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    PROFENOFOS

    EXPLANATION

    First draft prepared by Dr J.A. Quest,
    US Environmental Protection Agency, Washington, D.C., USA

         Profenofos is a broad spectrum organophosphate insecticide and
    acaricide.  Its mode of action is by inhibition of
    acetylcholinesterase.  Profenofos was evaluated for the first time by
    the present meeting.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Rats

         Four male and three female RAI rats received a single oral dose
    of approximately 4.8 mg/kg bw of randomly ring-labelled-14C
    profenofos (s.a. = 9.79 Ci/mg).  Within 6 days essentially all of the
    administered radioactive dose was eliminated in the urine (81.8% in
    males and 96.4% in females) and faeces (15.7% in males and 2.5% in
    females).  Most of the urinary and faecal excretions occurred within
    the first 24 hours of dosing.  The excretion t1/2 was less than 8
    hours for both sexes.  Only minor amounts of radiolabelled material
    were excreted in the expired CO2 (0.08% in males and 0.07% in
    females).  When the animals were sacrificed 6 days after dosing,
    detectable amounts of residual radioactivity were found only in the
    liver (0.013 ppm in males and 0.023 ppm in females) and kidney (0.007
    ppm in males and 0.008 ppm in females), while radiolabel in other
    tissues (fat, muscle, testis, ovary, brain) was below the limit of
    detection or (blood) quantitation (Ifflaender, et al., 1974).

         Male and female Harlan SD albino rats received single dermal
    applications of ring-labelled 14C profenofos at doses of 0.5 mg/kg
    (s.a. = 9.34 Ci/mg and 10 mg/kg (s.a. = 2.6 Ci/mg) in a 72-hour
    balance study.  Over the 72-hour absorption period, the total 14C
    recoveries averaged 92% to 95% of each applied dose in each sex (80%
    to 86% in urine, 2.2% to 3.9% in faeces, 0.09% to 1.8% in tissues,
    0.06% or less in blood, 3% or less in treated skin, and 5% or less in
    cage washings).  Excretion in expired CO2 was negligible (less than
    0.02%, as determined from a preliminary study using the highest dermal
    dose).  The calculated 50% absorption rates indicated that 14C-
    profenofos was absorbed at nearly the same rate for males and females
    regardless of the dose level; t1/2 absorption values were 17.9 and
    15.0 hours after treatment with the low dose in males and females,
    respectively, and 16.7 and 14.1 hours after treatment with the high
    dose in males and females, respectively.  The calculated 50% excretion
    rates (urine was the major route of excretion) occurred 18.1 and 17.4
    hours after treatment with the low dose in males and females,
    respectively, and 23.2 and 18.7 hours after treatment with the high
    dose in males and females, respectively.  Fifty percent of 14C-
    profenofos was excreted shortly after 50% had been absorbed indicating
    that profenofos and its metabolites were rapidly excreted, i.e., there

    was no lag time between absorption and excretion.  Levels of
    radioactivity in selected tissues (liver and kidney) and blood peaked
    in 2 to 8 hours, plateaued by 8 hours, and declined rapidly by 72
    hours  (Williams, et al., 1984).

    Hens

         Two white Leghorn hens received oral doses of ring-labelled
    14C-profenofos (s.a. = 19.1 ci/mg) for 14 consecutive days at a
    dose rate equivalent to 5 mg/kg in the feed.  A third hen served as an
    untreated control.  The total excretion over 14 days ranged from 81.3
    to 85.2% of the radioactive dose (81-84% in excreta, 0.02% in tissues,
    0.01% in blood, 0.21% in egg yolks, and 0.009% in egg whites).  The
    excretory plateau occurred after 5 to 9 days of dosing.  The kidney
    was the only tissue containing a notable amount of radioactivity
    (equivalent to 0.054 to 0.073 mg/kg whereas negligible levels
    (equivalent to 0.013 mg/kg or less) where found in liver, blood,
    muscle, skin and fat (Oakes, et al., 1986).

    Goats

         A single goat received oral doses of ring-labelled 14C-
    profenofos (s.a. = 26.2 Ci/mg) for 9 consecutive days at a level
    equivalent to 5 mg/kg in the diet.  A second goat served as an
    untreated control.  The total recovery of radioactivity over 9 days
    was 97.8% of the radioactive dose (85.8% in urine, 4.4% in faeces,
    5.8% in the rumen and intestinal contents, 1.0% in expired CO2, 1.0%
    in milk, 0.9% in tissues, and 0.6% in blood).  Based on urine, faeces,
    and milk data, the radioactivity in excretions and secretions reached
    a plateau by the second day of dosing.  The levels of radioactivity in
    tissues were the highest in the liver (0.096 mg/kg) and kidney (0.072
    mg/kg), and lower in fat (0.018 mg/kg) and heart, brain and skeletal
    muscle (0.004 mg/kg or less) (Thomas, et al., 1976).

    Biotransformation

    Rats

         The metabolism of ring-labelled 14C-profenofos was studied over
    a 24-hour period in the urine of RAI rats given a single oral dose of
    approximately 4.8 mg/kg bw.  Analysis of the urine via TLC in rats of
    both sexes indicated complete degradation of profenofos as no
    unchanged parent compound was present.  Four metabolites were observed
    in urine; the only one identified by TLC was the cleavage product, 4-
    bromo-2-chlorophenol, which was found in negligible amounts in freshly
    obtained urine.  This metabolite did not appear in the initial
    samples, indicating that other labile metabolites are cleaved to this
    phenol (Ifflaender, et al., 1974).

         In a second study, the metabolism of ring-labelled 14C-
    profenofos (s.a. = 26.2 Ci/mg) was investigated over a 2 day period
    in the urine and faeces of eleven male RAI rats given a single oral
    dose of 28.5 mg/kg bw.  The material was readily absorbed from the gut
    and excreted, with 90.4% and 3.6% of the administered dose excreted in
    urine and faeces within 24 hours.  The proposed metabolic pathways of
    the parent compound, profenofos, in the urine and faeces of rats is
    depicted in Figure 1.  The main features of this scheme are as
    follows:

         1.   Neither the intact parent compound profenofos (O-(-4-bromo-
              2-chlorophenol)-O-ethyl-S-n-propyl phosphorothioate) nor its
              corresponding phenol (4-bromo-2-chlorophenol) was detected
              in freshly obtained urine.

         2.   The major metabolic pathway in urine involves the
              depropylation of profenofos to Metabolite B, i.e., O-(4-
              bromo-2-chlorophenol)-O-ethyl phosphorothioate (7%), which
              is then desulfurated to Metabolite A2, i.e., 0-(4-bromo-2-
              chlorophenol)-O-ethyl phosphate (23%).  This, in turn,
              undergoes cleavage at the phenyl-ester bond giving rise to
              4-bromo-2-chlorophenol which is completely conjugated with
              glucuronic acid to Metabolite A1, i.e., 4-bromo-2-
              chlorophenol glucuronide (26%) and with sulfuric acid to
              Metabolite C, i.e., 4-bromo-2-chlorophenol sulfate (34%).

         3.   A second but more minor metabolite pathway in urine involves
              O-demethylation of profenofos to Metabolite D, i.e., O-(4-
              bromo-2-chlorophenol)-s-propyl phosphorothioate (less than
              0.5%).  This also undergoes conversion to 4-bromo-2-
              chlorophenol, and then to Metabolites A1 and C.

         4.   The faeces were reported to contain only small amounts of
              the parent compound, profenofos (2%), and its corresponding
              phenol, 4-bromo-2-chlorophenol (1%).  Additional metabolites
              were present in minute amounts (0.2% or less) but were not
              identified.  (Ifflaender and Mucke, 1976).

         In a third study, male rats (Tif:RAI-f strain) dosed orally with
    single doses of 0.19 or 1.80 mg/kg bw of ring-labelled 14C-
    profenofos excreted 78% to 81% of the dose in the urine within 24
    hours.  Upon acidic hydrolysis, 96% of the urinary metabolites were
    transformed to 4-bromo-2-chlorophenol.  The main urinary metabolites
    identified in this study were similar to those reported in Figure 1 by
    Ifflaender and Mucke, 1976 (i.e., Metabolites B, A2, A, and C were
    found in average distributions of 8%, 17%, 33%, and 38% of the urine
    radioactivity, respectively).  An exception was that a small amount
    (approximately 7%) of unconjugated 4-bromo-2-chlorophenol was also
    found in the present study.  From these data, the authors determined
    that the conversion factor to calculate the amount of profenofos taken

    up orally from the amount of 4-bromo-2-chlorophenol determined in 0-24
    hour urine after hydrolysis was 1.30 (for the 0.19 mg/kg dose) to 1.33
    (for the 1.80 mg/kg dose).  The data were independent of the dose
    within the range tested, and could serve as a urinary monitoring
    system for occupational exposure to profenofos (Mucke, 1986).

    Hens

         Two white Leghorn hens received oral doses of 5 ppm of ring-
    labelled 14C-profenofos over 14 days at which time excreta samples
    were selected for characterization of metabolites.  Most of the
    excreta residues were extractable (97%) and were divided between
    organic soluble (66%) and aqueous soluble (31%) materials.  Of the
    organic soluble fraction, 10.6% was unchanged profenofos and 52.8% was
    4-bromo-2-chlorophenol.  The aqueous soluble fraction was
    characterized as 4-bromo-2-chlorophenol (10.5%), its sulfate conjugate
    (15.5%; referred to as Metabolite C in rats, above), 0-(4-bromo-2-
    chlorophenol)-0-ethyl-phosphate (6.2%; referred to as Metabolite A2
    in rats, above), and 4-bromo-2-chlorophenol glucuronide (2.6%;
    referred to as Metabolite A1 in rats, above) (Oakes, et al., 1986).

    Goats

         A metabolism study in a single goat administered 5 mg/kg bw/day
    of ring-labelled 14C-profenofos in the diet for 9 consecutive days
    indicated that of the radioactivity in urine, 11% was 4-bromo-2-
    chlorophenol.  At least two other urinary metabolites were present,
    one of which was unknown (less than 2%) and the other most probably a
    sulfate conjugate (87%).  A major part (87%) of the residues
    identified in the liver was released as 4-bromo-2-chlorophenol upon
    hydrolysis (Thomas, et al., 1976).

    In Vitro studies

         Incubation of 25 nmol of ring-labelled 14C-profenofos with
    mouse liver microsomes containing NADPH resulted in the metabolic
    formation of several products, including desthiopropylprofenofos,
    despropylprofenofos, desethylprofenofos, and protein-bound
    radiocarbon.  Profenofos underwent little or no metabolism or
    incubation with mouse liver microsomes without NADPH (Wing, et al.,
    1984).

    FIGURE 1

    Effects on enzymes and other biochemical parameters 

         Profenofos is stereospecifically converted to a more potent
    inhibitor of acetylcholinesterase by mouse liver microsomal mixed-
    function oxidase system.  The chiral (-) isomer became a 34-fold
    better inhibitor of acetylcholinesterase in vitro, while the less
    toxic (+) isomer was deactivated by a factor of 2.  Prior treatment
    with mixed function oxidase inhibitors markedly decreased the
    activation and also protected against brain acetylcholinesterase
    inhibition and cholinergic symptoms resulting from (-) profenofos
    administration in chicks (Wings, et al., 1983).

    Toxicological studies

    Acute studies

         The acute toxicity of profenofos is given in Table 1.  The
    adverse signs of toxicity that were observed were generally similar
    for each route of compound administration.  These included non-
    specific symptoms such as dyspnoea, exophthalmos, ruffled fur and
    crooked body posture, and cholinergic symptoms such as sedation,
    salivation, discharge from eyes and nose, trismus, tremors, and tonic-
    clonic convulsions.  The symptoms were reversible in surviving
    animals.

    Short-term studies

    Rats

         A feeding study was performed in which groups of 25 male and 25
    female F344 rats received technical profenofos (90.6% a.i.) in the
    daily diet for up to 13 weeks.  Two control groups (basal diet) and
    eleven dose groups (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, and
    1000 ppm) were used.  The animals from one control group and the 0.3,
    3, 30, and 300 ppm test groups (15/sex/dose level) were on test for 13
    weeks.  The animals in all of the other test groups were sacrificed at
    weeks 2, 4 and 8 (5 to 15 rats/sex/group).  The results indicated that
    dose levels of profenofos of 10 to 1000 ppm produced a dose-related
    inhibition of cholinesterase activity in plasma and erythrocytes (more
    marked in females), that dose-levels of 100 to 1000 ppm produced
    reduced food intake and a dose-related reduction in body weight gain,
    and that dose-levels of 300 and 1000 ppm reduced brain cholinesterase
    activity.  These effects were observed in rats of both sexes. 
    Profenofos did not result in death of any of the treated animals.  No
    unusual signs of behavior or appearance were observed.  Results of
    haematology, clinical chemistry (excluding cholinesterase) and
    urinalysis examinations were unremarkable.  Necropsies performed at
    the various sacrifice intervals and at termination of the study did
    not reveal treatment-related gross changes.

        Table 1: Acute toxicity of Profenofos1

                                                                                  
    Species  Sex     Route          LD50         LC50     Reference
                                    (mg/kg bw)   (mg/l)
                                                                                  
    Mouse    M+F     Oral           298          --       Bathe, 1974a

    Rat      M+F     Oral           358-502      --       Bathe, 1974b
                                                          Kobel & Gfeffer, 1983
             M+F     Dermal         33002        --       Bathe, 1974c
             M+F     i.p.           585          --       Sachsse & Bathe, 1975
             M+F     inhalation     --           3-3.36   Sachsse & Ullmann, 1974a
                     (4hr)
                                                          Horath & Taylor, 1982

    Chinese  M+F     Oral           153          --       Bath & Sachsse, 1979
    hamster

    Rabbit   M+F     Oral           700          --       Sachsse & Ullmann, 1974b
             M+F     Dermal         4722         --       Sachsse & Ullmann, 1974c
             M+F     Dermal         1313         --       Cannelongo, 1982a
             M+F     Dermal         25404        --       Kuhn, 1988

    Dog      M+F     Oral           >3005        --       Bathe, 1974d
                                                                                  

    1    All studies performed using technical grade profenofos
    2    Intact skin, occlusive dressing (aluminum foil and plaster)
    3    Intact and abraded skin, occlusive dressing (polyethylene film)
    4    Intact skin, semipermeable dressing (orthopaedic stockinette)
    5    Acute oral toxicity could not be determined in dogs due to vomiting
         at doses of 300 mg/kg and higher.
    
         Profenofos technical (purity unspecified) was administered by
    inhalation (nose only exposure) to albino RAI rats for 21 days (6
    hours/day, 5 days/week) at mean concentrations of 0, 68, 219 and 449
    mg/m3 in air.  Nine males and nine females per group were exposed. 
    Four males and 4 females of the control and 219 mg/m3 group were
    kept for an additional 21 days without treatment (recovery group). 
    All rats of the 449 mg/m3 group (9/9M and 9/9F) and 1/9 females of
    the 219 mg/m3  group died during the first week after showing
    symptoms of exophthalmos, dyspnoea, tremor, ruffled fur, lateral
    position, and irritation/ secretion of the mucous membranes of the
    eyes.  Microscopic exams of these rats revealed the presence of marked
    congestion of the nasal mucous membranes, acute conjunctivitis, and
    severe interstitial keratitis.  In the remaining surviving animals of
    the 68 mg/m3 and 219 mg/m3 groups there were reductions in food
    consumption and body weight gain (seen in males throughout the study
    and in females over the first 7 to 10 days of the study), reductions
    in total plasma protein levels, and a dose-related inhibition of
    cholinesterase activity in plasma, red blood cells, and brain.  The
    magnitude of cholinesterase inhibition ranged from -40% to -70% for
    all 3 sites.  In addition, alpha-1 globulin levels were reduced and
    alpha-2 and beta globulin levels were increased in males of the 219
    mg/m3 group.  All of the above changes observed in the surviving
    rats were reversible upon cessation of treatment, with the exception
    of the reductions in plasma and red cell cholinesterase levels in rats
    of the 219 mg/m3 group which remained about 25% below control levels
    at the end of the 21-day recovery period.  Finally, necropsy of the
    surviving rats did not reveal any gross or microscopic pathological
    changes, although the related weights of most organs were increased in
    male rats due to the reduced weight gain incurred in these animals. 
    The NOAEL was less than 68 mg/m3 in air (lowest dose tested) in
    males and females, based upon reductions in food consumption, weight
    gain, and cholinesterase activity in plasma, red cells, and brain
    (Ullmann, et al., 1977).

    Rabbits

         In a dermal toxicity study, profenofos technical (89.8% pure) was
    diluted with polyethylene glycol and saline (70:30) to 2% and 5%
    solutions and applied to the skin of KA46 rabbits (Himalayan strain;
    3/sex/dose level) at doses of 0, 5, 20, and 100 mg/kg bw/day for 24
    hours/day, 5 days/week, for 21 days.  In the 0, 5, and 20 mg/kg bw/day
    treatment groups, 1 rabbit/sex/dose level was kept for an additional
    21 days without treatment (recovery group).  All of the rabbits
    treated dermally with 100 mg/kg bw/day of profenofos died within 6
    days after dosing was initiated.  These animals displayed moderate
    erythema and oedema of the skin, reduced food intake and body weight
    gain, various clinical signs of toxicity (dyspnoea, salivation,
    tremors, ataxia, sedation, and curved position), and inhibition of
    cholinesterase activity in plasma (-100%) and red cells (-50.3%) as
    measured on day 4 prior to deaths.  Histopathological examination of

    the high dose animals showed focal hypertrophy, haemorrhages and fatty
    changes of hepatocytes accompanied by necrosis of the liver
    parenchyma, and slight to moderate atrophy of lymphoid and thymic
    tissue.  Microscopic examination of the skin at the site of dermal
    application showed oedema, minute haemorrhages, small intradermal
    pustules, focal acanthosis and parakeratosis.  In the animals treated
    with the lower doses (5 and 20 mg/kg bw/day) of profenofos the
    observed toxic changes consisted of slight erythema and oedema at the
    application site, and inhibition of cholinesterase activity in plasm,
    red cells, and brain.  These effects disappeared during the recovery
    period.  No other unusual findings were observed in the lower dose
    group animals.  The NOAEL was less than 5 mg/kg bw/day (lowest dose
    tested) in male and female rabbits for short term dermal toxicity
    (Ullmann, et al., 1976).

         In a second dermal toxicity study, profenofos technical (92%
    pure) was suspended in purified water containing 0.5% Tween 80 and
    applied to the skin of albino rabbits (HAR:PC/CF (NZW) BR strain;
    5/sex/dose level) at doses of 0, 0.05, 1 and 10 mg/kg bw/day for 6
    hours/day, 5 days/week, for 21 days.  No deaths occurred in any
    treated animals. Profenofos administration produced slight erythema at
    the application site in mid dose males and females, and in high dose
    males.  Additional changes that appeared to be treatment-related were
    observed at the high dose level and included hyperactivity and soft
    faeces in males and/or females, significant reductions of
    cholinesterase activity (measured at terminal sacrifice) in plasma,
    red blood cells, and brain, increases in serum bilirubin (males) and
    gamma GT (females) levels, and a decrease in serum sodium levels
    (males).  No unusual histopathological findings occurred.  The NOAEL
    for subchronic dermal toxicity (excluding the occurrence of slight
    dermal erythema at the mid dose) was 1 mg/kg bw/day in males and
    females (Johnson, et al., 1984).

    Dogs

         In a 6-month study, groups of 7 male and 7 female pedigreed
    beagles were fed diets containing 0, 0.2, 2, 100, or 500 ppm of
    technical profenofos (88.1%-89.3% pure).  One male and one female of
    each group was kept for an additional 28 days on control diet
    (recovery groups).  The administered concentrations were calculated to
    be equivalent to 0, 0.007, 0.05, 2.9, and 14.4 mg/kg bw/day in dogs of
    both sexes.  Standard examinations for clinical signs of toxicity,
    ophthalmology, haematology, clinical chemistry (including plasma,
    brain, and red cell cholinesterase activity and plasma and liver
    carboxylesterase activities) and urinalysis parameters were performed
    at regular intervals throughout the study.  The animals were subjected
    to a battery of neurological exams (e.g., muscle strength and tone,
    reflexes, etc.), necropsied, and examined grossly for organ changes
    and histologically for tissue changes.

         Adverse findings were observed at dose levels of 2 ppm to 500 ppm
    and consisted of cholinesterase inhibition in plasma (males and
    females at 2, 100, and 500 ppm bw/day) and red cells (males and
    females at 100 and 500 ppm), carboxylesterase inhibition in plasma and
    liver (males at 100 and 500 ppm), reductions in erythrocyte,
    haemoglobin and haematocrit levels (males and females at 500 ppm; also
    occasionally at 100 ppm), and reduced food consumption (males at 500
    ppm over weeks 0-3).  The depressed haematological values were said to
    be within physiological limits, but it was noted that they did not
    increase with age as was the case in the control and lower dose group
    animals.  All those effects appeared to be reversible during the 4-
    week recovery period.  Aside from these changes, there were no other
    compound-related effects.

    Long-term/carcinogenicity studies

    Mice

         A long-term feeding study of profenofos technical (90.6% pure)
    was performed in albino mice (HaM/ICR Swiss, CR-CD 1 strain) in which
    dietary concentrations of 0, 1, 30, and 100 ppm were fed to 60
    males/dose group for 85 weeks and 60 females/dose group for 96 weeks. 
    The original design of the study was for 104 weeks, but because
    survival had reached 20% of the original number of mice in the mid-
    dose males and in the high-dose females due to accidental causes, the
    sacrifices were initiated early.  An additional 5 mice/sex/dose were
    studied at each dose level and were sacrificed after 52 weeks for the
    determination of cholinesterase activity in erythrocytes, plasma and
    brain; these animals were not examined histopathologically.  The
    administered concentrations were calculated to be equivalent to 0,
    0.14, 4.5, and 14.2 mg/kg bw/day in males and 0, 0.19, 5.8, and 19.2
    mg/kg bw/day in females.

         There were no clinical signs of toxicity and no significant
    effect of treatment on mortality.  There were no treatment related
    effects on food consumption or body weight gain, or at gross necropsy
    or after histopathological examination.  There were no increases in
    tumors that appeared to be related to compound administration.  With
    respect to clinical laboratory examinations, a significant dose-
    related inhibition of erythrocyte and plasma cholinesterase activity
    (generally ranging from -38% to -76%) was observed in mid- and high-
    dose males and females at week 53 (interim sacrifice animals) and at
    the termination of the study (week 85 in males and week 97 in
    females).  In addition, brain cholinesterase activity was
    significantly inhibited (about -25%) in high-dose females at the end
    of the study, whereas a trend (not significant) for this effect was
    observed in the males.  The NOAEL for male and female mice was 1 ppm
    in the diet (0.14 mg/kg bw/day in males and 0.19 mg/kg bw/day in
    females) based upon cholinesterase inhibition (Burdock, et al.,
    1981a).

    Rats

         Fischer 344 albino rats (60/sex/group) were fed profenofos
    technical (90.6% pure) at doses of 0, 0.3, 10, and 100 ppm for 2
    years.  An additional 10 rats/sex were also included in the control
    and high dose treatment groups, respectively.  Of these, 5/sex/group
    were sacrificed at 52 weeks (interim sacrifice), and 5/sex/group were
    placed on control feed after 52 weeks so that recovery studies could
    be conducted and these were then sacrificed during week 63 (recovery
    animals).  All of the animals in the study were examined
    histopathologically.  Plasma and erythrocyte cholinesterase activity
    was determined in 10 rats/sex/dose group (main study group) at weeks
    13, 26, 52, 78, and 105 and in the recovery animals at week 57.  Brain
    cholinesterase activity was determined in the interim and terminal
    sacrifice animals at weeks 53 and 105.  The administered
    concentrations of profenofos were calculated to be equivalent to 0,
    0.017, 0.56, and 5.7 mg/kg bw/day in males and 0, 0.02, 0.69, and 6.9
    mg/kg bw/day in females.

         There were no treatment-related clinical signs of toxicity,
    deaths, or changes in body weight gain.  No sustained changes in
    clinical chemistry parameters occurred which were considered to be
    treatment-related.  A dose-related inhibition of plasma and
    erythrocyte cholinesterase was observed in rats of both sexes at the
    mid- and high-dose levels; these effects were considered to be
    compound-related and were reversible as judged by their absence in the
    recovery group animals.  Brain cholinesterase was not altered by
    profenofos in this study.  Additional changes seen only at the high
    dose level included an increase in food consumption in females, an
    increase in relative thyroid gland weight in high dose males (seen in
    interim sacrifice and recovery group animals but not in terminal
    sacrifice animals, and not considered biologically significant), an
    increase in thyroid gland perifollicular cell hyperplasia in high dose
    males (i.e., 4/70 controls vs. 10/70 high dose), and an increase in
    liver neoplastic nodules in high dose females (i.e., 1/70 controls;
    3/60 low dose; 2/60 mid dose; and 6/70 high dose).  No increase in
    liver carcinomas occurred.  The latter histopathological findings were
    not considered to be compound-related changes.  The NOAEL was 5.7
    mg/kg bw/day (the highest dose tested).

    Reproduction study

         Groups of male (8/sex/dose) and female (16/sex/dose) albino rats
    in each of three generations (F0, F1, and F2) were fed diets
    containing 0, 0.2, 1.0, or 20 ppm profenofos (technical grade; 95.5%
    pure).  The dietary concentrations were equivalent to 0, 0.01, 0.05,
    and 1.0 mg/kg bw/day.  Parental animals were allowed to mature for 100
    days, mate, and produce 2 litters.  Eight males and 16 females from
    the second litters were retained at weaning as parental animals for 

    the succeeding generations.  The study was terminated following the
    weaning of the F3b litters.  Profenofos was administered
    continuously through the experiment.

         There were no compound related effects on body weight, mortality,
    behavior, or various parameters measuring fertility (fecundity index,
    male or female fertility index) in any of the parenteral animals. 
    Statistically significant reductions in cholinesterase occurred at 20
    ppm in erythrocytes (F0, F1, and F2 males and females) and
    plasma (F0 females).  In contrast, statistically increased plasma
    cholinesterase activity was seen in F0 females given 0.2 and 1 ppm
    and F1 males given 1 ppm, and brain cholinesterase activity was
    increased in F1 males and females given 1 and 20 ppm.  No adverse
    effects occurred in progeny with respect to litter size, viability,
    body weight, cholinesterase activity in erythrocytes, plasma or brain,
    or development throughout the study.  Postmortem gross and
    histopathologic examinations of parenteral animals and F3b weanlings
    were unremarkable (IBTL, Inc., 1978).  The NOAEL for reproductive
    effects was greater than 1.0 mg/kg bw/day in the diet (highest dose
    tested).

    Special studies on embryo/fetotoxicity

    Rats

         Groups of 20-27 pregnant rats (strain unspecified) were
    administered profenofos (technical grade; purity unspecified) via oral
    gavage at dose levels of 0, 10, 30, and 60 mg/kg bw from days 6 to 15
    of gestation (day 0 = day either spermatozoa  or vaginal plug found). 
    On day 21 of gestation, all dams were sacrificed and fetuses delivered
    by caesarean section.  Maternal toxicity was evident in the high-dose
    groups as indicated by a marked decrease in food consumption during
    the period of treatment.  No other adverse effects occurred in the
    dams.  Similarly, none of the doses of profenofos appeared to affect
    embryonic or fetal development and no teratogenic effects were
    observed.  The NOAEL for maternal toxicity was 30 mg/kg and that for
    fetotoxicity/teratogenicity was 60 mg/kg by oral gavage (Fritz,
    1974b).

         Groups of 23-25 pregnant rats (JCL-SD strain) received profenofos
    (technical grade; 95.8% purity) via intubation at dose levels of 0,
    18, 35, or 70 mg/kg bw/day from days 7 to 17 of gestation (day =day
    that a sperm plug was found). On day 21 of gestation, all dams were
    sacrificed under ether anaesthesia and fetuses delivered by caesarean
    section.  The doses of profenofos selected for testing were based upon
    the results of a preliminary range finding study in which 140 mg/kg
    bw/day caused death in 5/6 treated rats during days 8 to 15 of
    pregnancy.  Profenofos administration was associated with increases in
    body weight and water consumption in the dams at doses of 35 and 70
    mg/kg bw/day on days 17 to 21, and an increased level of food

    consumption at 70 mg/kg bw/day on days 14 to 21; these changes did not
    appear to be deleterious.  Although small increases in the weights of
    several organs (heart, spleen, liver, and right kidney) were seen at
    70 mg/kg bw/day, these were small in magnitude.  No treatment-related
    changes in mortality or behavior were observed, and no abnormal
    findings were observed at gross necropsy.  There were no adverse
    effects on the offspring with respect to resorptions, sex ratios,
    placental weights, body weights and lengths, or distribution of
    fetuses within the uterine horns.  External and visceral examinations
    of fetuses were unremarkable.  Skeletal examination of fetuses showed
    increased incidences of progeny with holes in the xiphoid at the mid
    and high doses (0% controls, 0% low dose, 18.8% mid dose, and 15.6%
    high dose) and delayed ossification of vertebral arches at the high
    dose (8.8% controls, 6.7% low dose, 0.5% mid dose, and 26.7%).  No
    historical control data was provided and it could not be determined if
    the findings were all from one litter or from multiple litters.  The
    NOAEL for maternal and developmental toxicity appeared to be 70 mg/kg
    bw/day by intubation (Sugiya et al., 1982).

         Groups of 25 pregnant rats (Sim:(SD)fBR strain) received
    profenofos (technical grade; 88.0% purity) via oral gavage at dose
    levels of 0, 10, 30, 60, 90, and 120 mg/kg bw/day from days 6 to 15 of
    gestation (day 0 = day either sperm or vaginal plug found).  On day 21
    of gestation, all dams were sacrificed using CO2 and fetuses
    delivered by caesarean section.  Maternal toxicity occurred at the
    high dose level as evidenced by increased mortality, reduced food
    consumption, and various clinical signs of toxicity (e.g.,
    hypoactivity or tremors, ocular porphyrin discharge, diarrhoea,
    dyspnoea, diuresis, and hypothermia).  Two of the 4 dams that died
    displayed these clinical signs whereas the other 2 did not.  In
    addition, 2 of the dams that died also showed scattered haemorrhages
    in the stomach upon gross necropsy.  None of the other doses tested
    produced changes in the pregnancy ratio, percentage of live or dead
    fetuses, number of resorptions, or live fetal weights or sex ratios. 
    Similarly none of the dose appeared to affect embryonic or fetal
    development and no teratogenic effects were observed.  The NOAEL for
    maternal toxicity was 90 mg/kg bw/day (Harris and Holson, 1982).

    Rabbits

         Groups of 20 pregnant Chinchilla rabbits were administered
    profenofos (technical grade; 89.5% purity) via intubation at dose
    levels of 0, 5, 15, and 30 mg/kg bw from days 6 to 18 of gestation
    (day 0 = day of mating).  On day 28 of gestation, all dams were
    sacrificed by cervical dislocation and fetuses delivered by caesarean
    section.  With the exception of a marginal reduction in food
    consumption from day 6 onward there were no unusual effects of
    profenofos on the does.  In addition, no adverse prenatal effects,
    malformations, or variations were observed.  The NOAEL for both
    maternal and development toxicity was 30 mg/kg bw/day by intubation
    (Fritz, et al., 1979).

         Groups of 16 pregnant New Zealand White rabbits were given
    profenofos (technical grade; 90.8% purity) by oral gavage at dose
    levels of 0, 30, 60, 90, and 175 mg/kg bw from days 6 to 18 of
    gestation (day 0 = day of mating).  On day 30 of gestation, all does
    were euthanized and fetuses delivered by caesarean section.  The doses
    of profenofos selected for testing were based upon the results of a
    preliminary range finding study in which doses up to 150 mg/kg bw did
    not produce any signs of toxicity.  Profenofos administration was
    associated with reduced maternal weight gain and food consumption at
    doses of 60 mg/kg bw or more, clinical signs of toxicity (e.g.
    diarrhoea, soft stools, oral/perianal discharges) at 90 mg/kg bw or
    more, and deaths in 9/16 (56.3%) of the does at 175 mg/kg bw.  Many of
    the does that died exhibited the above clinical signs of toxicity as
    well as signs of pinpoint stomach haemorrhages and yellow-discolored
    areas in the mesentery in the gastric region upon gross necropsy. 
    None of the doses tested produced changes in maternal pregnancy rates,
    in prenatal effects (e.g., percentage of live fetuses and live
    fetuses/litter, resorptions, litter size, fetal body weight, and sex
    ratios), or in malformations or variations.  The NOAEL for maternal
    toxicity was 30 mg/kg bw/day and that for developmental toxicity was
    175 mg/kg bw/day (Holson, 1983).

    Special studies on eye and skin irritation

         In two studies in rabbits, instillation of 0.1 ml of profenofos
    (undiluted technical material) into the conjunctival sac for 30
    seconds produced mildly irritating conjunctival reactions (redness and
    chemosis) which generally lasted for periods of up to 24 to 48 hours
    before dissipating (Sachsse and Ullmann, 1974e; Cannelongo, 1982d). 
    In one of the tests, 2 of 6 treated rabbits died within 3 days without
    apparent symptoms (Sachsse and Ullmann, 1974e).

         Profenofos (0.5 ml of undiluted technical grade formulation)
    produced death in one rabbit and slight to severe erythema in 2 of 5
    surviving rabbits when applied to shaved and abraded skin for 24
    hours.  The treated animals displayed toxic signs manifested as
    lateral and curved position, asynchronisms of the extremities, muscle
    spasms, and apathy (Sachsse and Ullmann, 1974d).

         In a second skin irritation study, application of profenofos (0.5
    ml of undiluted technical grade formulation) to intact and abraded
    rabbit skin produced death in 6 of 6 animals studied within 24 to 72
    hours.  Slight skin irritation (erythema and oedema) was observed
    (Cannelongo, 1982b).

    Special studies on genotoxicity

         Profenofos was negative in a variety of in vitro tests in
    bacteria, yeast, and mammalian cell systems that evaluated potential
    activity to produce gene mutations, gene conversion, mitotic crossing

    over, non-disjunction, and unscheduled DNA synthesis.  Profenofos was
    also negative in two in vitro tests, a dominant lethal assay in mice
    and a nucleus anomaly test in Chinese hamsters.  However, the compound
    was associated with the production of chromosome aberrations,
    micronucleus induction, and sister chromatid exchanges in the bone
    marrow at oral doses ranging from 36 to 216 mg/kg bw in a third
    in vivo study in mice.  The summary results of genotoxicity studies
    with profenofos are presented in Table 2.

    Special studies on skin sensitizing effect

         Profenofos was examined for skin sensitizing effects in 2 studies
    in guinea pigs.  Negative results were obtained in one test when
    animals received a series of 10 intracutaneous induction injections
    followed 14 days later by a single challenge injection of profenofos
    (0.1 ml of a 0.1% technical formulation).  A vehicle control group was
    also negative whereas dinitrochlorobenzene (positive control) produced
    marked sensitization (Sachsse and Ullmann, 1974f).  Positive results
    for dermal sensitization (i.e., very light erythema or oedema) were
    occasionally obtained in another test when animals received a series
    of 11 intradermal induction injections followed 14 days later by a
    single challenge injection (0.1 ml of 0.1% technical formulation) of
    profenofos.  Although 2,4-dinitrochlorobenzene (positive control) was
    consistently active in this study, a concurrent negative control group
    was not employed to facilitate an evaluation of the results
    (Cannelongo, 1982d).

    Special studies on neurotoxicity

         Delayed neurotoxic effects of oral doses of 21.7, 46.4, and 60
    mg/kg bw/day of technical profenofos were assessed in adult domestic
    chickens.  The compound was administered twice, 21 days apart.  The
    acute oral LD50 of the formulation was about 35 mg/kg bw.  Only the
    birds of the low dose group survived the two treatments with
    profenofos.  Signs of toxicity were also similar after both treatments
    with profenofos (e.g., salivation, asynchronisms of the extremities,
    curved position, apathy, and ruffled feathers); these were observed at
    the mid and high doses levels after the initial treatment on day 0,
    and also at the low-dose level after the second treatment on day 21. 
    Neither delayed neurotoxic symptoms nor histologic changes in spinal
    cord or peripheral nerve were observed.  A positive control group
    receiving 1000 and 2150 mg/kg bw TOCP showed the expected reactions
    (i.e., ataxia, deterioration of reflexes, and swelling, fragmentation
    and disruption of myelin sheaths) (Krinke  et al., 1974).


        Table 2:  Results of genotoxicity assays on profenofos.

                                                                                                                                              
    Test System                   Test Object            Concentration                             Purity  Results    Reference
                                                         of profenofos
                                                                                                                                              

    Ames Test1                    S. typhimurium         5,15,45,135, 405 g/0.1 ml in DMSO        ?       Negative   Arni and Muller, 1978
     (reverse mutation)           TA-98, TA-100,
                                  TA-1535, TA-1537

    Yeast Test1                   S. cerevisae           Nonactivated:                             91.8%   Negative   Arni and Muller, 1982
     (gene conversion, crossing   (D7 strain)            12.5-500 g/ml in DMSO
     over, reverse mutation)                             Activated: 0.640 -10000 g/ml in DMSO

    Yeast Test1                   S. cerevisae           39,156,625, 2500, 10000 g/ml in DMSO     90.0%   Negative   Hool and Muller, 1986
      (non-disjunction)           (D61.M strain)

    Mouse Lymphoma                L5178Y mouse           0.078, 0.156, 0.313, 0.625 g/ml in DMSO  91.8%   Negative   Strasser and Muller, 1982
      Forward Mutation            lymphoma cells
      Assay1                       (TK +/-)

    DNA Repair                    Rat hepatocytes        0.016, 0.08, 0.4, 2 nl/ml                 91.8%   Negative   Puri and Muller, 1982a
      Test2                       (UDS)3

    DNA Repair                    Human fibroblasts      0.32, 1.6, 8, 40 nl/ml                    91.8%   Negative   Puri and Muller, 1982b
      Test2                       (UDS)3

    Dominant Lethal Test          Mouse (male)           35, 100 mg/kg                             ?       Negative   Fritz, 1974a
                                  (NMRI-derived)         (single oral doses)

    Nucleus Anomaly Test          Chinese hamster        13, 26, 52 mg/kg (2 oral doses on         88.1%   Negative   Hool, et al., 1981
                                  bone marrow            consecutive days)
                                                                                                                                              

    Table 2 (contd)
                                                                                                                                              
    Test System                   Test Object            Concentration                             Purity  Results    Reference
                                                         of profenofos
                                                                                                                                              

    Somatic Cell Studies          Male Swiss mouse       36, 162, 216 mg/kg (single oral doses)    72%     Positive4  El Nahas, et al., 1988
    in Mice (sister chromatid     bone marrow
    exchange, micronucleus,
    chromosome aberration)

                                                                                                                                              

    1  With and without metabolic activation.
    2  No exogenous activation added.
    3  UDS = unscheduled DNA synthesis.
    4  Doses of 36-216 mg/kg produced increases in chromosome aberrations; doses of 162-216 mg/kg increased micronuclei formation and sister
       chromatid exchanges.
    

         In a second study, adult chickens received oral doses of 29.2,
    58.5, 117, and 234 mg/kg bw of profenofos (38% EC) on days 0 and 21. 
    The acute oral LD50 of the formulation was 127.0 mg/kg bw.  After
    treatment on day 0, death occurred in 0%, 6.6%, 55%, and 100% of the
    birds given doses of 29.2, 58.5, 117 and 234 mg/kg bw/day,
    respectively.  The increased mortality was accompanied by signs of
    cholinesterase inhibition (i.e., weakness, lethargy, and anorexia). 
    After treatment on day 21, death occurred in 0%, 7.1%, and 67% of the
    surviving birds given doses of 29.2, 58.5 and 117 mg/kg bw/day, and
    similar signs of cholinesterase inhibition were observed.  There were
    no delayed neurotoxic symptoms or histologic changes in brain, spinal
    cord, or sciatic nerves.  A positive control group using 500 mg/kg bw
    of TOCP exhibited clinical signs of delayed neurotoxicity (extreme
    weakness of legs and wings) and neuropathological lesions in the
    spinal cord and sciatic nerves (axonal degeneration and demyelination)
    (Fletcher et al., 1977).

         Profenofos (technical, 89.5% purity) was examined for delayed
    neurotoxicity in a third study in adult chickens.  In the first phase
    of the study (day 0), birds received oral doses of 30 and 45.7 mg/kg
    bw on the basis of preliminary acute toxicity studies in which an
    acute LD50 dose of 45.7 mg/kg bw was determined.  However, because
    of increased mortality rates at these dose levels (70% at 30 mg/kg bw,
    and 82% at 45.7 mg/kg bw), all surviving birds were redosed on day 21
    at a new estimated oral LD50 of 17.1 mg/kg bw.  At this dose level
    of profenofos, a mortality rate of 5% was observed.  The results
    indicated that profenofos produced signs of lethargy and salivation in
    treated birds, but no signs of delayed neurotoxicity or histological
    lesions in the brain, spinal cord, or peripheral nerves.  A positive
    control group using 500 mg/kg bw of TOCP exhibited clinical signs of
    delayed neurotoxicity (extreme weakness of legs and wings)  and
    lesions in the spinal cord and sciatic nerves (axonal degeneration and
    demyelination) (Reinart et al., 1978).

    Special studies on pesticide antagonistic agents

         A protective effect of atropine given early after orally
    administered profenofos in rats or intraperitoneally administered
    profenofos in chicks and mice was demonstrated by a reduction in
    mortality and toxic signs (e.g., salivation, tremors, sedation,
    convulsions) typical of anticholinesterase exposure.  The effect of
    oximes was limited (Sachsse and Bathe, 1976; Gfeller and Kobel, 1974;
    Glickman et al. 1984).

    Special studies on pesticide interactions

         No potentiating effects were found when mixtures of profenofos
    and the organophosphates methidathion, methacrifos or diazinon were
    given to rats in equitoxic doses (Sachsse and Bathe, 1977); (Sachsse
    and Bathe, 1978).

         Profenofos administered intraperitoneally to mice at 0.5 to 5.0
    mg/kg bw strongly inhibited the liver microsomal esterase(s)
    hydrolysing trans-permethrin.  The intraperitoneal toxicity LD50
    measured 24 hours after exposure of fenvalerate and malathion but not
    that of trans-permethrin was greatly increased when the compounds were
    given 1 hour after an intraperitoneal injection of 25 mg/kg bw of
    profenofos (Gaughan et al., 1980).


    Observations in humans

         A group of six male spraymen, aged 20 to 25 years, was monitored
    for whole blood cholinesterase activity over a period of 4 days while
    treating fully grown cotton with a formulation containing 400 grams
    profenofos and 40 grams cypermethrin per liter in organic solvents on
    a plantation in the Multan region of Central Pakistan in September
    1985.  The application equipment consisted of hand-held battery
    operated spinning disc devices.  The workers wore heavy cotton shirts
    with long sleeves, legs wrapped below the knees, and turbans which
    were often used to cover the face.  Cholinesterase activity was
    measured at the end of each of the 4 work days after thorough washing
    of the body.  The results indicated that there was a tendency toward
    inhibition of blood cholinesterase activity.  Compared to baseline
    pre-exposure cholinesterase readings, the average cholinesterase
    levels were 103.3%, 84.8%, 85.6%, and 81.2% of control activities on
    days 1, 2, 3, and 4, respectively.  The lowest individual values were
    72.7% and 73.1% of control levels on the fourth day in 2 of the 6
    workers (Loosli, 1989).

         No cases of poisonings in humans have been reported with either
    the active ingredient per se or with profenofos formulations.

    COMMENTS

         Profenofos administered orally to rats was well absorbed and was
    excreted primarily in the urine, but also in faeces.  Profenofos was
    biotransformed by a major pathway involving side chain depropylation,
    desulfuration, and phenyl-ester bond cleavage to yield 4-bromo-2-
    chlorophenol, and by a minor pathway involving side chain 0-de-
    ethylation, and subsequent phenyl-ester bond cleavage to the above
    phenol.  Both pathways culminated in conjugation with glucuronic and
    sulfuric acids.  No unchanged parent compound was found in urine. 
    Faeces contained only minute amounts of the parent compound, the
    intermediate phenol, and unidentified metabolites.  A similar
    absorption and excretion pattern was observed in hens and goats.  No
    unusual organ or tissue localization of 14C-labelled profenofos was
    observed.

         Profenofos has a moderate order of acute toxicity following oral
    and dermal administration.  It has been classified as moderately
    hazardous by WHO (WHO, 1990).

         In a dietary toxicity study in which rats were fed profenofos for
    8-13 weeks, the NOAEL was 100 ppm (equivalent to 5 mg/kg bw/day) based
    on the finding of brain cholinesterase inhibition at higher levels. 
    The observed reduction in erythrocyte cholinesterase at lower doses
    was not considered to be of toxicological importance.  Reduction in
    food consumption and body weight gain were considered to be a
    consequence of poor palatability of the compound.

         In a six-month feeding study in dogs, profenofos caused
    erythrocyte cholinesterase inhibition and plasma and liver carboxylase
    inhibition at levels of 100 ppm or more.  The highest dose level
    tested, 500 ppm, resulted in reductions in erythrocyte counts,
    haemoglobin and haematocrit levels and a decrease in food consumption. 
    All of the changes were reversible.  No changes in brain
    cholinesterase activity occurred.  As noted above, enzyme inhibition
    and reduced food consumption were not considered to be direct toxic
    effects of profenofos administration.  The NOAEL was 100 ppm (equal to
    2.9 mg/kg bw/day) based upon the observed haematological changes.

         In long-term feeding studies in mice and rats, no treatment-
    related increases in the incidence of neoplasms was observed.  In
    mice, brain cholinesterase inhibition occurred at the highest dose
    level tested, 100 ppm.  The NOAEL was 30 ppm (equal to 5.8 mg/kg
    bw/day in females) based on brain cholinesterase inhibition observed
    at the next higher dose level in females.  In rats erythrocyte
    cholinesterase inhibition occurred at dietary levels of 10 and 100
    ppm.  The highest dose level of 100 ppm was also associated with an
    increase in food consumption and a slightly elevated incidence of
    parafollicular cell hyperplasia.  This type of response is not seen in

    man following exposure to chemicals.  No effect on brain
    cholinesterase was observed.  The NOAEL was 100 ppm (equal to 5.7
    mg/kg bw/day).

         In a three-generation reproduction study in rats, reductions in
    cholinesterase activity occurred in erythrocytes (F0, F1, and F2
    males and females) at 20 ppm in the diet.  This was the highest dose
    tested.  No changes in brain cholinesterase activity occurred.  The
    NOAEL for systemic toxicity and reproduction was 20 ppm (equivalent to
    1.0 mg/kg bw/day) which was the highest dose tested.

         In three teratology studies in rats the NOAELs for maternal
    toxicity ranged from 30 to 90 mg/kg bw/day, based upon findings of
    reduced food consumption, clinical signs of toxicity (e.g., diarrhoea,
    dyspnoea, tremors, hypothermia) and increased mortality at higher dose
    levels.  No teratogenic activity was observed at dose up to and
    including 120 mg/kg bw/day.  The NOAEL for embryotoxicity/fetotoxicity
    (based on an increased incidence of variants) was 18 mg/kg bw/day.  In
    two rabbit teratology studies, the NOAEL for maternal toxicity was 30
    mg/kg bw/day, based upon findings of reduced food consumption and body
    weight gain, the occurrence of soft stools and diarrhoea, and
    increased mortality at higher dose levels.  No embryotoxic, fetotoxic,
    or teratogenic activity was observed at doses up to and including 175
    mg/kg bw/day.

         After reviewing all available in vitro and in vivo short-term
    tests, the Meeting concluded that there was no evidence of
    genotoxicity.

         The Meeting based the ADI for profenofos on the NOAEL of 1 mg/kg
    bw/day in the rat multigeneration study.  Although there was no
    evidence of any adverse effects at this dose level in the study, the
    absence of information on reproductive parameters at higher levels
    precluded the use of the NOAEL of 2.9 mg/kg bw/day in the 6-month
    feeding study in dogs.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    30 ppm, equal to 5.8 mg/kg bw/day in females.
         Rat:      20 ppm, equivalent to 1.0 mg/kg bw/day (reproduction).
         Rat:      100 ppm, equal to 5.7 mg/kg bw/day in males (long-term
                   study).
         Dog:      100 ppm, equal to 2.9 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.01 mg/kg bw.

    Studies which will provide information valuable in
    the continued evaluation of the compound

         Further observations in humans.
         An additional multigeneration study in rats using higher doses.

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    segment II (test for teratogenic or embryotoxic effects).  Project
    No.:  22741900.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd, Basle, Switzerland.

    Fritz, H., Becker, H., and Hess, R. (1979).  Seg. II reproductive
    study in rabbits, CGA 15'324 tech.  Project No.: 785565.  Unpublished
    report from Ciba-Geigy Ltd, Basle, Switzerland.  Submitted to WHO by
    Ciba-Geigy Ltd, Basle, Switzerland.

    Gaughan, L.C., Engel, J.L., and Casida, J.E. (1980).  Pesticide
    interactions:  Effects of organophosphorus pesticides on the
    metabolism, toxicity and persistence of selected pyrethroid
    insecticides.  Pesticide Biochemistry and Physiology 14: 81-85.

    Gfeller, W. and Kobel, W. (1984).  CGA 15'324 technical, tentative and
    antilethal study in the rat.  Project No.:  GU 820034.  Unpublished
    report from Ciba-Geigy Ltd, Basle, Switzerland.  Submitted to WHO by
    Ciba-Geigy Ltd, Basle, Switzerland.

    Gfeller, W., Kobel, W., Schaeppi, U., Zak, F., and Hess, R. (1981). 
    CGA 15'324 tech., 6-months toxicity study with dogs.  Project No.:
    790804.  Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Glickman, A.H., Wing, K.D., and Casida, J.E., (1984).  Profenofos
    insecticide bioactivation in relation to antidote action and the
    stereospecificity and acetylcholinesterase inhibition, reactivation,
    and aging.  Toxicity and Applied Pharmacology, 73: 16-22.

    Harris, S.B. and Holson, J.F. (1982).  A teratology study of CGA
    15'324 technical in albino rats.  Project No.:  282009.  Unpublished
    report from Science Applications, Inc., La Jolla, CA, USA.  Submitted
    to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Holson, J.F. (1983).  Teratology study (Seg II) in albino rabbits with
    CGA 15'324 technical.  Project No.: 283003.  Unpublished report from
    Science Applications, Inc., La Jolla, CA, USA.  Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Hool, G., Langauer, M., and Muller, D. (1981). Nucleus anomaly test in
    somatic interphase nuclei, CGA 15'324, Chinese hamster (test for
    mutagenic effects on bone marrow cells).  Project No.: 791557. 
    Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Hool, G. and  Muller, D. (1986).  Test for non-disjunction on
    Saccharomyces cerevisiae D61.M in vitro, CGA 15'324 tech. Project
    No.: 850811. Unpublished report from Ciba-Geigy Ltd, Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. 

    Horath, L.L. and Taylor, G.D. (1982).  Acute aerosol toxicity study in
    rats of CGA 15'324 technical FL 811528.  Project No.: 420-0921. 
    Unpublished report from Toxi-Genics, Inc., Decatur, IL, USA. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    IBTL, Inc. (1978).  Three generation reproduction study with CGA
    15'324 technical in albino rats.  Project No.: IBT 623-07924. 
    Unpublished report from Industrial Bio-Test Laboratories, Inc.,
    Northbrook, IL, USA.  Submitted to WHO by Ciba-Geigy Ltd, Basle,
    Switzerland.  Validated by United States Environmental Protection
    Agency.

    Ifflaender, U. and Mucke, W. (1976).  The metabolism of CGA 15'324 in
    the rat.  Project No.: 27/76.  Unpublished report from Ciba-Geigy
    Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-Geigy Ltd, Basle,
    Switzerland.

    Ifflaender, U., Mucke, W., and Esser, H.O. (1974).  Distribution,
    degradation and excretion of CGA 15'324 in the rat.  Project No.:
    16/74.  Unpublished report from Ciba-Geigy Ltd, Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd, Basle, Switzerland.

    Johnson, S., Tai, C.N., and Katz, R. (1984).  Profenofos technical,
    21-day dermal toxicity study in rabbits.  Project No.: MIN 842008. 
    Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Kobel, W. and Gfeller, W. (1983).  Acute oral LD50 in the rat, CGA
    15'324 tech. GU Project No.: 830188.  Unpublished report from Ciba-
    Geigy Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-Geigy Ltd.,
    Basle, Switzerland.

    Krinke, G., Ullmann, L., and Sachsse, K. (1974).  Acute oral LD50
    and neurotoxicity study of technical CGA 15'324 in the domestic fowl
    (Gallus domesticus).  Project No.: Siss 2850.  Unpublished report from
    Ciba-Geigy Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-Geigy
    Ltd., Basle, Switzerland.

    Kuhn, J.O. (1988).  Acute dermal toxicity study in rabbits, profenofos
    technical.  Project No.: 5522-88.  Unpublished report from
    Stillmeadow, Inc., Houston, TX, USA.  Submitted to WHO by Ciba-Geigy
    Ltd., Basle, Switzerland.

    Loosli, R. (1985).  Project No.: 850910.  Unpublished summary report
    from Ciba-Geigy Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-
    Geigy Ltd., Basle, Switzerland.

    Mucke, W. (1986).  The renal excretion of U-14C-Phenyl CGA 15'324 by
    male rats after oral administration (exposure monitoring).  Project
    No.: 13/86.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Oakes, T.L., Marco, G.J., and Ballantine, L. (1986).  Metabolism of
    14C-profenofos in chickens dosed at 5.0 ppm.  Project No.: ABR-
    86002.  Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Piccirillo, V.J. (1978).  90-day subacute oral toxicity study in rats,
    CGA 15'324 technical.  Project No.: 483-135.  Unpublished report from
    Hazleton Laboratories America, Inc., Vienna, VA, USA.  Submitted to
    WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Puri, E. and Muller, D. (1982a).  Autoradiographic DNA repair test on
    rat hepatocytes, CGA 15'324, (in vitro test for DNA damaging
    properties).  Project No.: 811490.  Unpublished report from Ciba-Geigy
    Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Puri, E. and Muller, D. (1982b).  Autoradiographic DNA repair test on
    human fibroblasts, CGA 15'324, (in vitro test for DNA damaging
    properties).  Project No.: 811658.  Unpublished report from Ciba-Geigy
    Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.  

    Reinart, D., Fletcher, D., Arceo, R.J., and Gordon, D.E. (1978).  42-
    day neurotoxicity study with CGA 15'324 technical in adult chickens. 
    Project No.:  IBT 8580-11187.  Unpublished report  from Industrial
    Bio-Test Laboratories, Inc., Decatur, IL. USA.  Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland and validated by the United States
    Environmental Protection Agency.

    Sachsse, K. and Bathe, R. (1975).  Acute intraperitoneal LD50 in the
    rat of technical CGA 15'324.  Project No.: Siss 5048.  Unpublished
    report from Ciba-Geigy Ltd., Basle, Switzerland.  Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Bathe, R. (1976).  The therapeutic activity of
    pralidoxim (PAM) and TOXOGONIN\ with regard to CGA 15'324 in the rat. 
    Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Bathe, R. (1977).  Potentiation study CGA 15'324
    versus 2 insecticides CA 13'005 (methidathion) and G 24'480 (diazinon)
    in the rat.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Bathe, R. (1978).  Potentiation study CGA 20'168
    versus 6 insecticides, C 177 (DDVP), C570 (phosphamidon), GS 13'005
    (methidation), G 24'480 (diazinon), CGA 15'324 and malathion.  Project
    No.: 404478 - Siss 6526.  Unpublished report from Ciba-Geigy Ltd.,
    Basle, Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Sachsse, K. and Ullmann, L. (1974a).  Acute inhalation toxicity of
    technical CGA 15'324 in the rat.  Project No.:  Siss 3647. 
    Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Ullmann, L. (1974b).  Acute oral LD50 of technical
    CGA 15'324 in the rabbit.  Project No.:  Siss 3647 Unpublished report
    from Ciba-Geigy Ltd., Basle, Switzerland.  Submitted to WHO by Ciba-
    Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Ullmann, L. (1974c).  Acute dermal LD50 of technical
    CGA 15'324 in the rabbit.  Project No.:  Siss 3647.  Unpublished
    report from Ciba-Geigy Ltd., Basle, Switzerland.  Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Ullmann, L. (1974d).  Skin irritation in the rabbit
    after single application of technical CGA 15'324.  Project No.: Siss
    3647.  Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Ullmann, L. (1974e).  Irritation of technical CGA
    15'324 in the rabbit eye.  Project No.:  Siss 3647.  Unpublished
    report from Ciba-Geigy Ltd., Basle, Switzerland.  Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Sachsse, K. and Ullmann, L. (1974f).  Skin sensitizing (contact
    allergenic) effect in Guinea pigs of technical CGA 15'324.  Project
    No.:  Siss 3647.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Strasser, F.F. and Muller, D. (1982).  L5178/TK+/- mouse lymphoma
    mutagenicity test, CGA 15'324 (in vitro test for mutagenic
    properties of chemical substances in mammalian cells).  Project No.:
    811491.  Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Sugiya, J., Yoshida, K., Tamaki, Y., Yokota, M., Abo, Y., and
    Kawakami, S. (1982).  Teratogenicity in rats administered CGA 15'324
    (profenofos) prenatally during the major organogenic period. 
    Unpublished report from Ciba-Geigy Ltd., Basle, Switzerland. 
    Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Thomas, R.D., Cassidy, J.E., and Marco, G.J. (1976).  Metabolism and
    balance study of 0-14C-CGA 15'324 in a lactating goat Project No.: 
    GAAC-76024.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Ullmann, L., Luetkemeier, H., Sachsse, K., Zak, F., and Hess, R.
    (1976).  CGA 15'324 technical 21-day dermal toxicity study in rabbits. 
    Project No.:  Siss 5119.  Unpublished report from Ciba-Geigy Ltd.,
    Basle, Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Ullmann, L., Luetkemeier, H., Sachsse, K., Zak, F., and Hess, R.
    (1977).  CGA 15'324, 21-day inhalation study on the rat.  Project No.:
    Siss 5119.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    WHO (1990).  The WHO recommended classification of pesticides by
    hazard and guidelines to classification 1990-1991 (WHO/PCS/90.1). 
    Available from the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland.

    Williams, S.C., Marco, G.J., Simoneaux, B.J., and Ballantine, L.
    (1984).  Percutaneous absorption of 14C-profenofos in rats.  Project
    No.: ABR-84023.  Unpublished report from Ciba-Geigy Ltd., Basle,
    Switzerland.  Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Wing, K.D., Glickman, A.H., and Casida, J.E. (1984). 
    Phosphorothiolate pesticides and related compounds:  Oxidative
    bioactivation and aging of the inhibited acetylcholinesterase. 
    Pesticide Biochemistry and Physiology, 21: 22-30.

    Wing, K.D., Glickman, A.H., and Casida, J.E. (1983).  Oxidative
    bioactivation of S-alkyl phosphorothiolate pesticides: 
    Stereospecificity of profenofos insecticide activation.  Science, 219:
    63-65. 


    See Also:
       Toxicological Abbreviations