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    GLYPHOSATE

    EXPLANATION

         Glyphosate has not been reviewed previously by the Joint Meeting.

    CHEMICAL NAME               N-(phosphonomethyl) glycine

    SYNONYM                     Roundup(R)

    STRUCTURAL FORMULA            O                    O
                                  "                    "
                                HOC - CH2 - NH - CH2 - P(OH)2

    MOLECULAR FORMULA           glyphosate:               C3H8NO5P
                                isopropylamine salt:      C6H17N2O5P

    MOLECULAR WEIGHT            glyphosate = 169.1
                                isopropylamine salt = 228.20

    PHYSICAL STATE              Non-volatile white solid

    MELTING POINT               230C (decomp.)

    SOLUBILITY                  12 g/l in water at 25C.
                                Insoluble in common organic solvents.

    IMPURITIES IN TECHNICAL MATERIAL:

         Formulations:          Roundup - aqueous concentrate with 360 g/l
                                glyphosate acid equivalents.

         Application:           By spraying as a 0.5 - 5% solution in
                                water or by wiping (rope-wick) as a 10 -
                                50% solution in water.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Rats

         After single oral doses of glyphosate (6.7 mg/kg b.w.) labelled
    with 14C in 3 positions, absorption was incomplete (males,
    approximately 15%; females, 35 - 40%). Excretion of absorbed material
    was almost entirely in urine, although biliary excretion and
    enterohepatic circulation did occur to a minor extent. Less than 1% of
    the radiolabel was respired as 14CO2. The 48-hour clearance was 94
    - 98% in males, 82 - 84% in females. The 120-hour clearance was 94% in
    both males and females. Tissue retention was correspondingly low and
    could be accounted for by incorporation of radiolabelled carbon
    residues into muscle tissue (Colvin & Miller, 1973a).

         The accumulation and depletion of 14C-glyphosate was
    investigated by its daily administration at levels of 0, 1, 10, or
    100 ppm for 14 days, followed by 10 days on a control ration.
    Determinations of tissue residues were made throughout the treatment
    and recovery periods. About 8.3 to 10.5% of the daily intake was
    excreted in urine in both males and females. By 6 days, elimination
    was approximately equal to intake. After cessation of treatment,
    excretion declined rapidly; 4 days later a redistribution into the
    excreta was seen, probably due to the mobilisation of previously
    established body loads. Most tissues reached maximum residue levels at
    10 days or less, with levels decreasing in the order: kidneys, spleen,
    fat, liver, ovaries, heart, and muscle. The maximum level in the
    kidneys at the high dose did not exceed 1 ppm on a fresh weight basis.
    The residues declined markedly once treatment ceased. The maximum
    level in the kidneys 10 days after withdrawal was 0.1 ppm, with
    0.12 ppm in fat (Colvin & Miller, 1973b).

    Rabbits

         New Zealand white rabbits, administered single oral doses of
    14C-glyphosate (6-8 mg/kg b.w.) cleared more than 40% of the
    radioactivity in 5 days or less. More than 80% of the 14C-activity
    appeared in the faeces, indicating poor oral absorption or extensive
    biliary excretion. The remaining radioactivity after 5 days was mostly
    recovered from the colon. Urinary excretion was 7 - 11% of the dose,
    with less than 1% found in respired 14CO2. Tissue retention was
    low (less than 0.1 ppm at 5 days), except for glyphosate labelled in
    the glycine-2 position, which was metabolised to carbon fragments and
    incorporated into tissues (Colvin & Miller, 1973c).

    Monkeys

         The percutaneous absorption of glyphosate from a commercial
    formulation was studied in rhesus monkeys using 14C-labelled
    material. Absorption was monitored by determining 14C-activity in
    urine, after estimating the extent of urinary excretion following an
    i.m. dose. Approximately 2% of the glyphosate in a single topical dose
    penetrated the skin of monkeys in a 7-day period. Penetration was
    slow, since only 0.4% of the applied dose appeared in the urine within
    24 hours after treatment (Maibach, 1983).

    Biotransformation

         The metabolism of glyphosate in rats was studied after single
    oral doses (6.7 mg/kg b.w.) labelled with 14C in 3 positions, or
    after single i.p. injections of the same dose, or after 12 days
    feeding with 14C-labelled glyphosate in the diet at 100 ppm.
    Regardless of the route of administration, the major radioactive
    component in urine and faeces was unchanged glyphosate. Minor peaks
    were attributable to impurities in the 14C-glyphosate rather than to
    metabolic conversion products (Moran et al., 1973).

    Biochemical studies on metabolites

         The metabolic fate of aminomethylphosphonic acid (AMP) was
    studied, as this was the only major metabolite of glyphosate found in
    biological systems. Male rats were given an oral dose of 14C-AMP
    (6.7 mg/kg b.w.) and excreta were collected for 120 hours. AMP was
    only moderately absorbed (approximately 20%). Excretion was almost
    exclusively via the urine, with less than 0.1% of the dose respired as
    14CO2. Tissue residues were less than 10 ppb (Colvin et al.,
    1973).

         Reaction of the secondary amine group of glyphosate with nitrite
    could result in the production of N-nitrosophosphonomethyl glycine
    (NPMG). Although this metabolite has never been detected in plant
    residues, a study was performed to determine its metabolic fate in
    rats. Animals received single oral doses of 13C/14C NPMG
    (1 mg/kg). Urinary excretion accounted for 78 - 93% of the dose within
    the first 24 hours, with a further 1 - 12% eliminated in faeces. The
    urinary radioactivity was due to unchanged NPMG. In a second phase of
    the study, animals were dosed orally with 13C/14C NPMG
    (30 mg/kg/day) for 5 days to produce the maximal residues in organs
    and tissues. Average excretion per day was 62% in urine and 31% in
    faeces, with a total recovery of 93%. The 14C-content of tissues
    after 5 days was low, ranging from 0.02 ppm in muscle to 0.90 ppm in
    lung. Radioactivity in the urine, faeces, and tissues was in the form
    of unchanged NPMG (Sutherland, 1978).

    Toxicological studies

    Special studies on mutagenicity

         Glyphosate was consistently without mutagenic effect in a range
    of short-term tests (see Table 1).

    Special study on reproduction

    Rats

         Groups of 12 male and 24 female Sprague-Dawley rats were given
    glyphosate (technical) in the diet at dose levels of 0, 3, 10, or
    30 mg/kg b.w./day for 60 days. Administration was continued throughout
    mating, gestation, and lactation for 2 successive litters (F1a and
    F1b) and repeated for 3 generations.

         Some deaths occurred in all treated groups, but there was no dose
    relationship and probably no association with treatment. No evidence
    of maternal or paternal toxicity was apparent. There were spurious
    differences between control and treated animals in mating and
    fertility indices, pregnancy rates, and pup survival. These effects
    were not dose-related, and an association with treatment was unlikely.
    Necropsy evaluation of all animals from the F0, F1b, and F2b
    parents and F3b pups indicated no treatment-related effects. The
    highest dose level of 30 mg/kg b.w./day was the no-observed-effect
    level in this study (Schroeder, 1981).

    Special studies on skin and eye irritation

         Technical glyphosate (99% pure; 0.5 ml of 25%-strength solution)
    and the isopropylamine salt of glyphosate (0.5 ml of undiluted
    material) applied to the intact and abraded skin of rabbits for 24
    hours produced no dermal irritation (Heenehan, 1979a; Branch, 1981a).

         The same volume of the undiluted commercial formulation under the
    same conditions as in the above experiment produced moderate to severe
    skin irritation, which persisted in 1/6 animals for the duration of
    the study (14 days). Other animals had recovered by 9 days
    (Heenehan, 1979b).

         Technical glyphosate (99% pure; 0.1 ml of 25%-strength solution)
    instilled into the eye of rabbits produced conjunctival redness,
    chemosis, and corneal opacity/ulceration. Washing the eyes with warm
    water, 20 seconds after application, did not prevent the irritation.
    All eyes were normal within 7 days (Heenehan, 1979c).

         Under the same conditions as in the preceding experiment, the
    same volume of the isopropylamine salt produced no irritation
    (Branch, 1981b).

        Table 1. Results of mutagenicity studies on glyphosate.
                                                                                                                 

    Test                 Test                 Concentration
    system               object               of glyphosate         Purity       Results         Reference
                                                                                                                 

    Ames test            S. typhimurium       0.1 - 1000            98.4%        negative1       Kier, 1978
                         strains TA98,        g/plate
                         TA100, TA1535,
                         & TA1537

    Rec assay            B. subtilis          20 - 2000             98.4%        negative2       Shirasu
                         strain H17           g/disc                                            et al., 1978
                         (rec+) and
                         M45 (rec-)

    Mutation             E. coli              10 - 5000             98.4%        negative1       Shirasu
       assay             strain WP2hcr        g/plate                                           et al., 1978

    Forward              Chinese hamster      0 - 20 mg/ml          98.7%        negative1       Li, 1983a
       mutation          ovary cells          (w/o activation;
       assay             (HGPRT locus)        5 - 25 mg/ml (with
                                              activation)

    Unscheduled          rat hepatocytes      0.0125 - 125          98.7%        negative        Williams,
       DNA repair                             g/ml                                              1983
       assay
                                                                                                                 

    Table 1.  (cont'd).
                                                                                                                 

    Test                 Test                 Concentration
    system               object               of glyphosate         Purity       Results         Reference
                                                                                                                 

    In vivo              rat bone marrow      200 - 1000            98.7%        negative        Li, 1983b
       cytogenetics                           mg/kg, i.p.
       study

    Dominant             mice                 200 - 2000            98.7%        negative        Rodwell,
       lethal                                 mg/kg, orally                                      1980a
       assay
                                                                                                                 

    1  Both with and without metabolic activation.
    2  Without metabolic activation.
        Special study on skin sensitization

         Undiluted glyphosate (0.2 ml) was applied dermally using the
    closed patch technique to the shaved backs of Hartley guinea pigs
    (5/sex). Application was for 6 hours/day, 3 days/week, for 3 weeks.
    Two weeks after the final dose, additional (0.2 ml) doses were applied
    to previously untreated areas. Dermal irritation was scored at 24 and
    48 hours after the induction and challenge doses. Glyphosate did not
    produce dermal sensitization in this model, but it did cause moderate
    to severe irritation when applied repeatedly to the same site
    (Auletta, 1983a).

         This study was repeated using 0.2 ml doses of an undiluted
    commercial formulation. A similar result was obtained to that using
    the technical material, namely, no skin sensitization, but cumulative
    skin irritation (Auletta, 1983b).

    Special studies on teratogenicity

    Rats

         Groups of 25 female Charles River CD-1 rats were administered
    glyphosate technical (97.7% pure) by gavage on days 6 - 19 of
    gestation. Daily dose levels were 0, 300, 1000, and 3500 mg/kg b.w.
    Control animals received only the vehicle (0.5% Methocel). Animals
    were observed for clinical signs and mortality. Body weights were
    recorded on gestation days 0, 6, 9, 12, 16, and 20. All surviving
    animals were sacrificed on day 20, and the usual teratological
    parameters were monitored. Approximately 50% of the fetuses were
    examined for internal anomalies and 50% were examined for skeletal
    anomalies.

         There were no adverse effects of treatment at the mid- and
    low-dose levels. Maternal toxicity was apparent at the high dose, with
    soft stools, diarrhoea, red nasal discharge, reduced body-weight gain,
    and 6 deaths by gestation day 17. The mean number of total
    implantations, viable fetuses, and mean fetal body weights were
    significantly reduced and early fetal resorptions were significantly
    increased at this dose level.

         There were no fetal malformations in the low- and mid-dose
    groups. In the high-dose group there was an increase in the number of
    fetuses with malformations, but the number of litters with
    malformations was not increased. This increase in malformations was
    attributable to dwarfism in one litter and bent tails in another. It
    was unlikely that these were related to treatment. In addition, an
    increase in the number of fetuses with unossified sternebrae was
    apparent at the highest-dose level, which was probably related to the
    severe maternal toxicity seen at this dose level. Accordingly,
    glyphosate was not teratogenic in rats in this study (Rodwell, 1980b).

    Rabbits

         Groups of 16 female Dutch belted rabbits received technical
    glyphosate by gavage in 0.5% Methocel on days 6 - 27 of gestation.
    Dose levels were 0, 75, 175, and 350 mg/kg b.w./day. The control group
    received the vehicle only. Animals were observed daily for clinical
    signs and mortality. Body weights were determined on gestation days
    0, 6, 12, 18, 24, and 28. All surviving females were sacrificed on
    gestation day 28, and the usual teratological parameters were
    examined. All fetuses were examined for both internal and skeletal
    anomalies.

         Maternal toxicity was apparent at the mid- and high-dose levels
    as diarrhoea, soft stools, and nasal discharge (high-dose only). Two
    mid-dose and 10 high-dose animals died during the study from unknown
    causes. One control animal died from pneumonia. Two control, 1
    mid-dose, and 1 high-dose animal aborted and were sacrificed. A slight
    decrease in mean fetal body-weight was seen in all treated groups
    compared to the control group, but the values were within historical
    limits. There were no treatment-related effects on the number of
    viable fetuses, early or late resorptions, or the fetal sex ratio.
    There were no fetal anomalies which could be considered as
    treatment-related, indicating a lack of teratogenicity in rabbits
    (Rodwell, 1980c).

    Acute toxicity

         Glyphosate and its isopropylamine salt have extremely low acute
    toxicity by oral, dermal and s.c. routes of administration. Toxicity
    was greater by the i.p. route, however (see Table 2).

         In animals which received lethal doses the most severe signs of
    toxicity which preceded death were breathing difficulty, ataxia, and
    occasional convulsive movements. At necropsy, discolouration was
    observed in the lungs, liver, and kidneys of animals which had died.

    Short-term studies

    Mice

         Groups of 15 male and 15 female Charles River CD-1 mice were fed
    glyphosate technical in their diet at dose levels of 0, 0.5, 1.0, or
    5.0% for 3 months. Animals were observed twice daily for clinical
    signs and mortality. Body weights and food consumption were recorded
    weekly. Complete gross necropsies were performed on all animals.
    Histopathological examinations were performed on 10 animals of each
    sex from the control and high-dose groups only.

        Table 2.  Results of acute toxicity studies on glyphosate (G), isopropylamine salt of
              glyphosate (IPA-G), and undiluted Roundup(R) formulation (R).
                                                                                              

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

    Mouse        oral               G                  > 10,000           Monsanto, 1986
                                    G                     1,538           Monsanto, 1986

                 s.c.               G in saline        6,250 (M)          Monsanto, 1986
                                                       7,810 (F)

                 i.p.               G in saline        545 (M)            Monsanto, 1986
                                                       740 (F)
                                    G                  134                Monsanto, 1986

    Rat          oral               G, R, &            > 5,000            Heenehan, 1979d
                                    IPA-G                                 Branch, 1981c

                 dermal             R                  > 17,600           Monsanto, 1986

                 inhalation         R                  LC50 = 3.18        Velasquez, 1982
                                                       mg/l (4 hours)

                 s.c.               G in saline        17,500             Monsanto, 1986

                 i.p.               G in saline        281 (M)            Monsanto, 1986
                                                       467 (F)
                                    G                  238                Monsanto, 1986

    Rabbit       oral               G                  3,800              Monsanto, 1986

                 dermal             G, R, &            > 5,000            Heenehan, 1979e
                                    IPA-G                                 Braun, 1979
                                                                          Branch, 1981d

    Goat         oral               G, R, & IPA-G      > 3,500            Rowe et al., 1983
                                                                                              
    
         There were no clinical signs of toxicity and there was no
    treatment-related mortality. Food consumption of males was increased,
    but not of females. Body-weight gain was reduced in both males and
    females at the high-dose level. Organ weights, gross necropsy
    examinations, and histopathology were unremarkable. Thus, a dietary
    level of 1.0% was without apparent effect (Tierney, 1979).

    Rats

         Groups of 15 male and 15 female Wistar-Imamichi rats were fed
    glyphosate technical (98.4% pure) in their diets at dose levels of 0,
    0.02, 0.2, 0.5, or 1.25% for 90 days. Animals were observed daily for
    clinical signs and mortality. Body weights and food consumption were
    recorded every 3 days. Haematological and urinary parameters were
    determined at 90 days. Gross necropsy and histopathology were
    performed on all animals.

         There were no mortalities and no clinical signs of toxicity. Body
    weights were slightly decreased in week 1 in both sexes, but not
    thereafter. There were no biologically significant changes in
    haematological, clinical chemical, or urinary parameters, or in organ
    weights. Gross necropsy and histological findings were unremarkable.
    Thus, a dietary level of 1.25% was without apparent effect (Tauchi,
    1979).

         A 4-week inhalation study was performed in rats with a one-third
    dilution of a commercial glyphosate formulation. Three groups of 15
    male and 15 female Sprague-Dawley rats were exposed to concentrations
    of 0.05, 0.16, or 0.36 mg diluted commercial formulation per litre of
    air, for 6 hours per day, 5 days per week, for 22 days. Toxicity was
    confined to irritant effects on the nasal turbinates, trachea, and
    lungs (Velasquez, 1983).

    Rabbits

         Three groups of 10 male and 10 female New Zealand rabbits were
    treated dermally with glyphosate technical 5 days per week for
    3 weeks. Dose levels were 100, 1000, or 5000 mg/kg b.w./day. The
    application site was occluded for 6 hours after application and then
    washed. The skin of 5 animals in each group was abraded before
    application. Toxicity was apparent only as slight dermal irritation at
    the 5000 mg/kg b.w./day dose level. There was no evidence of systemic
    toxicity (Johnson, 1982).

         The isopropylamine salt formulation of glyphosate was used in a
    further 21-day dermal study in rabbits, using the same procedures as
    in the preceding experiment. Six groups of 10 male New Zealand rabbits
    were treated with 76 or 114 mg/kg b.w. undiluted formulation 5 days
    per week for 21 days. Toxicity was apparent only as dermal changes,
    which were more pronounced on abraded skin, but which in all cases had
    healed by the end of a 28-day recovery period (Killeen, 1975).

    Dogs

         Groups of 6 male and 6 female beagle dogs were administered
    technical glyphosate (96.1% pure) in gelatin capsules at dose levels
    of 0, 20, 100, or 500 mg/kg b.w./day for approximately 1 year. All
    animals were observed at least twice daily for clinical signs and
    mortality. Body weights and food consumption were recorded weekly.
    Ophthalmoscopic examination was performed before testing and at
    termination. Haematologic and clinical chemical parameters were
    evaluated pre-test and at months 3, 6, and 12. Urine was collected at
    the same times for urinalysis. Gross necropsy and histopathological
    examinations were performed on all animals.

         There were no clinical signs of toxicity and no treatment-related
    mortality. There were no remarkable ophthalmological findings and no
    biologically-significant changes in haematological, clinical chemical,
    or urinary parameters. There were no treatment-related changes in body
    weight or organ weights and no remarkable findings at gross necropsy
    or after histopathological examination. The no-observed-effect level
    was considered to be 500 mg/kg b.w./day, the highest dose tested
    (Reyna, 1985).

    Long-term studies

    Mice

         In a combined chronic toxicity and carcinogenicity study, groups
    of 50 male and 50 female Charles River CD-1 mice were fed technical
    glyphosate in the diet for 24 months at levels of 0, 0.1, 0.5, or
    3.0%. All animals were observed twice daily for mortality and clinical
    signs of toxicity. Body weights and food consumption were determined
    weekly for 14 weeks, then every 2 weeks for the remainder of the
    study. Blood samples were taken from 10 animals/sex/group at 12 and 18
    months and from 12 males/group and all surviving females at 24 months.
    Gross necropsy was performed on all animals which died, were killed
    in extremis, or were sacrificed at study termination.

         There were no clinical signs of toxicity at any dose level.
    Slight decreases in body-weight gain were seen in both high-dose
    groups. Food consumption, feed efficiency, and water consumption were
    unremarkable. There were no treatment-related haematological effects
    or organ-weight changes. Hepatocyte hypertrophy, centrilobular
    hepatocyte necrosis, and chronic interstitial nephritis were increased
    in frequency in high-dose males. Proximal renal tubule epithelial
    basophilia/hypertrophy was increased in frequency in treated females.
    As the incidence of this lesion in the high-dose females was lower
    than that in the control males and in the treated males, and because
    the incidence in the high-dose females fell within the historical
    control range, this effect was not considered to be related to
    treatment. Hyperplasia of the urinary bladder was increased in
    frequency in mid- and high-dose males, but not in treated females.

         There were no statistically-significant increases in the
    frequency of neoplastic lesions in treated groups. The incidence of
    renal tubular adenomas in treated males was increased at the high-dose
    level (control, 0/49, but 1/49 on re-examination; low-dose, 0/49;
    mid-dose, 1/50; high-dose, 3/50). However, the incidence of this
    tumour in historical controls was between 0 and 7.1% and a
    treatment-related effect appears unlikely. The incidence of this
    tumour was not increased in treated females. The no-effect level in
    this study was determined to be 0.5% glyphosate, equal to
    814 mg/kg b.w./day in males and 955 mg/kg b.w./day in females
    (Hogan, 1983).

    Rats

         Groups of 50 male and 50 female Charles River Sprague-Dawley rats
    were fed technical glyphosate in their diets at dose levels of 3, 10,
    or 31 mg/kg b.w./day (males) and 3.4, 11, or 34 mg/kg b.w./day
    (females) for approximately 26 months. Animals were observed twice
    daily for clinical signs and mortality. Body weights and food
    consumption were determined intitially, weekly to 14 weeks, and
    biweekly thereafter. Blood and urine were collected from 10 animals/
    sex/group at 4, 8, 12, 18, and 24 months. Full haematological and
    clinical chemical determinations and urinalyses were performed on
    those samples. All animals were subjected to gross pathological and
    histopathological examinations.

         There were no clinical signs of toxicity and no effects of
    treatment on mortality. There were no treatment-related effects on
    body weight at the end of the study, but there was a consistent
    tendency for reduced body weights in treated males during most of the
    growth period. Haematology, blood chemistry, and urinalysis were
    unremarkable. There were no treatment-related effects on organ weights
    and no remarkable findings at gross necropsy or after histopatho-
    logical examination. There were no increases in tumours that were
    treatment related. The incidence of interstitial cell tumours of
    the testes was slightly high in the high-dose group (control, 0/15;
    low-dose, 2/26; mid-dose, 1/16; high-dose, 4/26). However, this tumour
    is common in aged rats and the incidence was not above historical
    control levels. The no-observed-effect level exceeded 31 mg/kg
    b.w./day in the diet (Lankas, 1981).

    Observations in humans

         The end-use dilution of commercial Roundup(R) formulations (1:9
    Roundup(R): water) was tested for dermal irritation/sensitization in
    humans using the repeated insult patch test. Aliquots of 0.9 ml were
    applied to 50 human volunteers (14 males, 36 females) 3 times per week
    for 5 weeks. The application site was occluded for 24 hours after
    application. A challenge application was made 2 weeks after the last
    application. No visible skin changes were observed in any subjects
    (Shelanski, 1983).

         The percutaneous absorption of 14C-labelled glyphosate from 3
    formulations of glyphosate was measured in excised human abdominal
    skin using an in-vitro technique. Glyphosate was found to be very
    poorly absorbed under these conditions, with the epidermis acting as
    the primary barrier (Franz, 1983).

    COMMENTS

         Glyphosate and its isopropylamine salt have extremely low oral
    toxicity. Orally administered glyphosate is incompletely absorbed from
    the gastrointestinal tract of rats, especially in males. It is
    excreted unchanged in the urine, although there is evidence of biliary
    excretion and enterohepatic circulation.

         Glyphosate is not teratogenic in rats or rabbits at doses
    producing maternal toxicity. It has no adverse effects on the
    reproduction of rats, although doses were significantly lower than
    those used in other studies. Glyphosate was without mutagenic activity
    both in vitro and in vivo.

         The chronic toxicity of glyphosate is low; the only significant
    toxicity seen in a number of animal bioassays was mild hepatotoxicity
    at high doses in mice. There is no evidence of carcinogenicity.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:  0.5% in the diet, equal to 814 mg/kg b.w./day
         Rat:    31 mg/kg b.w./day, administered in the diet.
         Dog:    500 mg/kg b.w./day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.3 mg/kg b.w.

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

         Further observations in man.

    REFERENCES

    Auletta, C.A. A dermal sensitisation study in guinea pigs with
    1983a     glyphosate formulation. Unpublished report from
              Bio/Dynamics, Inc. (Project No. 4234/82), E. Millstone, NJ,
              USA. Submitted to WHO by Monsanto Europe S.A., Brussels,
              Belgium.

    Auletta, C.A. Dermal sensitisation study in guinea pigs. Unpublished
    1983b     report from Bio/Dynamics, Inc. (Project No. 4235/82),
              E. Millstone, NJ, USA. Submitted to WHO by Monsanto Europe
              S.A., Brussels, Belgium.

    Branch, D.K. Primary skin irritation of Mon 0139 to rabbits.
    1981a     Unpublished report No. 800259 from Monsanto Environmental
              Health Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Branch, D.K. Primary eye irritation of Mon 0139 to rabbits.
    1981b     Unpublished report No. 800260 from Monsanto Environmental
              Health Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Branch, D.K. Acute oral toxicity of isopropylamine salt of glyphosate
    1981c     to rabbits. Unpublished report No. 80/261 from Monsanto
              Environmental Health Laboratory, St. Louis, MO, USA.
              Submitted to WHO by Monsanto Europe, S.A., Brussels,
              Belgium.

    Branch, D.K. Acute dermal toxicity of an isopropylamine salt solution
    1981d     of glyphosate. Unpublished report No. ML-80-261 from
              Monsanto Environmental Health Laboratory, St. Louis, MO,
              USA. Submitted to WHO by Monsanto Europe, S.A., Brussels,
              Belgium.

    Braun, W.G. Acute dermal toxicity study in rabbit with Roundup(R).
    1979      Unpublished report from Bio/Dynamics, Inc. (Project
              No. 4885/77), E. Millstone, NJ, USA. Submitted to WHO by
              Monsanto Europe S.A., Brussels, Belgium.

    Colvin, L.B. & Miller, J.A. The gross metabolism of N-phos-
    1973a     phonomethyl glycine-14C in the laboratory rat
              following a single dose. Unpublished report No. 297 from
              Monsanto Environmental Health Laboratory, St. Louis, MO,
              USA. Submitted to WHO by Monsanto Europe, S.A.,
              Brussels, Belgium.

    Colvin, L.B. & Miller, J.A. The dynamics of accumulation and depletion
    1973b     of orally ingested N-phosphonomethyl glycine-14C.
              Unpublished report No. 309 from Monsanto Environmental
              Health Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Colvin, L.B. & Miller, J.A. The gross distribution of N-phos-
    1973c     phonomethyl-glycine-14C in the rabbit. Unpublished
              report No. 298 from Monsanto Environmental Health
              Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Colvin, L.B., Moran, S.J., & Miller, J.A. The metabolism of
    1973      aminomethyl-phosphonic acid-14C in the laboratory rat.
              Unpublished report No. 303 from Monsanto Environmental
              Health Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Franz, T.J. Evaluation of the percutaneous absorption of Roundup(R)
    1983      formulation in man using an in vitro technique.
              Unpublished study No. UW-81-346 from University of
              Washington School of Medicine, Seattle, WA, USA. Submitted
              to WHO by Monsanto Europe, S.A., Brussels, Belgium.

    Heenehan, P.R. Primary dermal irritation study in rabbits. Unpublished
    1979a     report from Bio/Dynamics, Inc. (Project No. 428/77), E.
              Millstone, NJ, USA. Submitted to WHO by Monsanto Europe
              S.A., Brussels, Belgium.

    Heenehan, P.R. Primary dermal irritation study in rabbits. Unpublished
    1979b     report from Bio/Dynamics, Inc. (Project No. 429/77),
              E. Millstone, NJ, USA. Submitted to WHO by Monsanto Europe
              S.A., Brussels, Belgium.

    Heenehan, P.R. Rabbit eye irritation study. Unpublished report from
    1979c     Bio/Dynamics, Inc. (Project No. 428/77), E. Millstone, NJ,
              USA. Submitted to WHO by Monsanto Europe S.A., Brussels,
              Belgium.

    Heenehan, P.R. Acute oral toxicity study in rats with glyphosate
    1979d     technical. Unpublished report from Bio/Dynamics, Inc.
              (Project No. 4880-77), E. Millstone, NJ, USA. Submitted to
              WHO by Monsanto Europe S.A., Brussels, Belgium.

    Heenehan, P.R. Acute dermal toxicity study. Unpublished report from
    1979e     Bio/Dynamics, Inc. (Project No. 4881-77), E. Millstone, NJ,
              USA. Submitted to WHO by Monsanto Europe S.A., Brussels,
              Belgium.

    Hogan, G.K. A chronic feeding study of glyphosate in mice. Unpublished
    1983      report from Bio/Dynamics, Inc. (Project No. 2062/22),
              E. Millstone, NJ, USA. Submitted to WHO by Monsanto Europe
              S.A., Brussels, Belgium.

    Johnson, D.E. 21-Day dermal toxicity study in rabbits with glyphosate
    1982      technical. Unpublished report (Project No. 81/195) from
              International Research and Development Corporation,
              Mattawan, MI, USA. Submitted to WHO by Monsanto Europe S.A.,
              Brussels, Belgium.

    Kier. Salmonella mutagenicity assay of glyphosate. Unpublished report
    1978      No. 78/161 from Monsanto Environmental Health Laboratory,
              St. Louis, MO, USA. Submitted to WHO by Monsanto Europe,
              S.A., Brussels, Belgium.

    Killeen, J.C. A twenty one day dermal toxicity study of MON2134
    1975      (Roundup(R) formulation) in male rabbits. Unpublished
              report from Bio/Dynamics, Inc. (Project No. 1245/75),
              E. Millstone, NJ, USA. Submitted to WHO by Monsanto Europe
              S.A., Brussels, Belgium.

    Lankas, G.R. A lifetime feeding study of glyphosate (Roundup(R)
    1981      technical) in rats. Unpublished report from Bio/Dynamics,
              Inc. (Project No. 410/77), E. Millstone, NJ, USA. Submitted
              to WHO by Monsanto Europe S.A., Brussels, Belgium.

    Li, A.P. CHO/HGPRT gene mutation assay with glyphosate. Unpublished
    1983a     report No. ML-83-155 from Monsanto Environmental Health
              Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Li, A.P. In vivo bone marrow cytogenetics study of glyphosate in
    1983b     Sprague-Dawley rats. Unpublished report No. 83/236 from
              Monsanto Environmental Health Laboratory, St. Louis, MO,
              USA. Submitted to WHO by Monsanto Europe, S.A.,
              Brussels, Belgium.

    Maibach, M.I. Roundup(R) formulation. Elimination and dermal
    1983      penetration in monkeys. Unpublished report No. 81/349 from
              University of California School of Medicine. Submitted to
              WHO by Monsanto Europe, S.A., Brussels, Belgium.

    Moran, S.J., Colvin, L.B., & Ruepple, M.L. The metabolism of
    1973      aminomethyl-phosphonic acid-14C in the laboratory rat.
              Unpublished report No. 303 from Monsanto Environmental
              Health Laboratory, St. Louis, MO, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Reyna, M.S. Twelve month study of glyphosate administered by gelatin
    1985      capsule to beagle dogs. Unpublished report No. 83-137 from
              Monsanto Environmental Health Laboratory, St. Louis, MO,
              USA. Submitted to WHO by Monsanto Europe, S.A., Brussels,
              Belgium.

    Rodwell, D.E. Dominant lethal study in mice with technical glyphosate.
    1980a     Unpublished report No. 401-064 from International Research
              and Development Corporation, Mattawan, MI, USA. Submitted to
              WHO by Monsanto Europe, S.A., Brussels, Belgium.

    Rodwell, D.E. Teratology study in rats with technical glyphosate.
    1980b     Unpublished report No. 79/016 from International Research
              and Development Corporation, Mattawan, MI, USA. Submitted to
              WHO by Monsanto Europe, S.A., Brussels, Belgium.

    Rodwell, D.E. Teratology study in rabbit with technical glyphosate.
    1980c     Unpublished report No. 79/018 from International Research
              and Development Corporation, Mattawan, MI, USA. Submitted to
              WHO by Monsanto Europe, S.A., Brussels, Belgium.

    Rowe, L.D., Lovering, S.L., Wilson, R.D., Martin, B.W., Peterson,
    1983      H.O., Farr, F.M., & Moore, E.G. The acute oral toxicity of
              glyphosate, Roundup(R) formulation, and glyphosate
              isopropylamine salt in female goats. Unpublished report from
              USDA Veterinary Toxicology and Entomology Research
              Laboratory, College Station, TX, USA. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Schroeder, R.E. Three generation reproduction study with glyphosate
    1981      technical in albino rats. Unpublished report from
              Bio/Dynamics, Inc. (Project No. 2063/77), E. Millstone, NJ,
              USA. Submitted to WHO by Monsanto Europe S.A., Brussels,
              Belgium.

    Shelanski, M.V. Evaluation of potential hazards by dermal contact with
    1973      Mon2134 (use concentrations). Repeated insult patch test.
              Unpublished report from Shelanski Holding Co., PA, USA.
              Submitted to WHO by Monsanto Europe, S.A., Brussels,
              Belgium.

    Shirasu, Y., Moriya, M. & Toshihiro, O. Microbial mutagenicity testing
    1978      on CP67573 (glyphosate). Unpublished report No. 241/78 from
              Institute of Environmental Toxicology. Submitted to WHO by
              Monsanto Europe, S.A., Brussels, Belgium.

    Sutherland, M.L. Metabolism of N-nitrosophosphonomethylglycine in the
    1978      laboratory rat. Unpublished report No. MSL 0242 from
              Monsanto Environmental Health Laboratory, St. Louis, MO,
              USA. Submitted to WHO by Monsanto Europe, S.A., Brussels,
              Belgium.

    Tauchi, K. Sub-acute toxicity study of CP67573 (N-phosphonomethyl-
    1979      glycine) to the rat in dietary administration for 90 days.
              Unpublished report No. 79/112 from Institute for Animal
              Reproduction. Submitted to WHO by Monsanto Europe, S.A.,
              Brussels, Belgium.

    Tierney, W.J. Three month feeding study with technical glyphosate in
    1979      mice. Unpublished report from Bio/Dynamics, Inc. (Project
              No. 419/77), E. Millstone, NJ, USA. Submitted to WHO by
              Monsanto Europe S.A., Brussels, Belgium.

    Velasquez, D.J. Acute inhalation toxicity of Roundup(R) formulation to
    1982      male and female Sprague-Dawley rats. Unpublished report
              No. 81/201 from Monsanto Environmental Health Laboratory,
              St. Louis, MO, USA. Submitted to WHO by Monsanto Europe,
              S.A., Brussels, Belgium.

    Velasquez, D.J. Four-week study of 33 1/3% use-dilution of Roundup(R)
    1983      herbicide in water administered to male and female
              Sprague-Dawley rats by inhalation. Unpublished report
              No. 83/015 from Monsanto Environmental Health Laboratory,
              St. Louis, MO, USA. Submitted to WHO by Monsanto Europe,
              S.A., Brussels, Belgium.

    Williams, G.M. The hepatocyte primary culture/DNA repair test on
    1983      compound JJN-1020 using rat hepatocytes in culture.
              Unpublished report No. AH-83-181 from Naylor Dana Institute
              for Disease Prevention, Valhalla, NY, USA. Submitted to WHO
              by Monsanto Europe, S.A., Brussels, Belgium.
    


    See Also:
       Toxicological Abbreviations
       Glyphosate (EHC 159, 1994)
       Glyphosate (ICSC)