820K88003
                                     August,  1987
                                                           DRAFT
            FONOFOS

          Health Advisory
      Office of Drinking Water
U.S.  Environmental Protection Agency
I.  INTRODUCTION

        The Health Advisory (HA)  Program,  sponsored by the Office of Drinking
   Water (ODW), provides information on  the health effects, analytical method-
   ology and treatment technology that would  be useful in dealing with the
   contamination of drinking water.   Health Advisories describe nonregulatory
   concentrations of drinking water  contaminants at which adverse health effects
   would not be anticipated to occur over  specific exposure durations.  Health
   Advisories  contain a margin of safety to protect sensitive members of the
   population.

        Health Advisories serve as informal technical guidance to assist Federal,
   State and local officials responsible for  protecting public health when
   emergency spills or contamination situations occur.  They are not to be
   construed as legally enforceable  Federal standards.  The HAs are subject to
   change as new information becomes available.

        Health Advisories are developed  for one-day, ten-day, longer-term
   (approximately 7 years, or 10% of an  individual's lifetime) and lifetime
   exposures based on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not quantitatively incorporate any potential carcinogenic
   risk  from such exposure.  For  those substances that are known or probable
   human carcinogens, according to the Agency classification scheme (Group A or
   B),  Lifetime HAs are not recommended.  The chemical concentration values for
   Group A or  B carcinogens are correlated with carcinogenic risk estimates by
   employing a cancer potency (unit  risk)  value together with assumptions for
   lifetime exposure and the consumption of drinking water.  The cancer unit
   risk  is usually derived from the  linear multistage model with 95% upper
   confidence  limits.  This provides a low-dose estimate of cancer risk to
   humans that is considered unlikely to pose a carcinogenic risk in excess
   of the stated values.  Excess  cancer  risk  estimates may also be calculated
   using the One-hit, Weibull, Logit or  Probit models.  There is no current
   understanding of the biological mechanisms involved in cancer to suggest that
   any  one of  thes^ models is able to predict risk more accurately than another.
   Because each model is based on differing assumptions, the estimates that are
   derived can differ by several  orders  of magnitude.

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    Fonofos                                                     August, 1987
II.  GENERAL INFORMATION AND PROPERTIES
    CAS  No.   944-22-9
    Structural Formula
                       0-Ethyl-s-phenylethylphosphonodithioate

    Synonyms

         0   Difonate;  Difonatal;  Dyfonate;  Dyfonate®; Dyphonate*; ENT 25, 796;
            Fonophos;  Stauffer N2790 (Meister,  1983).

    Uses

         0   Soil insecticide (Meister,  1983).

    Properties  (Windholz et al.( 1983;  TDB,  1985)

            Chemical Formula               C10H15OS2P
            Molecular Weight               246.32
            Physical State (25°C)       Light yellow liquid
            Boiling Point                  130°C
            Melting Point                  —
            Vapor Pressure (25°C)          2.1  x 10~4 mm Hg
            Specific Gravity (20°C)        1.154
            Water Solubility (25°C)        Practically insoluble
            Octanol/Water Partition
              Coefficient
            Taste Threshold                —-
            Odor Threshold                 --
            Conversion Factor              —

    Occurrence

         0  Fonofos has  been detected in ground waters in California at  0.01 to
            0.03 ppb  (U.S.G.S. Regional Assessment Project, C. Eiden, 1985).

         0  Fonofos has  been found  in tailwater pit  sediment and water samples.
            Monitoring studies conducted in  1973 and 1974 in Haskell County,
            Kansas, showed that  the highest  concentrations found were 770 ppb
            for sediment and 5.9 ppb for water during 1974.  Mean peak concen-
            trations  were highest in June and July (Kadoum and Mock, 1978).

         0  Fonofos  (Dyfonate) has  been found in Iowa ground water; a typical
            positive  sample found was 0.1 ppb (Cohen et al«, 1986).

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Fonofos                                                    August, 1987

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Environmental Fate

     0  Under aerobic conditions,  fonofos at 10 ppm was degraded at a moderate
        rate with a half-life ranging from 3 to more than 16 weeks in soils
        varying in texture from loamy sand to clay loam to peat (McBain and
        Menn, 1966; Hoffman et al.,  1973; Hoffman and Ross, 1971;  Miles
        et al., 1979).  The major  degradate identified was 0-ethylethane
        phosphonothioic acid; other  degradates identified included fonofos
        oxon, O-ethylethane phosphonic acid, O-ethyl O-methylethyl phosphonate,
        diphenyl disulfide, methylphenyl sulfoxide, and methylphenyl sulfone
        (Hoffman et al., 1973; Hoffman and Ross,  1971).  The soil  fungus,
        Rhizopus japonicus rapidly degraded !4C-fonofos to yield dyfoxon,
        thiophenol, ethylethoxy phosphonic acid and methylphenyl sulfoxide
        (Lichtenstein et al., 1977).

     0  Fonofos is relatively immobile in a silt loam and sandy loam soil but
        relatively mobile in quartz  sand.  After 7 to 12 inches of water were
        added to 7-inch soil columns, 2 to 9% of the applied l^C-fonofos
        leached from the treated soil layer in Piano silt loam and Fox fine
        sandy loam columns.  When  a  quartz sand was leached with 7 inches of
        water, 50% of the applied  radioactivity was detected in the leachate.
        Dyfoxon, a fonofos degradate, and two unidentified compounds were
        found in the leachate of the silt loam soil (Lichtenstein et al.,
        1972).

     0  Fonofos is relatively mobile in runoff water from loam sand.  After
        30 days, only 0.54 to 1.2% of the applied l^C-fonofos was  recovered
        in runoff water from drenching a Sorrento loam soil on an inclined
        plane at a 15-degree slope.   Fonofos accounted for most of the
        recovered radioactivity, which was primarily adsorbed to the silt
        fraction (Hoffman et al.,  1973).

     0  Fonofos is not volatile from soil but is fairly volatile from water.
        Within 24 hours after .application, 15 to 16% of the 14C-fonofos applied
        volatilized from soil water   (a suspension of fine sand in tapwater or
        tapwater alone; 1% volatilized from a silt loam soil alone).
        !4C-Fonofos volatilized from soil water with a half-life of 5 days;
        80% of the applied radioactivity was volatilized at the end of 10
        days  (Lichtenstein and Schulz, 1970).

     0  In the field, fonofos dissipated with a half-life of 28 to 40 days
        when either a 10% G or a 4 ilb/gal EC formulation was applied at 4.8
        to 10 Ib ai/A to a sandy loam and two silt loam soils (Kiigemagi and
        Terriere, 1971; Schulz and Lichtenstein, 1971; Talekar et al., 1977).
        Using a root maggot bioassay, toxic fonofos residues in a  sandy loam
        field soil were detected up  to 17 weeks after the 10% G formulation
        was applied at 2 to 5 Ib ai/A.  Residues were detected up to 28 weeks
        after treatment when the same soil was maintained in a greenhouse
        (Ahmed and Morrison,  1972).

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     Fonofos                                                     August,  1987

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III. PHARMACOKINETICS

     Absorption

          0   McBain  et  al.  (1971) administered  14c-phenyl-labeled  fonofos  (99%
             purity, dissolved  in corn oil) orally  to  albino  rats  (two/dose)  at
             doses of 2,  4  or 8 mg/kg.  Only 7% of  the label  was recovered  in
             feces,  indicating  that  absorption  was  nearly complete (about  93%).
             Hoffman, et  al.  (1971)  reported essentially  identical results  in rats
             dosed with 0.8 mg/kg fonofos.  Measurements  of urinary,  fecal  and
             biliary excretion  indicated  that about 80 to 90% of the  dose  was
             absorbed from  the  gastrointestinal tract.

          0   Hoffman et al. (1971) administered single oral doses  of  35s-labeled
             fonofos (2.0 mg/kg; 99% purity) to rats.   About  32% of the  label was
             excreted in  feces. Measurement of biliary excretion  indicated that
             15%  of  the label in the feces came from the  bile.   The authors
             concluded  that about 17% had not been  absorbed.

     Distribution

          0   Hoffman et al. (1971) administered 35s_iabeied fonofos (2.0 mg/kg,
             13.4 mCi/mmol; 99% purity) to rats by  gavage (in safflower  oil);
             the  levels of  label in  blood and tissues  were measured for  16 days.
             Higher  levels  of radioactivity were found in the kidneys, blood,
             liver and  intestines, and lower levels were  found in  bone,  brain,
             fat, gonads  and muscle. Concentration values at 2 days  ranged from
             about 400  ppb  in the kidneys to about 70  ppb in  other tissues.  All
             values  were  10 ppb or lower  by day 8.   Tissue levels  declined  in
             first-order  fashion, with near total (99.3%) elimination during 2 to
             16 days after  dosing.

     Metabolism

          0   McBain  et  al.  (1971) administered  single  oral doses of 2, 4 or 8 mg/kg
             of ethyl or  phenyl-14C-labeled fonofos (97.5% or 99%  purity)  to male
             albino  rats  (two/dose). Only 2.6  to 7.1% was recovered  as  unchanged
             fonofos in the urine.   The remainder was  converted to a  variety of
             terminal metabolites, including:   0-ethylethane  phosphonothioic acid,
             0-ethylethane  phosphonic acid, and 0-conjugates  of 3- and 4-(hydrox-
             phenyDmethyl  sulfone.  McBain et  al.  (1971) reported that  fonofos
             was  converted  by rat liver microsomes in  vitro  to the more  toxic
             fonofos oxon,  but  only  traces of  this compound were excreted  by the
             intact  animal.
     Excretion
             McBain et al.  (1971)  administered single oral doses of 2,  4 or 8 mg/kg
             of 14C-labeled fonofos (97.5% or 99% purity) orally to male albino rats
             (two rats/dose).  When the label was on the phenyl ring,  recovery of
             was 90.7% in urine and 7.4% in feces.  When the label was on the ethyl
             group, recovery of label was 62.8% in urine and 31.8% in  feces.  Of
             this fecal label, 15.3% was found to be excreted in the bile.

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    Fonofos                                                     August,  1987

                                         -5-
            Hoffman et al.  (1971) dosed  rats  orally  with  14C-ethyl-labeled fonofos
            (0.8 mg/kg;  98% purity).  After 15  days,  average  recovery  of  label
            was 91% in urine,  7.4%  in feces and 0.35% in  expired  air.   Essentially
            all of the excretion occurred within 4 days.   In  rats dosed with
            35s-labeled  fonofos  (2  mg/kg; 99% purity),  average  recovery of label
            after 4 days was 62.5%  in the urine,  31.8%  in feces and  0.1%  in
            expired air.  Bile duct cannulation studies indicated that about 15%
            of the label in feces arose  from  biliary  excretion.
IV. HEALTH EFFECTS

    Humans

       j5hort-term Exposure

         0  The Pesticide  Incident Monitoring  System (PIMS)  database reported 21
            cases between  1966 and 1979 of  human toxicity resulting from exposure
            to fonofos.  Fourteen of  the cases involved fonofos  only,  and seven
            involved  mixtures.  Two fatalities occurred,  and four individuals
            required  medical  treatment.   No quantitative  exposure data and no
            description  of  adverse effects  were provided  (U.S.  EPA, 1979).

         0  One reported case of accidental ingestion involved  a woman who ate
            pancakes  prepared with a  formulation containing  fonofos.  No quanti-
            tative  estimate of the dose level  was provided.   The individual
            developed nausea, vomiting,  salivation,  sweating and suffered
            cardio-respiratory arrest.   She was treated at a hospital  and was
            found to  have  muscle fasciculation, blood pressure  of 64/0 mm Hg, a
            pulse rate of  46, pinpoint  pupils, and profuse salivary and bronchial
            secretions.  The  patient  also developed  a pancreatic pseudocyst.   The
            woman was discharged after  2 months of treatment.   A second individual
            who also  ate the  contaminated pancakes died (Hayes,  1982).

       Long-term Exposure

         0  No information  on the long-term exposure effects of  fonofos on humans
            was found in the  available  literature.

    Animals

       ghort-term Exposure

         0  Fonofos is an  organophosphorus  compound.  Acute  toxic effects of
            such compounds  are due largely, if not entirely, to  inhibition of
            cholinesterase  (ChE) and  acetylcholine accumulation  in the body
            (Derache, 1977).

         0  Reported  values for the oral LD50  of fonofos  for female rats range
            from 3.2  to  7.9 mg/kg, and  values  for male rats  range from 6.8 to
            18.5 mg/kg (Horton, 1966a,b; Dean, 1977).

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Fonofos                                                    August, 1987

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     0  Horton (1966a) administered single oral doses of fonofos (purity not
        specified) to rats (strain not specified).  Doses of 1.0 or 2.15 rag/kg
        did not produce visible symptoms.  Doses of 4.6 to 46 mg/kg elicited
        rapid appearance of fasciculations and tremors, salivation, exophthalmia
        and labored respiration, with females being somewhat more sensitive
        than males.  Gross autopsy of animals that died revealed congested
        liver, kidneys and adrenals and lung erythema.  Autopsy of survivors
        showed no effects.  Based on gross changes, a No-Observed-Adverse-Effect-
        Level (NOAEL) of 2.15 mg/kg was identified by this study.

     0  Cockrell et al. (1966) fed fonofos in the diet to dogs at levels of
        0 or 8 ppm for 5 weeks.  Based on the assumption that 1 ppm in the
        diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959), these
        doses correspond to 0 or 0.2 mg/kg/day.  Plasma and red blood cell
        cholinesterase were measured at 2 and 4 weeks; organ weights, brain
        cholinesterase and changes in gross pathology were measured at termination
        (5 weeks).  Following treatment, no systemic toxicity was observed;
        brain and plasma or red blood cell cholinesterase levels were
        unaffected.  No other details were provided.  This study identified
        a NOAEL of 8 ppm  (0.2 mg/kg/day).

     0  In a demyelination study, groups of 10 adult hens each received
        fonofos in the diet for 46 days (Woodard and Woodard, 1966).  Levels
        fed were equivalent to 0, 2, 6.32 or 20 mg/kg/day.  Only hens at
        20 mg/kg showed impairment of locomotion and equilibrium, and one
        showed histological evidence of possible demyelination of the
        peripheral nerves.  A NOAEL for demyelination of 6.32 mg/kg/day was
        indicated by the study.

   Dermal/Ocular Effects

     0  Reported dermal LD$Q values of fonofos for the rabbit (both sexes)
        ranged from 121 to 147 mg/kg (Horton, 1966a,b).  However, Dean (1977)
        determined a different LD5Q in rabbits:   25 mg/kg for females and
        100 mg/kg for males.

     0  Instillation of 0.1 mL undiluted fonofos  (about 23 mg/kg/day)
        in one eye of each of three rabbits caused negligible local irritation,
        but was lethal  to all within 24 hours  (Horton, 1966a,b; Dean, 1977).

      0  Dean  (1977) applied 0.5 mL undiluted fonofos  to closely  -lipped
        intact skin of  rabbits; no dermal irritation was reported but all
        animals died within 24 hours.

      0  Horn  et al.  (1966) applied fonofos  (10% granular) to intact or abraded
        skin  of New Zealand rabbits (five/sex/dose; the five animals included
        both  normal and abraded skin animals)  5 days  per week for 3 weeks  at
        doses of  0, 35  or 70 mg/kg.  Following treatment, dermal effects,
        general appearance and behavior, hematology,  organ weights, cholinesteras^
        levels, gross pathology and histopathology were evaluated.  No
        difference was  observed in any of the  responses between  the intact or
        abraded skin animals.  One normal and  one abraded skin males and one

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Fonofos                                                    August,  1987

                                     -7-
        normal skin female died in the 70 mg/kg group;  and one intact skin
        male died in the 35 mg/kg  group.   No irritation of the skin was
        observed at any dose tested for either intact or abraded skin.   In
        males, adrenal weights were increased by about 50% at 35 mg/kg, and
        by 70% at 70 mg/kg (p value not given).  Similar but smaller (15 to
        20%) increases in adrenal  weights were seen in females.   No hematological
        effects were observed at any dose tested.   No histopathological
        changes occurred except slight to moderate liver glycogen depletion
        at 70 mg/kg.  Reductions were observed in red blood cell, plasma and
        brain cholinesterase activity for both sexes of the treated groups.
        At 35 mg/kg, ChE in red blood cells was inhibited 70% (for both
        sexes), while plasma ChE levels were inhibited 74% (males) and 91%
        (females),  and brain ChE was inhibited 66% (males) and 89% (females).
        At 70 mg/kg, ChE in red blood cells was inhibited 36% (males) and 45%
        (females).   ChE in plasma  was inhibited 67% inhibited for both sexes.
        ChE in brain was inhibited 59% (males) and 57% (females).

   Long-term Exposure

     0  Daily oral  doses of fonofos in corn oil (at 0,  2, 4 or 8 mg/kg/day)
        for 90 days failed to elicit delayed neurotoxicity in adult hens
        (Miller et al., 1979, abstract only).  A minimum NOAEL of 8 mg/kg/day
        for delayed neurotoxicity  was indicated by these reported results.

     0  In a similar experiment (Cockrell et al., 1966), rats were fed diets
        containing 0, 10, 31.6 or  100 ppm for 13 weeks.  Based on the
        assumption that 1 ppm in the diet is equivalent to 0.05 mg/kg/day,
        these doses correspond to  0, 0.5, 1.58 or 5 mg/kg/day (Lehman,  1959).
        Cholinesterase was measured in serum and red blood cells before and
        after exposure, and brain  ChE was measured at termination.  At 100 ppm,
        there was significant inhibition of ChE in serum  (70%, females only),
        red blood cells (85%, females only) and brain (51% to 60%, both
        sexes).  Decreases of over 50% in red blood cell ChE in both males
        and females were reported  at the 31.6-ppm level.  At 10 ppm, the
        largest difference detected was a 23% decrease in red blood cell ChE
        in females; the authors did not consider this to be significant.
        All other ChE measurements at this dose were comparable between
        exposed and control animals.  Other observations were negative for
        compound effect, and there were no histopathological findings.   Based
        on ChE inhibition, the NOAEL in rats was identified as 10 ppm
        (0.5 mg/kg/day).

     0  Cockrell et al. (1966) fed fonofos in the diet to dogs at levels
        of 0, 16, 60 or 240 ppm for 14 weeks.  Based on the assumption that
        1  ppm in the diet is equivalent to 0.025 mg/kg/day, these doses
        correspond  to 0, 0.4, 1.5  or 6 mg/kg/day (Lehman, 1959).  Dogs showed
        increased lacrimation and  salivation plus convulsions (at 16 ppm),
        bloody diarrhea (at 60 ppm) or tremors and anxiety and increased
        liver weight  (at 240 ppm).  At 16 ppm, there was about 60% ChE inhibi-
        tion in erythrocytes and slight ChE inhibition in brain (female only).
        At 60 ppm,  ChE in red blood cells was inhibited 60% or more, and
        plasma ChE  was decreased about 20% (in males only) at week 13.   At
        the high dose (240 ppm), ChE was nearly totally inhibited in red

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Fonofos                                                    August, 1987

                                     -8-
        blood cells;  about 50% inhibited in plasma;  and moderately inhibited
        in brain.   Based on cholinesterase inhibition and systemic toxicity,
        a Lowest-Observed-Adverse-Effect-Level (LOAEL) of 16 ppm (0.4 mg/kg/day),
        the lowest dose tested, was identified.

     0  Pure-bred  beagle dogs were fed fonofos in the diet for 2 years
        (Woodard et al., 1969).  Groups of four males and four females each
        received 0,  16, 60 or 240 ppm fonofos.  Based on the assumption that
        1 ppm in the diet is equivalent to 0.025 mg/kg/day, these doses
        correspond to 0, 0.4, 1.5 or 6 mg/kg/day (Lehman, 1959).  After 14
        weeks,  the low dose (16 ppm) was reduced to  8 ppm (0.2 mg/kg/day),
        and this dose level was maintained for the duration of the study.
        Cholinesterase levels in plasma were inhibited about 50% at 240 ppm,
        about 25% to 50% at 60 ppm, and were not different from controls at
        the low dose (16 or 8 ppm).  In red blood cells, ChE levels were
        inhibited almost completely at the 240-ppm level and about 65% at
        60 ppm.  In animals receiving 16 ppm for 14  weeks, ChE in red blood
        cells was inhibited about 30%.  After reduction of the dose to 8 ppm,
        ChE levels returned to values comparable to  controls.  At sacrifice,
        no inhibition of ChE in brain was detected at any dose level.  At
        240 ppm, nervous, apprehensive behavior and  tremors were seen, and
        three dogs died, each with marked acute congestion of tissues and
        hemorrhage of the small intestinal mucosa.  At this dose level, also,
        serum alkaline phosphatase was increased, as were liver weights.
        Histopathological examination of animals receiving 240 ppm revealed a
        marked increase in basophilic granulation of the myofibril of the
        inner layer of the muscularis of the small intestine, and there were
        slight changes in the liver.  At 60 ppm, increased liver weight was
        observed.   At the low dose (16/8 ppm), the only effect was a single
        brief episode of fasciculation in one male dog at 5 months.  The
        author judged that this could not be ascribed with certainty to
        fonofos exposure.  For this study, the NOAEL for ChE inhibition and
        for systemic toxicity was 8 ppm (0.2 mg/kg/day).

      0  Albino rats received fonofos in the diet for 2 years at 0, 10, 31.6
        or 100 ppm (0, 0.5,  1.58 or 5 mg/kg/day, Lehman, 1959)  (Bannerjee
        et al., 1968).  Fonofos was judged not to have affected survival,
        food intake, body weight gain, organ weights or gross and histopatho-
        logical findings.  At 100 ppm, females showed tremors and nervous
        behavior, and males  had reduced hemoglobin and packed-cell volume.
        At 100 ppm, ChE was  markedly decreased in plasma  (50 to 75%), red
        blood cells (close to 100%) and brain (about 40%, in females only).
        At 31.6 ppra, there was moderate (about 50%) inhibition of ChE in red
        blood cells and plasma  (at weeks 26 and 52 only).  At 10 ppm, no
        decrease in ChE was  seen in brain or red blood cells, and no effect
        was seen in plasma,  except for a moderate decrease (40 to 56%) in
        males at weeks  19 and 26 only.  Based on cholinesterase inhibition,
        a NOAEL of 10 ppm  (0.5 mg/kg/day) is identified.

    Reproductive Effects

      0  Woodard et al.  (1968) exposed  three generations of rats to dietary
        fonofos at 0,  10 or  31.6 ppm.  Based on the assumption that  1 ppm in

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   Fonofos                                                    August,  1987

                                       -9-
           the  diet  is  equivalent  to  0.05 mg/kg/day  (Lehman,  1959),  this  corre-
           sponds  to doses of 0, 0.5  or  1.58 mg/kg/day.  No differences were
           detected  in  exposed dams with respect  to  mortality, body  weight  or
           uterine implantation  sites.   No  effects were  seen  in offspring on
           conception ratio, litter size, number  of  live-born and still-born,
           litter  weight  and weanling survival.   Skeletal and visceral examina-
           tion of offspring revealed no evidence of developmental defects.
           A minimum NOAEL of 31.6 ppm  (1.58 mg/kg/day,  the highest  dose  tested)
           was  identified.

      Developmental  Effects

        0   Groups  of pregnant mice each  received  10  daily doses of fonofos  by
           gavage  (0, 2,  4, 6 or 8 mg/kg/day)  on  gestational  days 6  through 15
           (Minor  et al.,  1982).   At  8 mg/kg/day, maternal food intake and  body
           weight  gain  were decreased.   At  6 mg/kg/day,  two dams experienced
           tremors and  died.  Increased  incidences of  variant ossifications of
           the  sternebrae (8 mg/kg/day)  and a  slight dilatation of the fourth
           ventricle of the brain  (4  and 8  mg/kg/day)  were observed,  but  the
           authors did  not interpret  this as evidence  of teratogenicity.  The
           NOAEL for fetotoxicity  identified in  this study was 2 mg/kg/day.

      Mutagenicity

        0   Fonofos,  with  or without metabolic  activation, was not mutagenic in
           each of five microbial  assay  systems  (the Ames  (Salmonella) test;
           reverse mutation in an  Escherichia  coli strain; mitotic recombination
           in the  yeast,  Saccharomyces  cerevisiae D3;  and differential toxicity
           assays  in strains of  _E. coli  and Bacillus subtilis) and in a test  for
           unscheduled  DNA synthesis  in  human  fibroblast cells  (Simmon, 1979).

      Carcinogenicity

        0   Groups  of 30 male and 30 female  CD  albino rats  (Charles River) each
           received  0,  10, 31.6  or 100  ppm  fonofos in  the diet  (0, 0.5,  1.58  or
           5 mg/kg/day) for 2 years  (Bannerjee et al.,  1968).  Based on gross
           and  histological examination, the authors detected no carcinogenic
           effects.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories (HAs)  are generally determined  for one-day,  ten-day,
   longer-term (approximately 7  years) and lifetime exposures if  adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following formula:

                 HA = (NOAEL or  LOAEL) x (BW) = 	   /L  (	  /L)
                        (UF) x (    L/day)
   where:
           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                            in mg/kg bw/day.

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Fonofos                                                    August, 1987

                                     -10-
                    BW = assumed body weight of a child (10 kg) or
                         an adult (70 kg).

                    UF = uncertainty factor (10, 100 or 1,000), in
                         accordance with NAS/ODW guidelines.

             	 L/day = assumed daily water consumption by a child
                         (1 L/day) or an adult  (2 L/day).

One-day Health Advisory

     No information was found in the available literature that was suitable
for determination of the One-day HA value for fonofos.  It is therefore
recommended that the Longer-term HA value for a 10-kg child of 0.02 mg/L
(20 ug/L,  calculated below) be used at this time as a conservative estimate
of the One-day HA value.

j*en-day Health Advisory

     No information was found in the available literature that was suitable
for determination of the Ten-day HA value for fonofos.  It is therefore
recommended that the Longer-term HA value for a 10-kg child (0.02 mg/L,
calculated below) be used at this time as a conservative estimate of the
Ten-day HA value.

Longer-term Health Advisory

     The 2-year feeding study in dogs by Woodard et al. (1969) has been
selected to serve as the basis for the Longer-term HA for fonofos.  In this
study, dogs received dietary fonofos at 0, 16, 60 or 240 ppm  (0, 0.4, 1.5 or
6 mg/kg/day).  After 14 weeks, marginal (about 30%) inhibition of ChE was
noted in red blood cells at the 16-ppm level; this dose was reduced to 8 ppm
(0.2 mg/kg/day) for the remainder of the study.  Following dose reduction,
ChE levels returned to those of controls.  At 60 ppm, dogs showed increased
liver weights and significant inhibition (25 to 65%) of ChE activity in
plasma and erythrocytes.  At 240 ppm, there was increased ChE inhibition and
increased mortality.  There were no toxic effects in dogs at  8 ppm (0.2 mg/kg/day),
with the possible exception of one brief episode of fasciculation in one dog
at 5 months.  This was not judged to be significant, and a NOAEL of 8 ppm
(0.2 mg/kg/day) was identified.  The 13-week feeding study in rats by Cockrell
et al.  (1966) has not been selected, since the rat appears to be less sensitive
than the dog.  The 14-week feeding study in dogs by Cockrell  et al.  (1966)
has not been selected since frank toxic responses were noted  at the lowest
dose tested in this study  (0.4 mg/kg/day).

     Using a NOAEL of 0.2 mg/kg/day, the Longer-term HA for a 10-kg child is
calculated as follows:

        Longer-term HA = (0»2 mg/kg/day) (10 kg) = 0.02 mg/L  (20 ug/L)
                            (100)  (1 L/day)

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Fonofos                                                    August, 1987

                                     -11-
where:
        0.2 mg/kg/day = NOAEL,  based on absence of systemic toxicity or ChE
                        inhibition in dogs exposed to fonofos in the diet for
                        2 years.
                10 kg = assumed body weight of a child.

                  100 = uncertainty factor, chosen in accordance with NAS/ODW
                        guidelines for use with a NOAEL from an animal study.

              1  L/day = assumed daily water consumption by a child.

     The Longer-term HA for a 70-kg adult is calculated as follows:

       Longer-term HA = (0-2 mg/kg/day) (70 kg) = 0.070 mg/L (70 ug/L)
                           (100)   (2 L/day)

where:

        0.2 mg/kg/day = NOAEL,  based on absence of systemic toxicity or ChE
                        inhibition in dogs exposed to fonofos in the diet for
                        1 month.

                70 kg = assumed body weight of an adult.

                  100 = uncertainty factor, chosen in accordance with NAS/ODW
                        guidelines for use with a NOAEL from an animal study.

              2 L/day = assumed daily water consumption by an adult.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The Lifetime HA
is derived in a three-step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor.  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

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Fonofos                                                    August, 1987

                                     -12-


     The 2-year feeding study in dogs by Woodard et al. (1969) has been
selected to serve as the basis for the Lifetime HA for fonofos.  Dogs received
dietary fonofos at 0, 16, 60 or 240 ppm (0, 0.4, 1.5 or 6 mg/kg/day) for 14
weeks.  Marginal (about 30%) inhibition of ChE was noted in red blood cells
at the 16-ppm level; this dose was reduced to 8 ppm (0.2 mg/kg/day).  Following
dose reduction, ChE levels returned to control.  At 60 ppm, dogs showed
increased liver weights and significant inhibition (25 to 65%) of ChE
activity in plasma and erythrocytes.  At 240 ppm, there was increased ChE
inhibition and increased mortality.  There were no toxic effects in dogs at
8 ppm  (0,2 mg/kg/day), with the possible exception of one brief episode of
fasciculation in one dog at 5 months.  This was not judged to be significant,
and a NOAEL of 8 ppm (0.2 mg/kg/day) was identified.  The 2-year feeding
study  in rats by Bannerjee et al.  (1968) has not been selected, since rats
appear to be less sensitive than dogs when doses are calculated on a body
weight (mg/kg) basis.

Step 1:  Determination of the Reference Dose (RfD)

                   RfD = -(-°*2 mg/kg/day) = Q.002 mg/kg/day
                              (100)

where:

        0.2 mg/kg/day = NOAEL, based on absence of systemic toxicity or ChE
                        inhibition in dogs exposed to  fonofos in the diet
                        for 2 years.

                  100 = uncertainty factor, chosen in  accordance with NAS/ODW
                        guideline  for use  with  a NOAEL from an animal study.

Step 2:  Determination of the Drinking Water Equivalent Level  (DWEL)

            DWEL =  (0.002 mg/kg/day)  (70 kg) ,  0>07 mg/lj  (70   /L)
                              (2 L/day)

where:

         0.002  mg/kg/day = RfD.

                  70 kg = assumed  body weight  of an adult.

                 2 L/day  = assumed  daily  water  consumption by  an  adult.

Step  3:   Determination of the Lifetime Health  Advisory

             Lifetime HA  =  (0.07 mg/L)  (20%)  =  0.014 mg/L  (14  ug/L)

where:

         0.07  mg/L = DWEL.

               20% = assumed  relative  source  contribution  from water.

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      Fonofos                                                    August, 1987

                                           -13-


      Evaluation of Carcinogenic Potential

           0  Groups of 30 male and 30 female albino rats (Charles River, Cesarean-
              derived) each received 0, 10,  31.6 or 100 ppm fonofos in the diet
              (0, 0.5, 1.58 or 5 mg/kg/day)  for 2 years (Bannerjee et al., 1968).
              Based on gross and histological examination, the authors detected no
              carcinogenic effect.

           0  IARC (1982) has not evaluated  the carcinogenic potential of fonofos.

           e  Applying the criteria described in EPA's guidelines for assessment
              of carcinogenic risk  (U.S.  EPA, 1986), fonofos may be classified in
              Group D:  not classified.  This category is for substances with
              inadequate animal evidence of  carcinogenicity.


  VI. OTHER CRITERIA,  GUIDANCE AND  STANDARDS

              No existing criteria,  guidelines or standards for oral exposure to
              fonofos  were located.

           0  The U.S. EPA Office of Pesticide Programs (OPP) has calculated an
              ADI of 0.002 mg/kg/day for fonofos.  This was based on a NQAEL of
              0.2 mg/kg/day (8 ppm)  for both ChE inhibition and systemic effects,
              in a 2-year feeding study in dogs (Woodard et al., 1969), and an
              uncertainty factor of 100.

           0  The Threshold Limit Value (TLV) for fonofos is 100 ug/m3 (ACGIH,
              1984).

              The U.S. EPA (1985) has established tolerances for fonofos in or on
              raw agricultural commodities that range from 0.1  to 0.5 ppm.


 VII. ANALYTICAL METHODS

              Analysis of fonofos is by a gas chromatographic (GC)  method applicable
              to the determination  of certain nitrogen-phosphorus-containing
              pesticides in water samples (U.S.  EPA, 1986b).  In this method,
              approximately 1 liter  of sample is extracted with methylene chloride.
              The extract is concentrated and the compounds are separated using
              capillary column GC.   Measurement is made using a nitrogen phosphorus
              detector.   The method  detection limit has not been determined for
              fonofos, but it is estimated that the detection limits  for analytes
              included in this method are in the range  of  0.1 to 2  ug/L.


VIII. TREATMENT  TECHNOLOGIES

              No information on treatment technologies  used  to  remove fonofos  from
              contaminated water was  found in the  available  literature.

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    Fonofos                                                     August,  1987

                                         -14-


IX. REFERENCES

    ACGIH.   1984.  American Conference  of Governmental  Industrial  Hygienists.
         Documentation  of  the  threshold limit  values  for  substances  in  workroom
         air, 3rd  ed.   Cincinnati,  OH:   ACGIH.

    Ahmed,  J. and  P.O.  Morrison.   1972.  Longevity of residues  of  four  organo-
         phosphate insecticides in  soil.   Phytoprotection.   53(2-3}:71-74.

    Bannerjee,  B.M.,  D.  Howard and  M.W. Woodard.*  1968.   Dyfonate (N-2790) safety
         evaluation by  dietary administration  to  rats for 105 weeks.  Woodard
         Research  Corporation. Unpublished study. MRID  00082232.

    Cockrell, K.O., M.W. Woodard  and  G. Woodard.*  1966.   N-2790 Safety evaluation
         by repeated  oral  administration to dogs  for  14 weeks and  to rats for  13
         weeks.  Woodard Research Corporation.  Unpublished  study.   MRID 0090818.

    Cohen,  S.Z., C.  Eiden  and  M.N.  Lorber.  1986.  Monitoring ground water for
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         titled:   Evaluation of Pesticides in  Ground  Water (in  press).

    Dean, W.P.* 1977.   Acute  oral  and  dermal  toxicity  (LD5o> in male and female
         albino rats.   Study No.  153-047.  International  Research  and Development
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    Derache,  R.  1977.   Organophosphorus pesticides.  Criteria  (dose/response
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         the Commission of the European Conmunities.  Oxford, England:   Pergamon
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    Hayes,  W.J.   1982.   Pesticides  studied in  man. Baltimore,  MD:   Williams and
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    Hoffman,  L.J., J.M. Ford and  J.J. Menn.  1971. Dyfonate metabolism studies.
         I.  Absorption, distribution,  and excretion  of O-ethyl S-phenyl ethyl-
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    Hoffman,  L.J., J.B. McBain and J.J. Menn.   1973.   Environmental  behavior
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         Unpublished study submitted  by Stauffer  Chemical Company, Richmond, CA.

    Hoffman, L.J.  and J.H. Ross.   1971.  Dyfonate soil  metabolism:  Project
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         Richmond, CA.

    Horn, H.J., G. Woodard and M.T. Cronin.*  1966.  N-2790 10% granular:
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         study.  MRID 00092438.

    Horton, R.J.*   1966a.  N-2790:   Acute oral LD5Q - rats;  acute  dermal toxicity -
         rabbits;  acute eye  irritation - rabbits.  Technical Report T-986.  Stauffer
         Chemical  Company.  Unpublished study.  MRID  00090806.

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Fonofos                                                    August, 1987

                                     -15-
Horton, R.J.*  1966b.  N-2790:   Acute oral LD50 - rats; acute dermal toxicity  -
     rabbits; acute eye irritation - rabbits.  Technical Report T-985.   Stauffer
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IARC.  1982.  International Agency for Research on Cancer, World Health
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Kadoum, A.M. and D.E. Mock.  1978.  Herbicide and insecticide residues in
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Kiigemagi, U. and L.C. Terriere.  1971.  The persistence of Zinophos and
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Lehman, A.J.  1959.  Appraisal of the safety of chemicals in foods, drugs and
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Lichtenstein, E.P., H. Parlar, F. Korte and A. Suss.  1977.  Identification
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Lichtenstein, E.P., and K.R. Schulz.  1970.  Volatilization of insecticides
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Lichtenstein, E.P., K.R. Schulz and T.W. Fuhremann.  1972.  Movement and
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McBain, J.B. and J.J. Menn.  1966.  Persistence of £-Ethyl-S-phenyl
     ethylphosphonodithioate (Dyfonate) in soils:  ARC-B-10.  Unpublished
     study submitted by Stauffer Chemical Company,  Richmond, CA.

McBain, J.B., L.J. Hoffman and J.J. Menn.  1971.  Dyfonate metabolism studies
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Meister, R., ed.  1983.  Farm chemicals handbook.  Willoughby, OH:  Meister
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Miles, J.R.W., C.M. Tu and C.R. Harris.  1979.  Persistence of eight
     organophosphorus insecticides in sterile and non-sterile mineral and
     organic soils.  Bull. Environ. Contam. Toxicol.  22:312-318.

Miller, J.L., L. Sandvik, G.L.  Sprague, A.A. Bickford and T.R. Castles.  1979.
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Minor, J., J. Downs, G. Zwicker et al.*  1982.  A teratology study in CD-1
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     Company.  Unpublished study.  MRID 00118423.

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Fonofos                                                    August, 1987

                                     -16-
Schulz, K.R. and E.P. Lichtenstein.  1971.  Field studies on the persistence
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Simmon, V.F.  1979.  In vitro microbiological mutagenicity and unscheduled
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TDB.  1985.  Toxicology Data Bank.  MEDLARS II.  National Library of Medicine's
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Talekar, N.S., L.T. Sun, E.M. Lee and J.S. Chen.  1977.  Persistence of some
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U.S. EPA.   1979.  U.S. Environmental Protection Agency, Office of Pesticide
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U.S. EPA.   1985.  United States Environmental Protection Agency.  Code  of
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Windholz,  M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds.  1983.   The
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     NJ:   Merck and Company, Inc.

Woodard, M.W., J. Donoso, J.P. Gray et al.*  1969.  Dyfonate (N-2790) safety
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Woodard, M.W., C.L.  Leigh and G. Woodard.*   1968.   Dyfonate  (N-2790)  three-
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     Unpublished study.  MRID 00082234.

Woodard, M.W. and G. Woodard.*   1966.  N-2790  {Dyfonate):  Demyelination
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     MRID  00090819.
 •Confidential  Business  Information submitted  to  the  Office of  Pesticide
  Programs.

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