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    PESTICIDE RESIDUES IN FOOD - 1979


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1979





    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Expert Group on Pesticide Residues
    Geneva, 3-12 December 1979



    2,4,5-T

    Explanation

    2,4,5-T was reviewed in 1969; however, no recommendations for an
    acceptable daily intake or for maximum residue limits were made. 
    Since that time, the results of additional toxicological and other
    studies have become available and are reviewed in this monograph
    addendum.

    Purity

    2,4,5-trichlorophenol, which is required for the preparation of
    2,4,5-T, is now only available from very few manufacturers.  All
    manufacturers known to the meeting confirm that their product contains
    less than 0.1 mg/kg of TCDD.  Surveys of 2,4,5-T manufactured from
    such material and marketed in many countries consistently show
    contents considerably below 0.1 mg/kg of TCDD.  For example, reports
    from U.S.A. (U.S. Environmental Protection Agency, 1979) show that
    they are generally below 0.02 mg/kg.

    Methods for the determination of TCDD in 2,4,5-T and its formulations,
    include procedures developed by the major manufacturer (Dow, 1975).

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical aspects

    Groups of 4 or 5 non-pregnant female Wistar strain rats were dosed
    orally with [1-14C]-2.4.5-trichlorophenoxyacetic acid at dosage
    levels of 0.04, 1.04 or 10.04 mg/rat (estimated to be equivalent to
    0.17, 4.3 or 41 mg/kg).  Four pregnant rats received 0.04 mg/rat.
    Excretion, expressed as percent of administered dose, was comparable
    in all groups, with 75 percent of the 14C appearing in urine and 8
    percent appearing in faeces within 24 hours.  By seven days, 85
    percent of the administered 14C was excreted via the urine and 11
    percent via the faeces.  No 14C was detected in expired air. 
    Analysis of urine showed 90-95 percent of the 14C was unchanged
    2,4,5-T.  Three minor metabolites (2 nonpolar and 1 polar) were
    detected but not identified.  Following administration of 1 mg
    [1-14C]-2,4,5-T to 9 non-pregnant rats, and of 0.04 mg to 6 pregnant
    rats, single animals sacrificed at various time intervals, and tissue
    analyses were performed.  Radioactivity was detected in all tissue,
    levels initially being highest in the stomach, but decreasing during
    the first 13 hours.  Kidney levels were also high and remained higher
    than other tissues during the 24 hours (pregnant) or 72 hours
    (non-pregnant) of the study.  In non-pregnant rats, no radioactivity
    was detected in any tissue except kidney at the 72 hours sacrifice.
    The average radioactive half-life in adult female rat tissues was 3.4
    hours.  In pregnant rats, placental 14C was higher than in any tissue
    other than kidney.  Fetal 14C-levels increased with increasing size.
    Average half-life of 2,4,5-T in the newborn was 97 hours.  A final

    experiment based on administration of multiple doses of 2,4,5-T before
    and after parturition indicated transfer via the placenta was
    considerably less than transfer via the milk.  In addition,
    distribution in pups differed from that in the adult, the highest
    concentrations being in blood rather than in the kidney (Fang, et
    al., 1973).

    Studies on the pharmacokinetics of 2,4,5-T using [carboxyl-14C]
    2,4,5-T were performed with groups of 3 male and 3 female rats, and 2
    male and 2 female dogs.  Sex differences were not apparent and data
    were combined at each dose level for the two species.  Rats received
    single oral doses of 5, 50, 100 or 200 mg/kg, and dogs 5 mg/kg.
    Plasma clearance rates decreased (half life 4-7, 4-2. 19.4 and 25.2
    hours) and volume distribution increased with increasing dose in the
    rat.  Reversible plasma protein binding of 2,4,5-T was unaffected by
    dose.  Excretion was primarily via the urine regardless of dose.
    However, increasing dose resulted in increased faecal excretion of
    2,4,5-T.  Half-life for elimination was 13.6, 13.1, 19.3 and 28.9
    hours at 5, 50, 100 and 200 mg/kg respectively.  At 5 and 50 mg/kg,
    urinary 14C was mainly unchanged 2,4,5-T.  A small amount of an
    unidentified metabolite was detected, increasing with dose at 100 and
    200 mg/kg.  Thus, in the rat it was apparent that distribution,
    elimination, and metabolism change with increasing dosage.  In the
    dog, plasma clearance and elimination of 2,4,5-T was much slower than
    in the rat.  The half-life of 2,4,5-T in plasma was 77 hours and the
    elimination half-life was 86.6 after 5 mg/kg dosing.  Urinary
    excretion exceeded faecal excretion, but the latter was much greater
    than in the rat.  Three unidentified urinary metabolites were
    detected. Thus, in the dog, distribution, elimination and metabolism
    differed markedly from the same parameters in the rat (Piper, et al,
    1973).

    Rats dosed intravenously at levels of 5 or 100 mg 14C-2,4,5-T/kg
    showed first order decrease of 2,4,5-T from plasma at 5 mg/kg, but a
    non-linear relationship governed clearance at 100 mg/kg.  Plasma
    clearance indicated half-lives of 4.33 ± 0.27 hours at 5 mg/kg,
    compared with 23.1 ± 4.9 hours (0.36 hours) and 5.30 ± 1.23 hours
    (36-72 hours) at 100 mg/kg.  Volume of distribution increased with
    increased dose level.  Excretion in urine was 96 percent of
    administered 2,4,5-T in 84 hours at 5 mg/kg, but only 85.8 percent in
    168 hours at 100 mg/kg.  Faecal excretion (2.78% in 84 hours at 5
    mg/kg expressed as percent of administered dose) increased with
    increased dose (7.33 percent in 84 hours at 100 mg/kg).  Urinary 14C
    was mainly unchanged 2,4,5-T (Sauerhoff, et al., 1976).

    In vitro experiments with rat and dog renal cortex slices indicate
    that in both species, kidney uptake is due to an active anion
    transport system with competitive inhibition of p-aminohippuric acid
    transport.  Plateau levels were attained in the tissue slices in the
    presence of oxygen, but only limited uptake occurred in the presence
    of nitrogen.  Reduction of potassium levels in the media, in the case
    of rat tissue, significantly reduced 2,4,5-T uptake.  No effect

    occurred in dog tissue with reduced media potassium levels.  Acetate
    did not alter accumulation of 2,4,5-T in rat tissue, but markedly
    enhanced it in dog tissue.  Reduced transport and accumulation in
    newborn rat kidney slices was also noted, supporting the hypothesis of
    renal elimination by active secretion of the compound (Hook, et al.,
    1974).

    TOXICOLOGICAL STUDIES

    Special Studies on Reproduction

    Four groups of Sprague-Dawley rats were fed 0 (16 males, 32
    females/group), 3 (10 males, 20 females/group), 10 (10 males, 20
    females/group) or 30 (16 males, 32 females/group) mg 2,4,5-T/kg body
    weight in a three-generation reproduction study.

    The 2,4,5-T was purified material containing less than 0.5 ppb
    2,3,7,8-tetrachlorodibenzo-p-dioxin.  The study design comprised
    single breedings of F0 and F1 parents, but two breedings of F2
    parents.  Gross and histopathology (as well as organ weights) of 5
    animals of each sex in each group were performed with all generations.
    No consistent effects of 2,4,5-T were noted with respect to parental
    body weight, food consumption, fertility index or gestation duration.
    Neither were consistent effects noted on litter size, sex ratio, birth
    weight, weanling weight, or on gross or histopathology.  Survival to
    weaning was significantly reduced in all 30 mg/kg dose level offspring
    and in F1, F2 and F3a offspring at 10 mg/kg.  Even so, except in
    the F3b litters, survival to weaning exceeded 90 percent.  Weanling
    liver weight ratios were increased in F2, F3a and F3b offspring at
    the 30 mg/kg dose level and thymus weight was decreased at 10 and 30
    mg/kg in the F3b offspring (Smith et al., 1978).

    Four groups of 20 male and 20 female Sprague-Dawley rats were fed 0,
    3, 10 or 30 mg 2,4,5-T/kg body weight in the diet in a standard
    three-generation, 2 litter/generation reproduction study.  The 2,4,5-T
    contained 0.05 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin. 
    Histopathology was performed on 10 males and 10 females/dose level
    from the F3b generation at 9 weeks of age.  All discarded parents and
    offspring were subject to gross pathological examination.  No
    consistent effects were observed with respect to parental food intake,
    water intake, body weight, fertility, or duration of gestation.  In
    the offspring, no consistent effects were noted with respect to litter
    size, sex ratio, survival to weaning, incidence of stillbirths, runts,
    or malformations, birth weights, weanling weight, viability or
    lactation indices, post-natal development (as judged by time of onset
    of hair growth, development of ears, cutting of teeth or opening of
    eyes), or sensory function (as judged by consciousness, emotional
    behaviour, activity and reactivity, central excitation, positions and
    posture, muscle tone, or reflexes).  Autopsies revealed no consistent
    gross or histopathological effects including absolute or relative
    organ weights (Leuschner, et al., 1978).

    Special Studies on Teratogenicity

    Mouse

    A total of 199 NMRI mice (group size 12-23) were treated on days 6-15
    of pregnancy with oral doses of 0, 20, 40, 80 or 120 mg/kg of 2,4,5-T
    acid (containing 0.1 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin) or
    2,4,5-T butoxyethylester, the dose for the latter being expressed as
    free acid.  At 80 and 120 mg/kg (toxic to the maternal animals),
    malformations (7.9 and 22.3 percent, respectively) and fetal loss
    (13.5 and 51.5 percent, respectively) were observed with 2,4,5-T acid.
    The ester caused effects only at 120 mg/kg, resulting in 11.6 percent
    malformations and 11.6 percent fetal loss (Frohberg, 1974).

    In a series of experiments on about 700 MNRI mice sacrificed on day 18
    of pregnancy (day 0 being the day when vaginal plugs were detected),
    Neubert and Dillman (1972) considered the effects of 2,4,5-T, TCDD,
    and the combination of the two compounds on induction of cleft palate.
    Dose levels of 2,4,5-T containing less than 0.02 ppm TCDD on days 6-15
    of gestation resulted in an increased cleft palate induction rate at
    45 mg/kg/dy.  No significant effects were noted at 30 mg/kg/day.  A
    sample of 2,4,5-T containing 0.055 ppm TCDD resulted in a significant
    increase in cleft palate incidence at 60 mg/kg, but an insignificant
    increase at 30 mg/kg.  TCDD caused an increased cleft palate incidence
    at 30 µg/kg, but not at 0.3 µg/kg.  Combination studies with 2,4,5-T
    containing less than 0.02 ppm TCDD with TCDD, using 30 mg 2,4,5-T/kg
    with 0.3 or 3.0 µg TCDD/kg, or 60 mg 2,4,5-T/kg with 0.1, 0.3 or 3.0
    TCDD/kg resulted in demonstration of potentiation in the cases where
    teratogenic doses of 2,4,5-T (60 mg/kg) was combined with a
    non-teratogenic dose of TCDD (0.3 µg/kg).  No potentiation occurred
    with 60 mg 2,4,5-T/kg in combination with 0.1 µg TCDD/kg. 
    Potentiation also occurred with 30 mg 2,4,5-T/kS combination with 3.0
    µg TCDD/kg, but not at any other combination levels.  The authors
    concluded that for potentiation of doses of 30 or 60 mg 2,4,5-T/kg to
    occur with TCDD, levels of TCDD contamination must exceed 1 ppm.

    Rat

    Groups of 25 female Sprague-Dawley rats were intubated with 1, 3, 6,
    12 or 25 mg 2,4,5-T/kg body weight on days 6-15 of pregnancy (day 0
    being the day of detection of positive vaginal smears).  A group of 50
    rats received the suspending vehicle (Methocel(R)) on a similar time
    schedule, at the maximum volume administered to test animals.  The
    2,4,5-T contained 0.5 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin.  All
    offspring were removed by Caesarean section on day 20.  Resorption
    rates were comparable in all groups, and no stillbirths were reported.
    Mean pup weight was comparable to, or slightly greater than, controls
    in all test groups.  Gross, skeletal and soft tissue examination of
    control and high dose offspring revealed minor abnormalities, the
    incidence being greater in the controls than in the high dose test
    group, except for delayed ossification of the fifth sternebra.  The
    increased incidence, with respect to this parameter, was within the
    normal incidence range of Sprague-Dawley rats (Emerson, et al 1971).

    Groups of 25 rats were dosed by intubation on days 6-15 of gestation
    (day 0 being the day of detection of positive vaginal smears) with 50
    mg 2,4,5-T/body weight, or on days 6-10 of gestation with 100 mg
    2,4,5-T/kg body weight.  Controls were given appropriate volumes of
    vehicle (Methocel(R)).  The level of
    2,3,6,7-tetrachlorodibenzo-p-dioxin in the technical 2,4,5-T was 0.5
    ppm.  Mortality of maternal animals was 80 percent at 100 mg/kg,
    preceded by marked body weight loss.  Resorption rate was slightly
    increased at 50 mg/kg (12.1 percent or 6.6 percent in controls) and
    markedly increased at 100 mg/kg.  At 100 mg/kg, only one litter
    provided viable fetuses.  Reduced pup weight and delayed ossification
    were noted in this litter.  At 50 mg/kg, pup weight was comparable to
    control values.  An increased incidence of delayed ossification of the
    skull was noted, as compared to controls (Sparschu, et al.,1971).

    Four samples of 2,4,5-T containing less than 0.5 ppm
    2,3,7,8-tetrachlorodibenzo-p-dioxin and one sample of the butyl ester
    of 2,4,5-T were administered to groups of Wistar rats, at dose levels
    up to 150 mg 2,4,5-T/kg body weight.  Treated groups ranged from 6-14
    pregnant females/dose level for 2,4,5-T and for the butyl ester, group
    size comprised 3 (150 mg/kg) or 6 (50 mg/kg) pregnant rats.  Dosing
    was via intubation on days 6-15 inclusive of pregnancy.  The day of
    detection of positive vaginal smears was deemed to be day 1 of
    gestation.  Parental animals were killed and fetus removed on day 22
    of gestation.  At 150 mg 2,4,5-T/kg, both samples tested at this dose
    caused reduced body weight gain in the gravidas, one of the two
    samples causing 3/3 deaths.  No signs of toxicity were observed with 3
    samples tested at 100 mg/kg; maternal weights were also unaffected by
    150 mg 2,4,5-T butyl ester/kg.  Litter size (based on viable fetuses)
    was unaffected by 2,4,5-T or its butyl ester.  However, incidence of
    dead fetuses, fetal weight and incidence of malformed fetuses
    increased with dose at the 100 and 150 mg 2,4,5-T/kg levels.  These
    effects were not apparent in the limited studies with butyl ester.
    Malformation observed with high doses of 2,4,5-T included wavy ribs,
    additional ribs, retarded ossification of frontal and parietal bones,
    a wide range of eternal defects, fused ribs, and micromelia.  In a
    second phase of the study, parents treated with 2 of the 4 samples of
    2,4,5-T were permitted to litter, and offspring were maintained for 12
    weeks.  Maximum dose level was 100 mg/kg.  Sex ratios, viability and
    rate of body weight gain to maturity was unaffected (Khera and
    McKinley, 1972).

    Rabbit

    Groups of 20 virgin New Zealand White rabbits, artificially
    inseminated, were dosed orally by gelatin capsule at 0, 10, 20 or 40
    mg 2,4,5-T/kg body weight on days 6-18 of gestation.  The 2,4,5-T
    contained 0.5 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin.  Offspring were
    removed by Caesarean section on day 29 of gestation.  Incidence of
    resorptions, stillbirth, and absorptions were not affected by 2,4,5-T
    administration.  Pup birth weight was non-significantly reduced in all
    test groups compared to controls.  The slight reduction was not dose
    related.  In the control and 40 mg/kg group, detailed visceral and

    skeletal examination did not reveal any abnormal incidence of minor
    malformation.  No major malformations were reported.  Postnatal
    mortality in the first 24 hours was 7, 26, 11 and 16 percent at 0, 10,
    20 and 40 mg/kg respectively.  The significance of this non
    dose-related effect is obscured by initially incorrect (low)
    incubation temperatures.  The cause of death appeared to be occluded
    nares.  On the last day of fetal collection, incidence of small and/or
    non-patent nares was 36, 25, 26 and 22 percent in controls, 10, 20 and
    40 mg/kg groups, respectively (Emerson et al., 1971).

    Monkey

    Four groups of ten pregnant Rhesus monkeys were dosed orally with 0,
    0.05, 1 or 10 mg 2,4,5-T/kg on days 22-38 of pregnancy.  The 2,4,5-T
    contained 0.05 ppm 2,3,4,7-tetrachlorodibenzo-p-dioxin.  Pregnancies
    were permitted to go to term and young were examined within 24 hours
    of birth and weaned at 4 months.  Sacrifice was at 1 year post-partum.
    During the study, no signs of maternal toxicity were reported.
    Incidence of stillbirths (1/10 at 1 mg/kg), abortions (1/10 at 0, 1/10
    at 1, and 2/10 at 10 mg/kg), duration of gestation, birth weight, and
    post-natal development were normal for the colony.  No malformation
    was detected in any offspring, including stillbirths. (The abortions
    at 1 and 10 mg/kg were prior to 50 days gestation and were not
    examined).  Clinical chemistry and hematology at 0, 6 and 12 months
    post-partum were stated to be within normal limits for the colony
    (Dougherty, et al., 1975).

    Sheep

    Eleven ewes, force fed 100 mg 2,4,5-T/kg body weight in ground alfalfa
    meal on days 14-36 of gestation, all produced normal offspring.  A
    further group of five ewes were force fed 113 mg 2,4,5-T/kg body
    weight for days 14-19 (one ewe), 14-27 (2 ewes) and 14-29 (2 ewes) of
    gestation.  These ewes also produced full-term normal lambs.  The
    2,4,5-T contained 1 ppm 2,3,4,7-tetrachlorodibenzo-p-dioxin.  The
    administration orally of 100 mg/kg body weight of the 2,4,5-T
    propylene glycol butyl esters to an unknown number of ewes did not
    result in any malformed offspring (Benns and Balls, 1971).

    Special Studies on Carcinogenicity

    Groups of XVII/G or C3Hf mice were given 2,4,5-T containing less than
    0.05 ppm total dioxins (0.02-0.03 ppm
    2,3,4,7-tetrachlorodibenzo-p-dioxin) in their drinking water at a
    level of 100 mg/L, for 2 months, followed by dietary administration at
    a level of 80 ppm in the diet for the remainder of their lifespan.
    Average survival time was significantly increased in XVII/G males and
    significantly decreased in C3Hf males.  The effective group size (i.e.
    surviving beyond 300 days), was between 32 and 44 for controls, and 19
    and 25 for test groups.  In the XVII/G mice, incidence of animals with
    tumors was 53 and 78 percent in female and male mice, comparative
    figures in the test groups being 84 and 75 percent.  The majority of
    tumors in all groups were lung tumors.  In C3Hf mice, incidence of

    animals with tumors was 21 and 49 percent in female and male controls,
    and 48 and 55 percent in female and male test animals.  The majority
    of the tumors was spontaneous hepatomas.  In females of the C3Hf test
    group, tumors not seen in the control group included a sebaceous
    squamous cell carcinoma, a squamous cell carcinoma and an osteogenic
    tumor with pulmonary metastasis.  It was concluded that 2,4,5-T was
    not tumorigenic in XVII/G mice, but in C3Hf mice, a significant
    increase occurred in the total yield of tumors in female mice
    (Muranyi-Kovacs, et al., 1976).

    Special Study on Mutagenicity

    Groups of 5 male rats from the F3b litters of a three-generation
    study utilizing 0, 3, 10 or 30 mg 2,4,5-T/kg body weight dose levels
    were sacrificed at 26 weeks of age, and metaphase chromosomes of
    spermatogoneal cells (40 cells/animal) were examined for gaps, breaks,
    atypical chromosomes, or pulverized metaphases.  A low incidence
    (comparable in all groups) of pulverized metaphases was recorded.  All
    other parameters were negative (Leuschner, 1978).

    Short Term Studies

    Monkey

    Twelve mg 2,4,5-T/kg administered for 18 consecutive days to male and
    female Rhesus monkeys produced toxic signs including loss of appetite,
    vomiting, and loss of body weight (Dougherty, et al., 1975

    Long-Term Studies

    Rat

    Groups of 50 male and 50 female Sprague-Dawley rats were fed 3, 10 or
    30 mg 2,4,5-T/kg body weight for 2 years.  Eighty-six rats/sex were
    maintained as controls.  An additional 10 rats/sex/group were
    initiated to provide an interim kill at about 120 days.  Dioxins
    (tetra-, hexa-, hepta-, and octa-chlorodibenzo-p-dioxins) were not
    detected in the 2,4,5-T.  Analytical sensitivity for each dioxin was
    at or below 0.4 ppb.  No effects were noted on food consumption,
    mortality, hematology, or clinical chemistry at any dose level.  Body
    weight was decreased in females at 30 mg/kg; male urine volume,
    coproporphyrin, and uroporphyrin excretion were increased at 30 mg/kg,
    and in the initial stages of the study, coproporphyrin excretion was
    increased at 10 mg/kg.  In females, coproporphyrin excretion was
    increased at 30 mg/kg only.  Organ weight ratios were increased in
    males at 30 mg/kg in the case of kidney at 120 days, and at 2 years
    the heart ratio only was increased.  Gross and histopathology
    indicated changes at 30 mg/kg in kidney in females (dose related
    increase in mineralization in renal papillae or renal pelvis at 10 and
    30 mg/kg), increased pigmentation (possibly iron, since the reaction
    to Mallory's stain increased) and in proximal convoluted tubular
    epithelium at 30 mg/kg); in males, decreased spontaneous chronic
    nephritis, accompanied by increased mineralization of pulmonary

    alveoli, myocardium, myocardial blood vessels, gastric mucosa, and
    muscles at 30 mg/kg.  Changes were also noted in liver and lung at 30
    mg/kg.  Tumor incidence was detailed and failed to indicate either
    overall increase in tumor incidence, changes in site specific
    incidence or changes in incidence of specific types of tumors (Kociba,
    et al., 1979).

    Groups of 60 male and 60 female Sprague-Dawley rats from the F1a
    generation of a reproduction study were selected (2-4 males and 2-4
    females/litter) at 6 weeks of age and were fed 0, 3, 10 or 30 mg/kg
    2,4,5-T/kg body weight via the diet for 130 weeks.  An additional
    group of 60 males and 60 females were fed untreated diet, the original
    control group being fed diet treated with acetone volatized off prior
    to feeding.  The 2,4,5-T contained 0.05 ppm
    2,3,4,6-tetrachlorodibenzo-p-dioxin.  Ten rats/sex/group were subject
    to an interim kill at 13 weeks.  With respect to behaviour, condition
    of faeces, mortality, water intake, food intake, body weight,
    hematology, chemical chemistry urinalysis, ophthalmology, auditory
    acuity, and dentition defects, all groups were comparable.  No
    consistent absolute or relative organ weight changes were noted at
    either 13 or 130 weeks with respect to 12 organs.  No dose or
    compound-related non-neoplastic lesions were observed.  Incidence of
    tumor-bearing animals was high in all groups, being greatest in the
    untreated controls (80 percent in males and 80 percent in females).
    There was no evidence of 2,4,5-T induced tumors with respect to total
    incidence, incidence of benign, or malignant tumors, altered tumor
    induction time, site-specific tumors or particular tumor types
    (Leuschner, et al., 1979).

    Observations in Man

    Seven males, 31-58 years of age, exposed to a single oral dose of 5 mg
    2,4,5-T (99% purity, with less than 0.05 ppm
    2,3,4,7-tetrachlorodibenzo-p-dioxin)/kg showed no clinical signs of
    poisoning as assessed by neurological evaluation, blood pressure,
    pulse rate, pulmonary function, electrocardiogram, chest X-ray, and a
    complete battery of urological, hematological and clinical chemistry
    parameters (Gehring, et al., 1973).

    Seven human volunteers received 5 mg/kg, which was followed by
    periodic blood sampling and urine and faecal collection.  Plasma
    elimination and excretion from the body followed first-order rate
    processes with half-lives of 23.01 and 23.06 hours, respectively.
    Distribution volume was low, the majority of the 2,4,5-T remaining in
    plasma, largely reversible bound to protein.  Excretion was mainly via
    the urine 88.5 percent of administered 2A5-T being excreted unchanged
    via this route in 96 hours.  In three of faeces, collectively
    accounting for a complete 48 hour voiding, less than 1 percent of the
    administered dose was detected (Gehring, et al., 1973).

    COMMENTS

    A review of the new data available to this meeting showed that no
    teratogenic effects of 2,4,5-T have been reported, at the highest dose
    levels tested, in rabbit, monkey or sheep.  However, at high dose
    levels, terata can be induced in rat and mouse.

    There are no data indicating carcinogenic potential of 2,4,5-T in rat
    or in three strains of mice.  In a fourth strain, a questionable
    increase in tumor incidence occurred in females.

    Pharmacokinetic and pharmacodynamic data suggest that the dog is an
    inappropriate species for toxicological extrapolation to man.  A rat
    carcinogenicity study performed with 2,4,5-T containing 0.05 ppm
    2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), demonstrated a "no
    observable effect" level of 3 mg/kg body weight/day.

    The meeting felt that there were minimal concerns regarding the
    presence of residues of 2,4,5-T in food, but could not ignore the
    toxicological problems associated with the toxic contaminant
    2,3,7,7-tetrachlorodibenzo-p-dioxin.  The high safety margin utilized
    in estimating the temporary acceptable daily intake reflects these
    concerns.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

    Rat:  Dietary administration of 3 mg/kg/bw/day

    Estimate of Temporary Acceptable Daily Intake for Man

    0-0.003 mg/kg body weight.

    RESIDUES IN FOOD AND THEIR EVALUATION

    Use Pattern

    2,4,5-T is a selective herbicide widely used in crop production and in
    the management of forests, ranges and industrial, urban and aquatic
    sites.  Broad-leafed plants are generally susceptible whereas most
    grasses, coniferous trees and certain legumes are relatively
    resistant.  It is widely used to control broad-leafed weeds in wheat,
    barley, rice and grain sorghums to suppress unwanted hardwood trees
    and brush, to reduce competition with conifers already established or
    to prepare sites for the regeneration of conifers in forests; also on
    grazing lands to control unpalatable and noxious plants and to kill
    brush and small trees that reduce their productivity.  In addition
    there are various industrial and urban uses including the control of
    brush on rights-of-way, of various noxious weeds.

    The phenoxy herbicides, including 2,4,5-T, were discovered nearly 40
    years ago, and despite the more recent development of many other
    herbicides, they remain major tools in vegetation management (Emmelin,
    1977).  We can expect their continued use in each of these
    applications (National Academy of Sciences, 1968).

    2,4,5-T, a weak acid, is only slightly soluble in water and petroleum
    oils (Crafts, 1961).  Although the acid is biologically active, it is
    normally converted to water-soluble esters or oil-soluble esters for
    convenience in handling and application.  The amino forms are diluted
    with water and sprayed on foliage or injected undiluted into trees
    (Bovey, 1977).  Esters are sprayed as oil solutions or as emulsions
    with water.  Although the strengths of commercial formulations are
    expressed in terms of the equivalent content of the parent acid,
    esters generally have greater herbicidal activity than the amino
    forms; but they are more expensive.  Esters may evaporate from foliage
    after application, releasing fumes that can move outside the treated
    area and cause injury to sensitive plants elsewhere.  This hazard can
    be reduced by the use of low-volatile (long-chain) esters, but these
    cost more than the high-volatile (short-chain) esters and are less
    effective as herbicides in some situations (Craftes, 1961).  Mixtures
    of 2,4-D and 2,4,5-T are commonly employed in brush control (Crafts,
    1975a).

    A problem with grazing lands is that livestock often consume forage
    plants and leave weedy plants untouched.  The result is that valuable
    species can be suppressed while unpalatable or noxious ones remain
    free to prosper under reduced competition.  In the absence of proper
    management, weeds can come to predominate, often to the exclusion of
    forage species.  Because of their low cost, high activity, suitability
    for low-volume application and ability to kill most broad-leafed
    plants, including woody species, without injury to grasses and certain
    legumes, 2,4,5-T herbicides are widely used in pasture and range
    management (Way and Chancellor, 1976).

    Uses of 2,4,5-T herbicides in forestry include the preparation of
    sites for tree establishment, selective weeding to release preferred
    species from competing woody plants (Byrnes, 1960) and to deal with
    situations leading to populations of destructive animals (Marquis,
    1975).  They are applied from aircraft, by ground broadcast sprays and
    by treating individual trees.  Rates of herbicide application for both
    aerial and ground broadcast treatments generally range from 2 to 4
    kg/ha of 2,4,5-T. (Bovey, 1977).

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    When 2,4,5-T herbicides are sprayed on vegetation, a residue of the
    herbicide is deposited on plant foliage, on soil, on fences, poles and
    structures, and often onto surface waters.  Of the herbicide deposits
    on leaves, some is absorbed into the living tissues, often killing the
    plant (Audus, 1976; Kearney and Kaufman, 1975; Ashton and Crafts,
    1973).  The residue remaining in the tissues of dead plants is largely
    decomposed as plant material rots; however, some is released into the

    soil.  The herbicide remaining in surviving plants is broken down over
    a period of a few days to few weeks.  Forage from pastures and ranges
    treated with 2,4,5-T has initial residues in and on the plant material
    of about 100 mg/kg per kg of chemical applied per hectare (Morton et
    al., 1967).  Initial residues in and on forage rarely exceed 300 mg/kg
    and this only on sparse vegetation from the heaviest allowable rates
    of use on grazing lands (Clark et al., 1975).  Forage residues
    decline with a half-life of one to two weeks.  Thus, within two to
    four weeks, levels have usually fallen into the range of one half to
    one sixteenth of the initial value.

    Residues on Grasses and Forage

    Bovey and Hour (1972) detected from 27 to 140 mg/kg 2,4,5-T on the day
    of application of 0.5 kg/ha and 53 to 144 mg/kg from 1 kg/ha
    applications on native or tame pasture grasses.  Similar amounts using
    similar rates of 2,4,5-T per hectare have been reported in other
    studies (Bovey et al., 1974; Bovey et al., 1975; Morten et al.,
    1967).

    Baur et al (1969) applied 2,4,5-T in the form of the 2-ethyl hexyl
    ester at the rate of 2 kg/ha alone and with 0.5, 1 and 2 kg/ha of
    picloram to pastures supporting infestations of woody plants.
    Recovery of 2,4,5-T acid and ester from woody and grass tissues was
    greatest when applied along with picloram.  Residue concentration in
    all treatments, however, was usually less than 10 and 0.1 mg/kg, 1 and
    6 months, respectively, after application.

    Bovey and Baur (1972) analysed forage grasses from 5 locations in
    Texas with wide variations in grass species, soils and climate.  These
    areas had been treated with propylene glycol butyl ether esters of
    2,4,5-T at 0.5 and 1 kg/ha.  An average of 98% of the 2,4,5-T was lost
    from all treated areas 6 weeks after treatment.  After 26 weeks the
    residue levels on grass ranged from 0 to 0.05 mg/kg.

    In two separate studies, Bovey et al. (1974, 1975) applied a 1:1
    mixture of triethylamine salt of 2,4,5-T and picloram at a total of 1
    and 2 kg/ha on pasture land in central Texas.  Repeat treatments were
    made every 6 months to the same area for a total of 5 applications.
    Herbicide content of native grasses was highest (28 to 113 mg/kg)
    immediately after spraying, degraded rapidly after each treatment, and
    tended to disappear before each new application was made.  There was
    no accumulation of 2,4,5-T in vegetation.  Other investigators report
    similar results (Scifres et al., 1977; Norris et al., 1977;
    Radosevich and Winterlin, 1977).

    Baur et al. (1969) found most of the 2,4,5-T applied at 2 kg/ha as
    the 2-ethyl hexyl ester to live oak disappeared in 6 months.  However,
    small amounts, both the acid (0.09 mg/kg) and ester (0.23 mg/kg) of
    2,4,5-T could be detected 6 months after application.  More 2,4,5-T
    was found in live oak tissue at 1 and 6 months from the top of the
    plant than the middle and lower stem due to the top portion
    intercepting more spray initially than lower regions.

    Norris et al. (1977) determined residues of 2,4,5-T in 4 species of
    forest vegetation after 2 successive annual applications of herbicide
    (4 kg/ha as iso-octyl ester applied in diesel oil by helicopter).
    Their results show a sharp decrease in herbicide concentration the
    first month after application.  The mean half-life of 2,4,5-T for all
    species was about 2 weeks after both the first and the second
    applications.  The rate of residue decline slowed up after 3 months.
    One year after application, residues ranged from 0.48 mg/kg in vine
    maple foliage to 0.07 mg/kg in blackberry runners and foliage.
    2,4,5-T residues were below detectable limits (0.01 mg/kg) in all
    species except vine maple 2 years after the first application.  The
    rate of decline of 2,4,5-T residues in vegetation after the second
    application was similar to the first except that 1 year after the
    second application no detectable residues were present in any of the
    sprayed vegetation.

    Morton et al. (1967) studied the disappearance of 2,4,5-T over a
    3-year period from a pasture containing several herbaceous species.
    Most experiments showed half-lives to 2 to 3 weeks after application
    in green tissue.  The half-life in grass litter was slightly longer (3
    to 4 weeks).  Shorter persistence in green tissues was attributed to
    dilution by growth.  Rainfall was important in hastening herbicide
    disappearance.

    As a result of environmental and species differences encountered in
    natural situations, modelling or predicting herbicide kinetics and
    concentration in plants and hence potential exposures of herbivores,
    is very difficult.  However, generalised herbivore exposures may be
    estimated by examining typical residue levels on plants after spray
    operations.  The maximum concentrations immediately after spraying are
    found in grasses (40 to 160 mg/kg per kg/ha).  While it might be
    expected that residues from the volatile esters would initially fall
    off more rapidly (i.e. until esters are hydrolyzed), the data show
    greater variability among plant species than among formulations of
    compounds.  The residue-time pattern illustrates a 2-phase pattern of
    persistence.  A fast phase with a half-life of about 1 to 3 weeks,
    probably represents volatilization and wash-off from plant surfaces.
    The remaining low levels of herbicide may persist for longer than 5
    months in some species.

    In 1969, Dow conducted special studies to determine maximum residue of
    phenoxy herbicides from direct application to grass in four U.S.A.
    locations (Gentry, 1970, Leng 1972).  The residues declined with a
    half-life of 1 to 2 weeks depending upon geographic location and
    within 16 weeks all residues had declined to 0.1 to 7.3 (average 3)
    mg/kg for each kg of herbicide applied per hectare.

    Morton et al. (1967) found 90 to 300 mg/kg 2,4,5-T on grasses
    immediately following application to 2 kg/ha of 2,4,5-T.  The range of
    residues from a 0.5 kg/ha application varied from 50 to 110 mg/kg due
    to the type and condition of grass at the time of application.
    Obviously, more spray will be intercepted by a thicker stand of grass.

    Radosevich and Winterlin (1978) set out to measure the persistence of
    2,4-D and 2,4,5-T in chaparral brush growing in an environment
    characterised by moist cool winters which are followed by about 5
    months of hot dry conditions.  Following the applications of 2,4,5-T
    at the rate of 4. 5 kg/ha 1023 mg/kg of 2,4,5-T was recovered
    immediately after application.  Within 2 days the level of chamise and
    grass had fallen to 18% and 32% respectively of the initial deposit.
    At the end of 30 days the residue in these plant materials had
    declined to 1.3 and 3% of the initial deposit.  There was further
    steady decline so that at the end of 12 months the deposit on chamise
    was only 0.02% of the original deposits.

    Residues in Berries

    Spraying with 2,4,5-T is frequently recommended for control of brush
    in woodland during summer when young conifers are likely to be least
    susceptible to the herbicide.  The danger of spraying at a time when
    such bush fruits as raspberries are likely to be picked and consumed
    was examined in trials in 1972 and 1973 by Olberg et al (Olberg 1973
    and Olberg et al 1974).  It appears that 2,4,5-T applied at 5kg/ha,
    in 2 formulations in mid-summer, caused relatively fast leaf wilt, but
    green berries continued to ripen and became "conspicuously large and
    beautiful".

    Residue levels were determined in fruits picked at various times
    between 0 and 41 days after application.  The results present a
    confusing picture, possibly due to the shielding of fruit by leaves.
    Initial residue levels were markedly different in the 2 years of the
    study.  The first year results with 1 formulation show a 4-fold
    decrease in residue levels in 41 days, but virtually no change in
    residue levels over the same period of the second formulation.  In the
    second year, initial residue levels were much higher by a substantial
    margin.  These levels declined relatively quickly, however, with a
    mean half-life of 8.6 days for the first 15 to 17 days after
    treatment.  There was a marked reduction in the rate of decrease after
    that time.  By the end of the measurement period, which ranged from 29
    to 41 days on different plots, residue levels varied from 0.05 to 22.2
    mg/kg but the results were compounded to some degree by apparent
    2,4,5-T residues in untreated fruits.

    In Finland residues of 2,4,5-T from 0.07 to 15 mg/kg were found in
    lingonberries when samples were collected 2 to 13 weeks after aerial
    spraying of forests (Siltanen and Rosenberg, 1978).  By contrast,
    Maier-Bode (1972) found only 1 mg/kg 2,4,5-T on unidentified wild
    berries in Sweden on the day of treatment by aircraft, due no doubt to
    the shielding by overhead foliage.  Work in Britain has shown that
    blackberry fruit harvested 3 days after spraying with 2,4,5-T at 3
    kg/ha contained 100 mg/kg of 2,4,5-T (Brown and MacKenzie, 1971). 
    Fully-ripened fruit remained in good condition for 3 to 4 days, but
    then developed mold and began to drop from the bushes, while immature
    fruit failed to ripen following treatment.

    Blackberries which grow in forests, hedgerows and roadsides in many
    countries are major weed pests in other countries where biological
    constraints do not operate to prevent their proliferation and invasion
    of pastures, range lands, orchards and similar situations.  Donaldson
    and Irvine (1979) reported observations on the effects of spraying of
    2,4,5-T on the development of blackberry fruit and on the residue
    levels in the fruit at various times after spraying of bushes bearing
    ripe fruit.  The bushes were sprayed to the point of run off with a
    0.07% solution of the butoxyethanol ester of 2,4,5-T.  Development of
    the tagged fruit was followed over the next few weeks.  Samples of
    ripe fruit were collected just prior to spraying, immediately after
    and 3, 7, hours, 1, 2, 3, 4 days, 1 and 2 weeks after spraying.

    The initial effect of the 2,4,5-T which was a slight twisting of the
    tips of the canes, was apparent 1 day after the treatment, but this
    could easily escape the notice of a person unfamiliar with this
    herbicide.  After about a week the foliage began to turn yellow which,
    together with the pronounced twisting of the ends of the canes and
    leaf petioles, would indicate that the bushes had been sprayed.  The
    symptoms then became progressively more severe, until after about 6
    weeks the bushes appeared to be dead.

    The residues of 2,4,5-T present in ripe blackberry fruit at various
    intervals after spraying ranged from 19.4 mg/kg immediately after
    spraying to 11 mg/kg 2 weeks later.  After 2 weeks the sprayed fruit
    was no longer suitable for picking and no further analyses were
    carried out.

    Residues in Mushrooms

    Residues of 2,4,5-T as high as 1.7 mg/kg have been detected in
    mushrooms collected from woodland areas 3 to 11 days after spraying
    with 2,4,5-T ester at 1.5 to 2.3 kg/ha (Olberg, Kallfass and Wolff,
    1978).  In Finland residues of 2,4,5-T from less than 0.02 mg/kg to
    1.8 mg/kg were found in wild mushrooms when samples were collected 2
    to 13 weeks after aerial spraying of forests (Siltanen and Rosenberg,
    1978).

    Residues in Rice

    No residues of 2,4,5-T were detected in grain or hulls of rice treated
    twice with 2,4,5-T at 0.75 and 1.5 kg/ha and harvested 50 or 84 days
    after the last application.  Residues found in rice straw ranged from
    1 to 13 mg/kg using alkaline extraction and/or hydrolysis which is
    about 10 times more than found using solvent extraction in the
    presence of acid (Dow, 1973).

    Residues in other cereals

    At the 1970 meeting, data on the level and fate of 2,4,5-T residues on
    barley, oats, rye and wheat were calculated.  It was concluded that a
    MRL of 0.05 mg/kg was needed.  Likewise, a much higher limit was
    required for cereal straws.

    Residues on Sugarcane

    Sugarcane growing in Florida was treated twice with 2,4,5-T at 1 kg/ha
    using a triethylamine salt formulation.  Samples of immature cane were
    collected at intervals and analysed for residues using a gas
    chromatographic method with a validated sensitivity of 0.05 mg/kg.
    The residue in whole raw sugarcane decreased rapidly from 10 mg/kg at
    1 day after the second application to less than 0.05 mg/kg at normal
    harvest 26 weeks later.  Traces of 2,4,5-T present in sugarcane at
    early harvest were found to occur principally in the bagasse (fibre)
    portion of the stalk and amounted to 0.1-0.4 mg/kg in that by-product.
    The sugarcane juice contained less than 0.05 mg/kg.  Samples of juice
    spiked with 0.1 to 0.4 mg/kg 2,4,5-T were put through the sugar
    process in a pilot factory and showed that traces of residue in mixed
    juice would become concentrated 5-fold in factory syrup and 9-fold in
    first molasses.  The residue in raw sugar would be half the level (if
    any) in the juice from which it was derived (Dow, 1970).

    Residues in Apples

    Data obtained by personnel at Cornell University indicated that
    treatment of apples with a solution containing 20 to 40 mg/L of
    2,4,5-T to prevent preharvest drop caused a residue of less than 0.3
    mg/kg 2,4,5-T immediately after application.  This residue decreased
    to less than 0.1 mg/kg within 3 days of treatment even at double the
    registered rate of application.  Residues of 2,4,5-trichlorophenol
    were not detected in treated fruit.  Analyses were performed by
    measurement of radio-activity and by gas chromatography (Dow, 1971).

    Residues in Meat

    Feeding studies were conducted during 1969 and 1970 with 2,4,5-T in
    the total ration of dairy cows, beef cattle or sheep for intervals of
    2 to 4 weeks (Leng, 1972, 1977).  Groups of 3 beef calves were
    maintained for 4 weeks on a complete ration containing 2,4,5-T and
    were slaughtered the day following the last feeding.  Additional
    groups of calves were given the highest level of herbicide and were
    slaughtered 1 week after replacement of treated feed with untreated
    feed.  The levels fed to treated calves were 100, 300, 900 and 1800
    ppm.  Samples of muscle, fat, liver and kidney were analysed for
    residues of 2,4,5-T and its corresponding phenol.  The methods of
    analysis were based on gas chromatography of methyl esters of the
    parent acid and methyl esters of the phenol.  The methods were
    validated to the sensitivity of 0.05 mg/kg in each tissue.  The
    residue data obtained were published (Jensen et al., 1972; Leng
    1972).

    Calves slaughtered while ingesting 300 ppm 2,4,5-T in the total ration
    contained average residues of 0.1 to 0.28 mg/kg in muscle, fat and
    liver and 3.3 mg/kg in kidneys.  Proportionally higher average
    residues were found in tissues of animals fed 900 and 1800 ppm of
    2,4,5-T and slaughtered without withdrawal, but the levels varied
    considerably among individual animals in each group.  Nevertheless,

    the highest residues found in beef kidney was equivalent to only 0.4%
    of the daily dose of 2,4,5-T fed to that animal each day for 4 weeks
    prior to slaughter.  In cases where residues were found in certain
    tissues 1 week after withdrawal, they amounted to only 5% of those
    found in similar tissues of animals slaughtered without withdrawal
    from rations containing 1800 ppm of 2,4,5-T.  Residues decline rapidly
    in tissues as soon as animals started to eat untreated feed.

    No 2,4,5-trichlorophenol was found in the muscle and fat of animals
    fed even at the highest level.  The residues in kidney were generally
    below 0.5 mg/kg for all levels of feeding and averaged residue of
    2,4,5-T in the same tissue.  As with the parent compound, residues of
    the phenol disappeared rapidly when the animals were given untreated
    feed.

    Clark et al., (1975) reported studies aimed at determining the level
    and fate of residues in tissues of sheep.  Groups of sheep received
    2000 ppm in their rations for 28 days after which some of the animals
    were slaughtered and samples of muscle, fat, liver and kidney were
    collected.  7 days after the treated feed had been replaced by
    untreated feed, the remaining animals were killed and sampled.  As
    shown in Table 1, significant residues were found only in tissues
    taken from animals at the end of the 28-day feeding period.  The
    highest residues occurred in kidney where 27.2 mg/kg of 2,4,5-T and
    0.9 mg/kg of 2,4,5-trichlorophenol were found.  This feeding level is
    at least 100 and probably more than 500 times the maximum that sheep
    would receive under practical conditions.

    Clark and Palmer (1971) report that the residue of 2,4,5-T was less
    than 0.1 mg/kg in tissues of a sheep given a single oral dose of 25
    mg/kg body weight 2,4,5-T propylene glycol butyl ether ester or in
    omental fat of sheep given 4 daily doses of 0.15 or 0.75 mg/kg of the
    same formulation.  Residues of 2,4,5-T as high as 368 mg/kg of tissues
    were found in tissues of sheep acutely poisoned by repeated doses of
    250 mg/kg of 2,4,5-T acid or the above ester formulation.  Low levels
    of apparent residues were found in the omental fat of cattle given
    daily oral doses of 0.15 or 0.75 mg/kg propylene glycol butyl ether
    ester of 2,4,5-T orally for up to 32 weeks of treatment.

    Residues in Milk

    St John et al., (1964) found that dairy cows given 2,4,5-T in their
    ration at 5 ppm for 4 days, completely eliminated 2,4,5-T as soluble
    salts in the urine 2 days after dosing stopped.

    Leng (1972), Bjerke et al., (1972) report studies in which groups of
    3 cows were fed 0, 10, 30, 100, 300 or 1000 ppm of 2,4,5-T in the
    total ration continuously for intervals of 2 or 3 weeks at each level,
    followed by untreated feed for 1 week after withdrawal from the 1000
    ppm ration.  Samples of milk and cream obtained at specific intervals
    throughout the study were analysed.  Average residues found in milk
    and cream are given in Table 2.



        Table 1.  Residues of 2,4,5-T and 2,4,5-Trichlorophenol in Sheep Fed 2,4,5-T for 28 Daysa (Clark et al, 1975)

                                                                                                                    

                                                        Residues found, ppmb
                                                                                                                    
                         Muscle                    Fat                       Liver                     Kidney
                                                                                                                    
    2,4,5-T in                2,4,5-T                  2,4,5-T                    2,4,5-T                   2,4,5-T
    feed, ppm      2,4,5-T    phenol        2,4,5-T    phenol         2,4,5-T     phenol          2,4,5-T   phenol
                                                                                                                    

    2000            1.00        0.13          0.27      <0.05           2.29        6.1             27.2     0.90
    2000 (+ w)c     0.05       <0.05         <0.05      <0.05          <0.05        4.4             0.06     0.81
                                                                                                                    

    a  Average of three animals per group (data for individual animals are available).
    b  Not corrected for recovery.
    c  (+ w) = 7-day withdrawal.


    Table 2.  Average Residues of 2,4,5-T and 2,4,5-Trichlorophenol in Milk and Cream from Cows Fed 2,4,5-T for 2 or 
    3 weeks at Each Level Followed by Untreated Feed for 1 Week

                                                                                                            
                                     2,4,5-T,ppm                                2,4,5-Trichlorophenol, ppm
                                                                                                            
       upm                   Milk                Cream                      Milk            Cream
     2,4,5-T              Cow Number           Composite                  Cow Number      Composite
     in Diet        36        41        30                      36        41        30
                                                                                                            
        10         0.05      0.05      0.05      0.05          0.05      0.05      0.05     0.05
        30         0.05      0.05      0.05      0.05          0.05      0.05      0.05     0.05
       100         0.05      0.05      0.05      0.05          0.06      0.06      0.05     0.06
       300         0.05      0.06      0.20      0.07          0.08      0.12      0.10     0.10
      1000         0.35      0.31      0.54      0.26          0.16      0.27      0.26     0.19
    1000 + 0       0.05      0.05      0.05      0.05          0.05      0.05      0.05     0.05
                                                                                                            
    


    The data showed that no detectable residues occurred in milk of cream
    of cows ingesting 10 to 30 ppm 2,4,5-T, but traces of
    2,4,5-trichlorophenol (0.06 mg/kg) appeared in milk and cream at 100
    ppm 2,4,5-T in the ration and of both 2,4,5-T and
    2,4,5-trichlorophenol at levels of 2,4,5-T, equivalent to 300 ppm and
    1000 ppm in the total ration; but no residues were found in milk or
    cream when cows were given untreated feed for 1 to 3 days after 3
    weeks on the high level of 1000 ppm in the total ration.

    In the light of these findings and of the fact that total diets during
    milk production seldom, if every, consist entirely of freshly-treated
    forage containing maximum residues of phenoxy herbicides, it can be
    concluded that no residues are likely to be found in milk or cream of
    cows grazing pastures treated with 2,4,5-T. 

    Residues in Wildlife

    Garcia et al., (1979) searched for residues of 2,4,5-T in aquatic
    samples from a reservoir gathering water from a watershed in Texas
    that was extensively treated with 2,4,5-T for brush control.  No
    2,4,5-T was detected in whole fish or in 5 tissues from turtles.
    Seven of 22 preparations from turtles contained traces of 2,4,5-T, the
    highest 0.013 mg/kg.  The turtles containing 2,4,5-T were more
    herbivorous than those in which 2,4,5-T was absent.

    Newton and Norris (1968) studied blacktail deer whose habitat had been
    treated with a combination of 2,4,5-T and 2,4-D.  Residues of 2,4,5-T
    were found in organs such as brain, kidney, lung, lymph nodes, spleen,
    thyroid, as well as blood and urine.  The highest concentration ranged
    from 0.006 to 0.192 mg/kg.  Concentrations in flesh rarely reached
    detectable levels and the ruminant was able to degrade and eliminate
    the herbicide soon after ingestion.

    Residues in Food Commodities

    Results of the FDA Market Basket Surveys for 1964 through 1974
    indicate that residues of 2,4,5-T are not occurring in food
    commodities.  With the exception of 3 isolated values reported early
    in the Market Basket Survey, no 2,4,5-T has been found using an
    analytical method judged to have a limit of detection of 0.002 mg/kg
    (Duggan et al., 1967, Martin and Duggan 1968, Corneliussen 1969,
    1970, 1972).

    FATE OF RESIDUES

    In Animals

    St John et al., (1964) showed that dairy cows receiving 2,4,5-T in
    their feed completely eliminated 2,4,5-T as soluble salts in the urine
    2 days after dosing stopped.  Clark et al., (1975) showed that sheep
    receiving massive doses of 2,4,5-T daily for 28 days in feed
    eliminated the herbicide in the urine mainly unchanged although there
    was a small conversion to 2,4,5-trichlorophenol.  Clark and Palmer

    (1971) showed that a sheep given a single oral dose of 25 mg/kg of the
    propylene glycol butyl ether ester of 2,4,5-T showed a peak
    concentration of 10 mg/L of the unmetabolised ester in blood 3 and 4
    hours post-treatment.  Within 72 hours, approximately 86% of the
    administered dose was recovered from urine as the unmetabolised ester,
    and 1.4% was recovered as free 2,4,5-T.  Leng (1977) reported that
    residues of the phenoxy herbicides in treated food or feed crops were
    readily absorbed in the gut of animals and were excreted rapidly in
    the urine, largely as unchanged phenoxy acid.  Some conjugation
    occurred, particularly at higher dosage levels, but the basic
    structure of the herbicide was not readily altered in animals.

    Haque et al., (1975) studied the binding of 2,4,5-T with the protein
    of bovine serum albumin.  A weak binding appears to be possible.
    Herne (1966) reported the major route of elimination of 2,4,5-T from
    pigs, calves and rats dosed with 100 mg/kg was in the urine.  Repeated
    doses did not result in the retention or accumulation of the
    herbicide.  A cow which received 5 ppm 2,4,5-T in its feed eliminated
    substantially all of the chemical within 2 days following exposure and
    no 2,4,5-T was found in the milk (St John et al., 1964).

    In Plants

    The persistence of 2,4,5-T residues in vegetation may vary from year
    to year depending on weather conditions.  The length of time required
    for half of the 2,4,5-T residues to disappear from forage ranged from
    1.6 to 2.6 weeks in one study (Morton et al., 1967).  Precipitation
    markedly reduced the residues, indicating they were primarily a
    surface deposit.  However, even in the absence of precipitation, the
    residues diminished with time due to growth dilution and metabolism of
    herbicide by the plant (Morton et al., 1967).  Any 2,4,5-T that is
    washed from the foliage into the soil will contribute very little to
    residues in subsequent plant growth.  The chlorophenoxy acetic acid
    herbicides are poorly absorbed and translocated following exposure of
    roots (Crafts and Yamaguchi, 1960).

    Fitzgerald et al., (1967) studying the degradation of 2,4,5-T in
    woody plants, reported that the n-butyl ester of 2,4,5-T is degraded
    in sweet gum (liquid amber) and southern red oak (Querous) to yield
    2,4,5-trichlorophenol.  Basler et al., (1964) established that
    2,4,5-T is decomposed in excised leaves from woody plants.  Morton
    (1966) showed that approximately 80% of the 2,4,5-T absorbed by
    mesquite leaves was metabolised after 24 hours.  Numerous other
    investigations have also shown the importance of metabolism in
    detoxification and loss of phenoxy herbicides within many plant
    species.

    Leaves and stems of plants are the main receptors of foliar-applied
    herbicides.  Apart from their function in decarboxylation, breakdown,
    and conjugation of the herbicide, leaves and plant parts may abscise
    from the plant and fall to the soil where the tissue and any residual
    herbicide is subject to weathering and decay.  Aerial parts of plants
    may also be removed by mowing machines or clipped and consumed by

    grazing animals.  If the herbicide does not kill or stop growth of the
    plant, the herbicide will be diluted by the growth and biomass
    accretion of the organism.  On plant surfaces, 2,4,5-T is lost by
    photodegradation and the volatilisation in a manner similar to that
    for bosphorum soils.  Rainfall is also reported to be an important
    means of accelerating herbicide loss from plant surfaces (Bovey et
    al., 1974, Morton et al., 1967).  Loos (1975) has recently reviewed
    the degradation of 2,4,5,-T and other phenoxy herbicides in plants.
    In general, because of the widely different degradative pathways, the
    phenoxy herbicides do not persist in plants.

    Investigations by Winston and Ritty (1972) indicated that 2,4,5-T is
    decomposed to form carbon dioxide, inorganic chlorides and water;
    chlorophenols are not end-products to this decomposition.  Reinhart
    (1965) provided supporting evidence.  The upper half of a 10-hectare
    timbered watershed in northern West Virginia was logged and then half
    was treated with 10 kg/ha 2,4,5-T ester to kill all vegetation.  No
    odour contaminants (phenols or catechols) were found in numerous water
    samples taken from the stream draining the treatment watershed.

    Morton et al., (1967) using technical grade 2,4,5-T labelled in the
    carboxyl position carbon-14, found its apparent half-life averaged 1.6
    weeks in green tissues of native grasses in Texas and 1.7 weeks in
    litter.

    In Forest Litter

    Montgomery and Norris (1970) have reviewed the information available
    on the fate of 2,4,5-T in the forest environment, the forest floor
    being a major receptor of aerially-applied 2,4,5-T.  Norris (1966)
    reported 5.3% decomposition of 2,4,5-T in 29 days in the highly
    organic layers of the forest floor.  In another study, 87% of the
    2,4,5-T was degraded in 2 months (Norris 1969).

    About 60% of the 2,4,5-T in solution was absorbed at equilibrium
    (30°C) which was attained in a few hours (Norris 1970).  The extensive
    inter-reaction of 2,4,5-T with forest floor suggests that only limited
    leaching should occur.  A lack of 2,4,5-T residues in streams flowing
    from treated areas (Norris 1967) suggests that a combination of rapid
    degradation and resistance to leaching prevents stream contamination.
    Newton (1971) has calculated from studies on the kinetics of
    degradation by micro-organisms that 2,4,5-T has a half-life of 7 weeks
    in the forest floor.  Investigations by Winston and Ritty (1972) and
    Reigner et al., (1968) indicate that 2,4,5-T is decomposed to form
    carbon dioxide, inorganic chlorides and water; objectionable
    chlorophenols are not end-products of this decomposition.  Norris et
    al., (1977) reported on the persistence of 2,4,5-T in a Pacific
    Northwest forest.  The authors found that 6 months after the
    application at 2.24 kg/ha, the level of herbicide in the forest floor
    declined 90%; after 1 year, less than 0.02 kg/ha remained in the
    forest floor.  The authors found little leaching from the forest floor
    into soil.

    Norris (1970) published extensive studies from which it appears that
    the degradation of 2,4,5-T follows first-order kinetics when
    recoveries of 2 concentrations are compared.  A lag period,
    characteristic of degradation of other herbicides, is found also with
    2,4,5-T.

    In Soil

    The persistence of 2,4,5-T in soil varies, but it does not usually
    carry over from one growing season to the next.  Residual lifetime is
    influenced by climatic conditions and populations of soil
    micro-organisms (Alexander and Aleem 1961).  Biological detoxication
    may be complete within a few weeks or may require up to 9 months
    (Newman et al., 1952, Warren, 1954).  Where conditions are
    favourable, 2,4,5-T may be detoxified in one month (Warren 1954).  The
    2,4,5-trichlorophenol, which is a degradation product of 2,4,5-T, is
    even more readily metabolised than the parent compound (Alexander and
    Aleem, 1961).

    In Water

    Current information indicates, although some 2,4,5-T may enter streams
    flowing through or adjacent to areas being sprayed, residue levels in
    streams will be very low.

    Norris (1971) reported the results of an intensive study of stream
    contamination from spray projects on range and forest lands in Oregon
    which showed that peak concentrations of 2,4,5-T seldom exceeded 0.1
    mg/L and that herbicide residues persisted for only a few hours in
    nearly all streams.  Norris speculated, however, that application of
    2,4,5-T to marshy areas may result in residues at a higher level for a
    longer period in nearby streams.  Other papers on the fate of 2,4,5-T
    in water under laboratory and field conditions have been published by
    Kenaga, (1974); Bovey et al., (1975); Norris and Moore (1971); and
    Manigold and Shulze (1969).

    Photodecomposition

    Photochemical decomposition of 2,4,5-T in aqueous media utilising
    wavelengths in the region of 300-450 nm was reported by Crosby and
    Wong (1973).  The breakdown was slow, with approximately 10% of the
    2,4,5-T undergoing photolysis after 180 hours of irradiation.  In
    sunlight, the photolysis of 2,4,5-T was very slow.  However, the
    presence of low levels of acetone or riboflavin in the solution
    resulted in a marked increase in the rate of disappearance, with 80%
    being degraded in 48 hours.  In these experiments using sensitizers,
    2,4,5-trichlorophenol was confirmed as the degradation product.

    Presence and fate of the Dioxin, TCDD

    In the 2,4,5-T manufacturing process, the especially toxic dioxin,
    2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), is formed when the
    reaction temperature is in excess of temperatures above 160°C.  The

    formation of TCDD during the production of 2,4,5-trichlorophenol was
    demonstrated by Kimmig and Schulz (1957).  A number of researchers
    have reported on the formation of TCDD by the thermal decomposition of
    the sodium salt of 2,4,5-trichlorophenol under alkaline conditions
    during the manufacturing process.

    After concern arose in 1969 about the extremely toxic properties of
    TCDD, manufacturing methods were changed and carefully controlled by
    manufacturers.  By 1971 industry had reduced the TCDD content in
    commercial samples of 2,4,5-T to less than 1 mg/kg.  Current
    manufacturing specifications require 2,4,5-T to contain less than 0.1
    mg/kg TCDD.  Several countries now produce commercial 2,4,5-T
    containing less than 0.05 mg/kg TCDD.

    Getzendaner and Hummel (1975) reported on the disappearance of TCDD
    from grass after spraying it with 12 kg/ha 2,4,5-T.  The loss of TCDD
    is consistent with the work on photodegradation by Crosby et al.,
    (1971), Crosby (1977, 1977a) and Crosby and Wong (1976, 1977), Botre
    1978, and Plimmer, 1978.  Negative findings have been reported from
    monitoring studies for TCDD in a variety of likely substrates using a
    GC/MS method developed by Stehl et al., with low part per trillion
    sensitivity.  The results of these analyses include beef fat (Kocher
    et al., 1978), cows milk (Mahle et al., 1977), fish, human milk,
    rice, water and soil (Shandoff et al., 1977), all collected from
    areas where herbicide 2,4,5-T had been used for up to 30 years for the
    control of weeds and brush.

    In a study (Jensen et al., 1978), sheep were fed on a diet
    containing 300 parts per 106 (i.e. ppm) of 2,4,5-T and 150 parts per
    1012 (i.e. trillion) of TCDD for 28 days.  At the end of this period,
    it was found that fat and liver contained the highest residue,
    accumulating twice the diet level.  Muscle contained the least at 20
    parts per trillion or about 1/5 the diet level.

    Koeher et al., (1978) have presented data on cattle taken from areas
    where 2,4,5-T is known to have been used.  These samples were
    collected to represent typical situations from which beef might enter
    commercial channels, as well as one case in which the potential for
    residues for TCDD was exaggerated.  In spite of major difficulties in
    interpreting the data from the GC-MS technique at low parts per
    trillion levels with much interference from other chlorinated residues
    in fat (DDE, dieldrin, PCB's etc) it was generally concluded that the
    samples were substantially free of TCDD even from the area where the
    use pattern was exaggerated.

    Another study was conducted in an attempt to find TCDD in milk of
    cattle grazing on pastures or range which had been treated with
    2,4,5-T (Mahle et al., 1977).  The results of analysis of milk from
    cows grazing on grass treated with 2,4,5-T were indistinguishable from
    those from the control milk obtained from a supermarket remote from
    areas where 2,4,5-T might be used.  Shadoff et al., (1977) reported
    the outcome of a search for TCDD in an environment exposed annually to

    2,4,5-T herbicides.  No evidence was found that TCDD is accumulating
    in the environment under the conditions of annual 2,4,5-T use to
    control weeds in rice in the USA.

    Jensen et al., (1978d) reported the results of an investigation into
    the possible presence of TCDD residues in rice grains from fields
    treated with 2,4,5-T.  No trace of TCDD could be found.  Another
    environmental sampling was conducted by Newton (1975).  In a
    reforestation project, 2,4,5-T was applied, and 10 mountain beavers (a
    herbivorous rodent which collects succulent plants and stores them
    underground) were collected from within the treated area 2 months
    after the application.  No TCDD was found in the beavers using a
    method sensitive to 3 parts per trillion.

    TCDD is immobile in soil (Helling et al 1973).  The possibility of
    ground water contamination in virtually non-existent (Kearney et al,
    1972).  A recent National Academy of Science report on drinking water
    stated that 2,4,5-T and TCDD had never been detected in drinking
    water; the limit of detection was in the parts per trillion (National
    Research Council 1977).  Following treatment of brush with 2,4,5-T in
    Texas, soils, lake sediments, organic matter, turtles and fish tissues
    were analysed for residues of TCDD.  None of the samples collected
    over a 13-month period contained TCDD (Garcia et al., 1979), when a
    method of analysis sensitive to TCDD only at ppb level was used.

    METHODS OF RESIDUE ANALYSIS

    Methods for the determination of TCDD in 2,4,5-T and related materials
    have been published by Dow Chemical Company (1975).  These are capable
    of determining TCDD at levels down to 0.01 mg/kg.

    The various analytical techniques for the determination of 2,4,5-T
    residues are documented and described in several reviews (Thier, 1974;
    Cochrane and Purkayastha, 1973; Yip, 1975; National Research Council
    of Canada, 1978).  Gas chromatographic analysis is most commonly used
    for the estimation.

    Several studies have confirmed the conjugation of
    chlorophenoxyalkanoic acids with plant substituents.  Such conjugation
    has occurred as ester linkages with glucose and as amide linkages with
    amino acid and proteins.  Therefore, tissues for analysis of 2,4,5-T
    residues require a preliminary liberation of these "recalcitrant"
    residues when present.  This can be achieved by incorporating a
    hydrolytic extraction step.  However, extraction of 2,4,5-T by
    acidified organic solvents has been used in the majority of published
    methods with no provision for a hydrolysis step.  Hence "recalcitrant"
    residues have previously gone undetected.

    For residue monitoring, conversion of the free acids to the methyl
    ester using boron trifluoride has proved to be the most popular
    derivatizing procedure.  The methylation is simple to carry out, does
    not require specialised equipment, gives almost 100% conversion to the
    methyl ester and introduces the least contamination by interfering

    compounds.  A clean-up stage, commonly with a Florisil column, is
    frequently included after derivatization.

    Residues of TCDD might be expected to be found in environmental
    components in the range of 1-10 ng/kg (parts per trillion).  The only
    methodologies developed to date which are capable of this sensitivity
    are high resolution mass spectrometry and high resolution mass
    spectrometry/gas chromatography (Stehl et al., 1979).  The
    time-consuming cleanup for the detection of dioxins and the expense of
    the instrumentation for this detection indicate than an extensive
    monitoring programme for dioxins in the environment is not too likely
    in the immediate future.

    NATIONAL MAXIMUM RESIDUE LIMITS

    Few national governments appear to have established maximum residue
    limits for 2,4,5-T in raw agricultural commodities.  The following
    limits were reported to the meeting.

                                                        mg/kg
    Australia

    potable water                                       0.02

    Germany

    wild mushrooms                                      2
    other food of plant origin                          0.05

    Netherlands

    fruit, vegetables (not potatoes)                    0
    spices                                              0

    Switzerland

    cereals                                             0.01

    APPRAISAL

    2,4,5-T herbicides have been used extensively for almost 30 years for
    the control of woody weeds of range land, pasture, forests, some
    cereal crops, rice, sugarcane, as fruit setting and stop-drop sprays
    on certain crops such as apricots and apples and for the control of
    unwanted vegetation on industrial land, rights-of-way, etc.

    Commercial 2,4,5-T can contain traces of the toxic dioxin TCDD.  The
    meeting was informed that in recent years all known manufacture has
    ensured that the TCDD content is below the upper limit recommended by
    FAO (0.1 mg/kg).

    Following the evaluation of 1970 extensive data have become available
    on the nature and fate of 2,4,5-T and TCDD residues in many

    environmental components including food crops, livestock and water.
    These data indicate that approved uses of 2,4,5-T herbicides are
    unlikely to give rise to residues in drinking water or in food at
    levels above 0.02 mg/L and 0.05 mg/kg respectively.  Wild mushrooms
    and wild vaccinium berries gathered from recently sprayed forests may
    contain residues at levels of the order of 2 mg/kg and 5 mg/kg
    respectively.  This view is confirmed by extensive monitoring
    programmes which have failed to detect residues in food components or
    water at levels much above the limit of determination.

    In the case of food crops on which 2,4,5-T is applied, the meeting
    recommended that the MRL be at or about the limit of determination.

    Following the request of the previous meeting, methods for the
    determination of TCDD in 2,4,5-T and formulations, have become
    available with a limit of determination in the region of 0.01 mg/kg.
    These are being employed to monitor the quality of 2,4,5-T herbicides
    on the world market.  In view of the low level of TCDD in technical
    2,4,5-T and in formulated 2,4,5-T herbicides (0.01 mg/kg), the rate of
    use of 2,4,5-T, the situations in which it is used and the knowledge
    that TCDD is readily degraded in sunlight, the meeting agreed that
    there was no likelihood of TCDD residues occurring in food.

    RECOMMENDATIONS

    The following limits apply to 2,4,5-T determined and expressed as
    2,4,5-trichlorophenoxy acetic acid:

                                                                  
           Commodity                                 MRL (mg/kg)
                                                                  
           Apples, apricots                             0.05*
           Barley, oats, rice, rye, wheat               0.05*
           Sugarcane                                    0.05*
           Milk, meat, meat by-products, eggs           0.05*
           Cereal straw                                 2
                                                                  

    (*  At or about the limit of determination.)

    Further Work of Information

    Required by 1981:

    1.  Information on the level of 2,3,7,7-tetrachlorodibenzo-p-dioxin in
        2,4,5-T from a wide range of manufacturers;

    2.  Studies on the potential of bioaccumulation of the 2,4,5-T
        contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin in mammalian
        tissues.

    Desirable:

    1.  Studies to investigate the possibility of interaction between
        2,4,5-T and 2,3,7,8-tetrachlorodibenzo-p-dioxin with respect to
        carcinogenic potential;

    2.  Data on epidemiological studies with 2,4,5-T.

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    See Also:
       Toxicological Abbreviations
       T, 2,4,5- (AGP:1970/M/12/1)
       T, 2,4,5- (Pesticide residues in food: 1981 evaluations)