. High incidences of pituitary adenoma were observed
    in all groups, but the rates (males: 34/70, 36/57, 32/50, 37/54, and
    36/69; females, 39/69, 50/60, 52/54, 41/47, and 43/66) were within the
    historical control range (males, 34-70%; females, 67-86%). There was
    no evidence of carcinogenicity. The NOAEL was 25 ppm, equal to
    0.97 mg/kg bw per day in males, based on the lowered body-weight gain
    at 75 ppm (Aughton, 1989).

    (d)  Reproductive toxicity

    Rats

         A preliminary range-finding study was conducted in which groups
    of six male and six female Sprague-Dawley CD rats received
    fenpyroximate (purity, 97.3%) mixed into the diet at concentrations of
    10, 50, or 200 ppm for seven weeks, from 15 days before mating to day
    4  post partum, for two generations. There were no treatment-related
    changes in behaviour or appearance in F0 or F1 animals, and there
    were no deaths. Significant reductions in body-weight gains were
    observed in parental animals of each sex at 200 ppm, and food
    consumption was reduced at this dose due to unpalatability (Higgins,
    1988).

         A two-generation (one litter per generation) study was conducted
    with groups of 24 male and 24 female Sprague-Dawley CD rats that
    received fenpyroximate (purity, 97.3%) mixed into the diet at
    concentrations of 0, 10, 30, or 100 ppm, from 14 weeks before mating
    up to weaning of the F1 generation (14 weeks before mating, three
    weeks of mating, three weeks' gestation, 25 days' lactation) and then
    from weaning of the F1 generation to weaning of the F2 generation.
    The mean daily intakes of fenpyroximate were 0.67, 1.99, or 6.59 mg/kg
    bw per day for F0 males 0.83, 2.44, or 8.60 mg/kg bw per day for F0
    females, 0.78, 2.33, or 8.45 mg/kg bw per day for F1 males, and 0.96,
    2.82, or 9.92 mg/kg bw per day for F1 females during the premating
    period. There were no treatment-related abnormalities in behaviour or
    appearance in F0, F1, or F2 animals throughout the study.
    Significant reductions in body-weight gain were observed at 100 ppm in
    males of the F0 and F1 generations throughout the study and in F0
    females up to parturition. Food consumption was significantly reduced
    in F0 males at 100 ppm during the period before mating. There were no
    treatment-related changes in the oestrus cycle, mating performance
    (percent mating, conception rate, or fertility index), length of
    gestation, gestation index, or parturition index in F0 or F1
    animals. Significantly reduced body-weight gains were seen during
    lactation in F1 and F2 offspring at 100 ppm. There were no
    treatment-related Changes in litter size, viability, sex ratio,
    initial body weight at birth, or developmental indices (pinna
    unfolding, hair growth, tooth eruption, or eye opening) in the F1 and
    F2 generations. The absolute and relative weights of the testes and
    epidymides were significantly increased at termination of the study in
    F1 males fed 100 ppm, but the weights were only 10% greater than
    those of controls, and macroscopic and histopathological examinations
    revealed no treatment-related changes in the reproductive organs. The
    NOAEL was 30 ppm, equal to 1.99 mg/kg bw per day in F0 males,
    2.44 mg/kg bw per day in F0 females, 2.33 mg/kg bw per day in F1
    males, and 2.82 mg/kg bw per day in F1 females, based on reductions
    in body-weight gain in animals of each sex at 100 ppm (Higgins,
    1989a).

    (e)  Developmental toxicity

    Rats

         Groups of 22 pregnant Sprague-Dawley CD rats received
    fenpyroximate (purity, 97.6%) suspended in 1% aqueous carboxy-
    methylcellulose and 0.1% Tween 80 by gavage at 0, 1, 5, or 25 mg/kg bw
    per day on days 6-15 of gestation. Three females in the group at
    5 mg/kg bw per day died due to a technical error; all surviving
    animals were sacrificed on day 20 of gestation. A slight loss of body
    weight after the first dose, a significant increase in water
    consumption, and a slight reduction in food consumption were seen
    during the first six days of treatment in rats at 25 mg/kg bw per day.
    No other maternal toxicity was observed. There were no treatment-

    related effects on litter parameters. Slight increases in the
    incidences of skeletal variations were seen in fetuses in all treated
    groups. The incidences of unilateral and bilateral additional 14th
    thoracic rib(s) were 2.4 and 1.4% in controls, 5.2 and 4.8% at 1 mg/kg
    bw per day, 5.0 and 1.7% at 5 mg/kg bw per day, 8.2 and 7.7% at
    25 mg/kg bw per day, and 0-4.2 and 0-3.5%, in historical controls,
    respectively. The increases were not dose-dependent, but the percent
    incidence in fetuses and the number of litters with the skeletal
    variation at the highest dose, 25 mg/kg bw per day, exceeded the
    historical control range. There was no evidence of teratogenicity at
    doses up to and including 25 mg/kg bw per day. The NOAEL in this study
    was 5 mg/kg bw per day, based on slightly decreased body weight in
    maternal rats and the increased incidence of skeletal variations in
    fetuses at 25 mg/kg bw per day (Higgins, 1989b).

    Rabbits

         In a preliminary study, groups of four pregnant New Zealand white
    rabbits received fenpyroximate (purity, 98.4%) suspended in 1% aqueous
    carboxymethylcellulose and 0.1% Tween 80 by gavage at doses of 0, 1.0,
    2.5, or 5.0 mg/kg bw per day on days 6-19 of gestation. Maternal
    toxicity was seen as marked reductions in body-weight gain and reduced
    defaecation, food consumption, and water consumption at 5.0 mg/kg bw
    per day. Increased post-implantation loss was also recorded at this
    dose, as were reduced fetal weight and multiple anomalies (increased
    incidences of small fetuses, oedema of head and/or ventral part of
    neck, and thorax, fore- and hind-limb flexure). The NOAEL for
    fetotoxicity was 2.5 mg/kg bw per day, based on reduced fetal weight
    and art increased incidence of anomalies at 5.0 mg/kg bw per day
    (Bailey, 1989).

         Groups of 15 pregnant New Zealand white rabbits received
    fenpyroximate (purity, 97.6%) suspended in 1% aqueous carboxymethyl-
    cellulose and 0.1% Tween 80 by gavage at doses of 0, 1.0, 2.5, or
    5.0 mg/kg bw per day on days 6-19 of gestation. Two females receiving
    2.5 mg/kg bw per day were killed when moribund; necropsy revealed a
    respiratory tract infection in one (14 days after treatment) and
    evidence of gastrointestinal tract disturbance in the other (26 days
    after treatment). All surviving animals were sacrificed on day 29 of
    gestation. A transient decrease in body weight and in food consumption
    and an increased incidence of reduced defaecation were observed at
    5.0 mg/kg bw per day; a significant decrease in body weight was
    observed at 2.5 mg/kg bw per day. Slight increases in the rate of
    abortion and of total litter loss were observed in rabbits at 2.5 and
    5.0 mg/kg bw per day: 0/15 in controls, 0/15 at 1.0 mg/kg bw per day,
    7.7% (1/13) at 2.5 mg/kg bw per day, 13.3% (2/15) at 5.0 mg/kg bw per
    day, and 0-14.3% in historical controls. The changes in body weight
    and abortion rate at 2.5 mg/kg bw per day were slight but dose-
    dependent. There was no evidence of fetotoxicity or teratogenicity at
    doses up to 5.0 mg/kg bw per day. The NOAEL for maternotoxicity was
    2.5 mg/kg bw per day (King, 1989).

    (f)  Genotoxicity

         The results of studies on technical-grade fenpyroximate (purity,
    97.3%) are summarized in table 3. The studies include those for
    point mutations, mutation of mammalian cells  in vitro, chromosomal
    aberrations, micronucleus formation  in vivo, DNA repair ( rec
    assay), and unscheduled DNA synthesis. All of the positive controls
    used gave the expected responses. There was no evidence of
    genotoxicity.

    (g)  Special studies

    (i)  Dermal and ocular irritation and dermal sensitization

         The primary ocular irritation potential of fenpyroximate (purity,
    98.4%) as a fine powder was evaluated in male New Zealand white
    rabbits by grading and scoring according to the method of Draize.
    Changes due to irritation were observed in the conjunctivae of eyes
    treated with 0.1 g of fenpyroximate for 1 h to two days after
    treatment. Rinsing slightly reduced the severity of the changes.
    Fenpyroximate is classified as a mild primary irritant (Kosaka,
    1988a). A fenpyroximate formulation (5% suspension concentrate) was
    moderately irritating to the eyes of female New Zealand white rabbits
    receiving 0.1 ml (Teale, 1990a).

         Fenpyroximate (purity, 98.4%) applied as a fine powder moistened
    with distilled water was not irritating to the skin of male New
    Zealand white rabbits, graded and scored according to the method of
    Draize (Kosaka, 1988b). Little or no dermal irritation was seen after
    application of 0.5 ml of the 5% suspension concentrate to female New
    Zealand white rabbits (Hayes, 1990).

         The dermal sensitizing potential of fenpyroximate (purity, 98.4%)
    was studied in female Hartley guinea-pigs by the maximization test.
    Fenpyroximate was given at 0.1 ml per animal at 5% by intradermal
    injection and 25% by local application for induction and then given
    at 25% by local application for challenge. The positive control was
    2,4-dinitrochlorobenzene (at 0.1, 1, and 0.5%, respectively). The
    positive control group was sensitized by 100% and the fenpyroximate-
    treated group by 36%. Fenpyroximate thus had moderate dermal
    sensitizing potential (Kosaka, 1988c).

         The delayed dermal sensitizing potential of fenpyroximate
    (purity, 98.4%) was studied in female Dunkin-Hartley guinea-pigs by
    the method of Buehler. A dose of 0.5 ml of 50% aqueous fenpyroximate
    was applied to the skin three times weekly for induction; the animals
    were then challenged by applications of 50 or 25% w/w aqueous

        Table 3.  Results of tests for the genotoxicity of fenpyroximate
                                                                                                                          

    End-point           Test system                   Concentration                 Purity    Results        Reference
                                                      or dose (solvent)             (%)
                                                                                                                          

     In vitro
    Reverse mutation    S. typhimurium TA98,          0-5000 g/plate (DMSO)        97.3      Negative       May (1988)
                        TA100, TA1535, TA1537,
                        TA1538 ( S9), E. coli WP2
                        uvrA ( S9)

    Mutation            Chinese hamster               0-330 g/ml (acetone)         97.3      Negative       Hodson-Walker
                        V79 lung cells                                                                       (1988a)
                        hprt locus ( S9)

    Chromosomal         Human lymphocytes             0-20 g/ml (acetone)          97.3      Negative       Hodson-Walker
    aberration          ( S9)                                                                               (1988b)

    DNA repair          B subtilis H17, M45           0-500 g/disc (DMSO)          97.3      Negative       Watanabe (1990)
                        ( S9)

    Unscheduled DNA     Fischer 344 rat primary       0-1.02 g/ml (DMSO)           97.3      Negative       Cifone (1989)
    synthesis           hepatocytes

     In vivo
    Micronucleus        CD-1 mice                     0-2000 mg/kg bw orally        97.3      Negative       Hodson-Walker
    formation                                                                                                (1988c)
                                                                                                                          

    DMSO, dimethyl sulfoxide; S9, 9000   g supernatant
        fenpyroximate two weeks after the third induction. The positive
    control was 2,4-dinitrochlorobenzene (0.3% for induction, 0.05 and
    0.025% for challenge). The positive control group showed the expected
    response, but fenpyroximate had no effect (Teale, 1990b).

         A 5% suspension of fenpyroximate had no delayed dermal
    sensitizing potential in female Dunkin-Hartley guinea-pigs tested by
    the method of Buehler (Teale, 1990c).

    (ii)  Acute delayed neurotoxicity

         Twelve adult Sterling Ranger hybrid hens were administered
    fenpyroximate (purity, 97.0%) suspended in 0.5% aqueous
    methylcellulose by catheter at a dose of 5000 mg/kg bw twice, on days
    1 and 22 after insemination. A single oral dose of tri- ortho-cresyl
    phosphate was used as the positive control. All surviving birds were
    sacrificed on days 43-45. No deaths, abnormal neurological signs, or
    treatment-related lesions in the nervous system were observed in
    treated hens, whereas the positive control caused high mortality,
    locomotor impairment, and degenerative changes in the spinal cord and
    upper cervical bulbs, resulting in delayed neurotoxic responses
    (Cummins, 1989).

    3.  Observations in humans

         The results of medical surveillance of workers manufacturing a 5%
    formulation of fenpyroximate were reported. Ocular and dermal
    irritation were seen in July and November 1990 and March 1991. The
    concentrations of fenpyroximate in the air at eight to nine sites in
    the working place were 0.117 mg/m3 in January 1991, 0.012 mg/m3 in
    April 1991, 0.005 mg/m3 in November 1991, and 0.004 mg/m3 in January
    1993; however, the actual exposure of the workers to fenpyroximate was
    not determined (Nokata, 1992, 1994).

    Comments

         Fenpyroximate was relatively well absorbed by rats after oral
    administration. Absorbed fenpyroximate was excreted predominantly via
    the biliary route, with lesser amounts in urine. The residual levels
    in organs and tissues after 168 h were low. There was no evidence of
    bioaccumulation.

         Fenpyroximate was extensively metabolized in rats; 23 metabolites
    were identified. No parent compound was found in the urine;
    metabolites found in the excreta represented 0-11% of the administered
    dose. Multiple pathways have been proposed for the metabolism of
    fenpyroximate, including oxidation, hydroxylation, demethylation,
    hydrolysis, and isomerization.

         Fenpyroximate has slight to moderate acute oral toxicity (oral
    LD50 = 440-520 mg/kg bw in mice and 245-480 mg/kg bw in rats); it is
    acutely toxic by inhalation (LC50 in rats = 0.21-0.36 mg/m3). WHO
    has not classified fenpyroximate for acute toxicity.

         In a 13-week study in rats in which fenpyroximate was
    administered in the diet at concentrations of 0, 20, 100, or 500 ppm,
    the NOAEL was 20 ppm, equal to 1.3 mg/kg bw per day, and was based on
    decreased body-weight gain and lowered plasma protein levels in
    females fed 100 ppm. In a 13-week study in dogs, fenpyroximate was
    administered orally in capsules at doses of 0, 2, 10, or 50 mg/kg bw
    per day. The NOAEL was 2 mg/kg bw per day, on the basis of decreased
    body-weight gain and clinical signs, such as an increased incidence of
    diarrhoea, emaciation, and slight bradycardia, at 10 mg/kg bw per day.
    In a 52-week study of similar design, with doses of 0, 0.5, 1.5, 5, or
    15 mg/kg bw per day, the NOAEL was 5 mg/kg bw per day, on the basis of
    decreased body-weight gain and total protein levels at 15 mg/kg bw per
    day.

         In an 18-month study of carcinogenicity in mice given dietary
    concentrations of 0, 25, 100, 400, or 800 ppm, the NOAEL was 100 ppm,
    equal to 9.5 mg/kg bw per day, and was based on decreased body-weight
    gain, absolute body weight, and food consumption in animals of each
    sex at 400 ppm. There was no evidence of carcinogenicity. In a
    104-week study in rats given dietary concentrations of 0, 10, 25, 75,
    or 150 ppm, the NOAEL was 25 ppm, equal to 1 mg/kg bw per day, based
    on decreased body weight and body-weight gain in males at 75 ppm.
    There was no evidence of carcinogenicity.

         In a two-generation (one litter per generation) study of
    reproductive toxicity in rats given dietary concentrations of 0, 10,
    30, or 100 ppm, the NOAEL for maternal and developmental toxicity was
    30 ppm, equal to 2 mg/kg bw per day, on the basis of decreased body-
    weight gain in animals of the F0 and F1 generations at 100 ppm.

         In a study of developmental toxicity in rats given doses of 0, 1,
    5, or 25 mg/kg bw per day by gavage, the NOAEL for maternal toxicity
    and fetotoxicity was 25 mg/kg bw per day, the highest dose tested.
    There was no evidence of embryotoxicity or teratogenicity. In a study
    of developmental toxicity in rabbits given doses of 0, 1, 2.5, or
    5 mg/kg bw per day by gavage, there was no evidence of embryo- or
    fetotoxicity or teratogenicity at any dose. The NOAEL for maternal
    toxicity was 2.5 mg/kg bw per day on the basis of minor effects at
    5 mg/kg bw per day.

         Fenpyroximate has been adequately tested for genotoxicity in a
    range of tests  in vitro and  in vivo. The Meeting concluded that it
    is not genotoxic.

         Two high doses, given 21 days apart, to hens did not cause gait
    abnormalities or morphological changes in the nervous system.

         An ADI of 0-0.01 mg/kg bw was established on the basis of the
    NOAEL of 1 mg/kg bw per day for reductions in body-weight gain and
    plasma protein concentration in the 104-week study in rats and a
    safety factor of 100.

    Toxicological evaluation

     Levels that cause no toxic effect

    Mouse:    100 ppm, equal to 9.5 mg/kg bw per day (18-month study of
              carcinogenicity)

    Rat:      25 ppm, equal to 1 mg/kg bw per day (104-week study of
              carcinogenicity)

              30 ppm, equal to 2 mg/kg bw per day (study of reproductive
              toxicity)

    Rabbit:   2.5 mg/kg bw per day (maternal toxicity in study of
              developmental toxicity)

    Dog:      5 mg/kg bw per day (52-week study of toxicity)

     Estimate of acceptable daily intake/or humans

         0-0. 01 mg/kg bw

     Studies that would provide information useful for continued evaluation
     of the compound

         Observations in humans

        Toxicological criteria for setting guidance values for dietary and non-dietary exposure to fenpyroximate
                                                                                                                          

    Exposure                      Relevant route, study type, species               Results, remarks
                                                                                                                          

    Short-term (1-7 days)         Oral, lethality, mouse and rat                    LD50 = 245-520 mg/kg bw
                                  Eye, irritation, rabbit                           Irritating
                                  Eye, irritation, human                            Irritating
                                  Skin, sensitization, guinea-pig                   Sensitizing
                                  Dermal, lethality, rat                            LD50 > 2000 mg/kg bw
                                  inhalation, lethality tat                         LC50 = 0.21-0.36 mg/m3

    Medium-term (1-26 weeks)      Repeated 21-day toxicity, dermal, rat             NOAEL = 300 mg/kg bw per day based
                                                                                    on reduced body-weight gain and
                                                                                    increased liver weight
                                  Repeated four-week inhalation, toxicity, rat      NOAEL = 2 mg/m3 based on increased
                                                                                    lung weight and mucosal change in nasal
                                                                                    passages
                                  Repeated 13-week dietary, toxicity, rat           NOAEL = 1.3 mg/kg bw per day based
                                                                                    on reduced body-weight gain and
                                                                                    lowered plasma protein level
                                  Dietary, two-generation reproductive              NOAEL = 2 mg/kg bw per day for
                                  and developmental toxicity, rat                   maternal and developmental toxicity
                                  Gavage, developmental toxicity, rat, rabbit       NOAEL = 2.5 mg/kg bw per day for
                                                                                    maternal toxicity; no fetotoxicity or
                                                                                    teratogenicity

    Long-term (> one year)        Repeated dietary, two-year toxicity and           NOAEL = 1 mg/kg bw per day based on
                                  carcinogenicity, mouse; rat                       reduced body-weight gain and lowered
                                                                                    body weight; no carcinogenicity
                                                                                                                          
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    Kosaka, T. (1988c) NNI-850: Dermal sensitization study in guinea
         pigs. Unpublished report No. 87-0099 from the Institute of
         Environmental Toxicology, Tokyo, Japan. Submitted to WHO by Nihon
         Nohyaku Co., Ltd, Tokyo, Japan.

    Mahon, C.R. (1993) Dermal absorption of 14C-fenpyroximate following
         a single dermal application to male Sprague-Dawley rats.
         Unpublished report No. SC910039 from Battelle Columbus, Ohio,
         USA. Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    May, K. (1988) NNI-850 (technical grade): Assessment of mutagenic
         potential in amino-acid auxotrophs of  Salmonella typhimurium
         and  Escherichia coli (the Ames test). Unpublished report
         No. 89/NHH039/1010 from Life Science Research Ltd, Suffolk,
         United Kingdom. Submitted to WHO by Nihon Nohyaku Co., Ltd,
         Tokyo, Japan.

    Mitchell, J.M. (1990) Acute oral toxicity study in rats. Test
         material: NNI-850 Flowable-R. Unpublished report No. 5795-90 from
         Bio-dynamics Inc., New Jersey, USA. Submitted to WHO by Nihon
         Nohyaku Co., Ltd, Tokyo, Japan.

    Mitchell, J.M. (1991) Acute dermal toxicity study in rats. Test
         material: NNI-850 Flowable-R. Unpublished report No. 5975-90 from
         Bio-dynamics Inc., New Jersey, USA. Submitted to WHO by Nihon
         Nohyaku Co., Ltd, Tokyo, Japan.

    Motoba, K., Suzuki, T. & Uchida, M. (1992) Effect of a new acaricide,
         fenpyroximate, on energy metabolism and mitochondrial morphology
         in adult female  Tetracnychus urticae (two-spotted spider mite).
          Pestic. Biochem. Physiol., 43, 37-44

    Nishizawa, H., Motoba, K., Suzuki, T., Ohsima, T., Hamaguchi, H. &
         Uchida, M. (1993) Metabolism of fenpyroximate in rats.
          J. Pestic. Sci., 18, 59-66.

    Nokata, M. (1992) Effect of fenpyroximate in human-eye and skin
         irritation. Unpublished report No. H-4001 submitted to WHO by
         Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Nokata, M. (1994) Effect of fenpyroximate on factory workers.
         Unpublished report No. H-4003 submitted to WHO by Nihon Nohyaku
         Co., Ltd, Tokyo, Japan.

    Sharp, D.E. (1990a) Pharmacokinetics of a [pyrazole-14C] NNI-850 in
         rats (high and low doses). Unpublished report No. HLA 6283-104
         from Hazleton Laboratories America, Inc., Maryland, USA.
         Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Sharp, D.E. (1990b) Pharmacokinetics of a [benzyl-14C] NNI-850 in
         rats (high and low doses). Unpublished report No. HLA 6283-103
         from Hazleton Laboratories America, Inc., Maryland, USA.
         Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Sharp, D.E. (1991a) Metabolism and disposition of a [pyrazole-14C]
         NNI-850 in rats. Unpublished report No. HLA 6283-102 from
         Hazleton Laboratories America, Inc., Maryland, USA. Submitted to
         WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Sharp, D.E. (1991b) Metabolism and disposition of a [benzyl-14C]
         NNI-850 in rats. Unpublished report No. HLA 6283-101 from
         Hazleton Laboratories America, Inc., Maryland, USA. Submitted to
         WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Takahashi, K. (1987) NNI-850: 18-Month oral oncogenicity study in
         mice. 4 week dose range finding study Unpublished report No. IET
         87-0034 from the Institute of Environmental Toxicology, Tokyo,
         Japan. Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Takahashi, K. (1988) NNI-850: 18-Month oral oncogenicity study in
         mice. 4 week dose range finding study. Unpublished report No. IET
         87-0186 from the Institute of Environmental Toxicology, Tokyo,
         Japan. Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.

    Takahashi, K. (1990) NNI-850: 18-Month oral oncogenicity study in
         mice. Unpublished report No. 87-0036 from the Institute of
         Environmental Toxicology, Tokyo, Japan. Submitted to WHO by Nihon
         Nohyaku Co., Ltd, Tokyo, Japan.

    Taninaka, K. (1993) Fenpyroximate, a new acaricide.  Agrochem. Jpn,
         62, 15-17.

    Teale, H.J (1990a) Primary eye irritation study, NNI-850 Flowable-R.
         Unpublished report No. A/E/24652 from Toxicol Laboratories
         Limited, Herefordshire, United Kingdom. Submitted to WHO by Nihon
         Nohyaku Co., Ltd, Tokyo, Japan.

    Teale, H.J. (1990b) NNI-850 Technical/Delayed dermal sensitization
         test in the guinea pig. Unpublished report No. A/B/22645 from
         Toxicol Laboratories Ltd, Herefordshire, United Kingdom.
         Submitted to WHO by Nihon Nohyaku Co, Ltd, Tokyo, Japan.

    Teale, H.J. (1990c) NNI-850 Flowable/Delayed dermal sensitization test
         in the guinea pig. Unpublished report No. A/B/22646 from Toxicol
         Laboratories Ltd, Herefordshire, United Kingdom. Submitted to WHO
         by Nihon Nohyaku Co, Ltd, Tokyo, Japan.

    Tsu-Han Li (1991a) [Benzyl-14C] fenpyroximate: Biliary excretion in
         the rat. Unpublished report No. 7189-001 from Southern Research
         Institute. Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo,
         Japan.

    Tsu-Han Li (1991b) [Pyrazole-14C] fenpyroximate: Biliary excretion in
         the rat. Unpublished report No. 7189-002 from Southern Research
         Institute. Submitted to WHO by Nihon Nohyaku Co., Ltd, Tokyo,
         Japan.

    Watanabe, M. (1990) NNI-850: DNA repair test (rec-assay). Unpublished
         report No. 88-0072 from the Institute of Environmental
         Toxicology, Tokyo, Japan. Submitted to WHO by Nihon Nohyaku Co.,
         Ltd, Tokyo, Japan.

    Wilkinson, G.E., Ryan, M.J & Peters, A.C. (1992) 21-Day repeated-dose
         dermal toxicity study of fenpyroximate in the rat. Unpublished
         report No. SC920009 from Battelle Columbus, Ohio, USA. Submitted
         to WHO by Nihon Nohyaku Co., Ltd, Tokyo, Japan.
    


    See Also:
       Toxicological Abbreviations