-  January 1992
                   Health  and Ecological Criteria Division
                       Office of Science and  Technology
                                Office of Water
                     U.S. Environmental  Protection Agency
                             Washington, DC  20460
                                                            Printed on Recycled Paper


                                              January  1992


Health and Ecological Criteria Division
   Office  of Science and  Technology
            Office of Water
 U.S.  Environmental  Protection Agency
         Washington, DC  20460


                                 TABLE  OF  CONTENTS


      LIST OF TABLES	      vii

      FOREWORD	     viii


  I.  SUMMARY	      1-1


      A.   General  Properties	. .	     II-l
      8.   Occurrence	     II-4
      C.   Environmental  Fate	     11-4


      A.   Absorption	    III-l
      B.   Distribution	    III-l
      C.   Metabolism	    III-2
      0.   Excretion	    III-2
      E.   Bioaccumulation  and Retention	  .    III-4
      F.   Summary	    111-4



      A.   Short-term Exposure	      V-l

          1.  Lethality	      V-l
          2.  Other Effects	      V-3
          3.  Dermal/Ocular Effects   	      V-6

      B.   Long-term Exposure  	      V'6
      C.   Carcinogenicity	      V-9
      0.   Reproductive/Teratogenic  Effects 	  ... 	     V-10
      E.   Mutagenicity	     V-13

          1.  Gene Mutation Assays  (Category  1)   	     V-16
          2.  Chromosome Aberration  Assays (Category  2)   	     V-18
          3.  Other Mutagenic Mechanisms (Category  3)   	     V-19
          4.  Conclusions	     V-19

      F.   Summary	     V-20

 VI.  HEALTH EFFECTS IN HUMANS 	  .....     Vl-1

                            TABLE OF CONTENTS (continued)



       A.  Mammals	     VII-1
       8.  Plants	     VII-1
       C.  Synergistic Effects  	     VII-1
       D.  Summary	     VII-1


       A.  Procedures for Quantification of Toxicological Effects ....    VIII-1

           1.  Noncarcinogenic Effects  	    VIII-1
           2.  Carcinogenic Effects 	    VIII-4

       B.  Quantification of Noncarcinogenic Effects for Picloram ....    VIII-6

           1.  One-day Health Advisory  	    VIII-6
           2.  Ten-day Health Advisory  	    VIII-6
           3.  Longer-term Health Advisory  	    VIII-7
           4.  Reference Dose and Drinking Water Equivalent  Level    .  .  .    VIII-9

       C.  Quantification of Carcinogenic Effects for Picloram  	   VIII-10
       D.  Summary  .	VIII-11

  IX.  REFERENCES	      IX-1

Table No.
1 1 -2

Physical and Chemical Properties of Picloram . 	

Tolerances for Picloratn 	 	

Summary of Quantification of Toxicological Effects for

     Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986,
requires  the Administrator of the Environmental Protection  Agency to publish
Maximum Contaminant Level Goals (MCLGs) and promulgate National Primary Drinking
Water  Regulations  for  each  contaminant,  which,   in  the  judgment  of  the
Administrator, may have an  adverse effect on public health  and which is known or
anticipated to occur in public water systems.  The MCLG is  nonenforceable and is
set at a level  at which  no known or anticipated adverse health effects in humans
occur and which allows for an adequate margin  of safety.   Factors considered in
setting the MCLG include health effects data and sources of exposure other than
drinking water.

     This  document provides  the  health  effects  basis   to  be considered  in
establishing the MCLG.   To achieve this objective,  data  on  pharmacokinetics,
human exposure, acute and chronic toxicity to  animals and  humans, epidemiology,
and mechanisms  of toxicity  were evaluated.    Specific  emphasis is  placed  on
literature data providing dose-response information.  Thus, while the literature
search and evaluation performed  in support of this document was comprehensive,
only the  reports considered  most pertinent in the derivation of the MCLG are
cited in the document.  The comprehensive literature data base  in  support of this
document includes information published up to April 1987;  however,  more recent
data  have been added  during  the review process  and in response  to  public

     When adequate health effects data exist,  Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime) are included in this document.   These values are not
used in setting the MCLG, but serve as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.

                                                                James R.  Elder
                                     Office of Ground Water and Drinking Water

                                                               Tudor T.  Davies
                                               Office of Science of Technology
                                      vi ii

                                  I.  SUMMARY

     Picloram (4-amino-3,5,6-trichloropicolinic acid) is a widely used herbi-
cide available in a number of formulations under the trade name Tordon®.   The
acid form is soluble in water at 0.4 g/L, and its salts are highly soluble
(greater than 400 g/L at 25°C).  The solubility of the acid in organic solvents
(acetone) is 19.8 g/L.  Picloram is stable in dilute aqueous solution, but it
is subject to both photochemical degradation (half-life in water of about 2 to
7 days) and microbial degradation.  Picloram is relatively persistent in  soils
(half-life of 30 to 400 days, depending on conditions) and is removed from soil
primarily by leaching following rain or irrigation.

     Picloram is readily absorbed (90%) from the gastrointestinal (GI) tract of
mammals.  It distributes throughout the body, with some preferential  accumula-
tion in the kidneys.  Picloram administered in a single dose is not significantly
metabolized {less than 20%) and i.s excreted unchanged (within 48 hours in
rats and dogs), primarily  (80 to 90%) in the urine, with some picloram appearing
in the feces.  Small amounts may appear in the milk of females.  Clearance of
picloram from the plasma is biphasic in rats, with halflives of 29 and 228
minutes.  In sheep, picloram is cleared within 96 hours.  Because of  its  rapid
clearance, significant accumulation and retention of picloram does not occur.
Picloram is rapidly absorbed from the human GI tract (90%) and is rapidly
excreted in the urine (75% within 6 hours) in an unaltered form.
     Humans may be exposed to picloram from drinking water, food, and amoient
air.  Picloram has been found in surface and groundwater samples at concentra-
tions of 0.13 ug/L and 1.00 ug/L, respectively (85th percentile for all non-
zero samples) (STORET, 1987).  Tolerances  for picloram on raw agricultural
products and foods cannot  be used to estimate typical dietary intake.

     Picloram is moderately toxic to animals, with 1050 values ranging from
about 1,500 mg/kg body weight (bw) in mice to 8,000 mg/kg bw in rats.   Clinical
convulsions, tremors), weakness, diarrhea, and weight loss.   The liver appears
to be the organ most affected by picloram.  Liver enlargement is a common
consequence in animals ingesting doses of 150 mg/kg/day or more.  Other tissues
are not seriously affected, although the incidence of renal  disease may be

     Chronic ingestion of picloram (370 to 740 mg/kg/day for 80 weeks)  induced
formation of neoplastic nodules of the liver in female rats.  No increase  in
tumors was observed in mice.  Although one study concluded that data suggested
the induction of benign liver tumors in female rats, this conclusion was not
substantiated in other studies.  Picloram has little mutagenic activity in
microbial systems, has little effect on animal reproduction, and is not
teratogenic.                                                    "               '

     Almost no information was found in the available literature regarding  the
effects of picloram on humans.  Picloram is poorly absorbed  through human skin,
and dermal application does not produce sensitization.

     The mechanism of picloram toxicity in animals has not been investigated.
Its herbicidal effectiveness is a consequence of its auxin-like activity, which
causes abnormal  plant growth and development.  In animals, no clear synergistic
interactions of  picloram with other chemicals have been observed.
     Using data  selected from the literature, a Ten-day Health Advisory (HA)
was calculated.   No information was found in the available literature  that  was
suitable for calculation of a One-day HA.  The Ten-day HA for a 10-kg  child
will be used at  this time as a conservative estimate of the  One-day HA. Using


a No-Observed-Adverse-Effect Level (NOAEL) of 200 mg/kg/day from a 14-day study
with dogs, a 10-day HA value of 20,000 ug/L was calculated for children.  Using a
NOAEL of 7 mg/kg/day from a 26-week study with dogs, Longer-term HA values of
70U and 2000 ug/L were calculated for children and adults, respectively.  A
NOAEL of 7 mg/kg/day from the same 26-week oral exposure study in dogs was used
to calculate a Reference Dose (RfD) of 0.07 mg/kg/day and a Drinking Water
Equivalent Level (DWEL) of 2000 ug/L for picloram.  All these calculations assume
that 100% of the human exposure to picloram is via drinking water, and are in
agreement with the Picloram Health Advisory of the U.S. EPA (1987).
     A Suggested-No-Adverse-Response Level (SNARL) for chronic exposure  to
picloram at 1.05 mg/L has been published by the National Research Council.
Tolerance levels of picloram  in food established  by the U.S. EPA under FIFRA
range from 0.05 ppm in milk and eggs to 5.0 ppm in kidney.




     Picloram (4-amino-3,5,6-trichloropicolinic  acid)  is  a  polychlorinated
aromatic hydrocarbon with the structure shown below.
     The free acid is slightly soluble in water (0.4 g/L  at  25aC)  but  more  sol-
uble in organic solvents (e.g., 19.8 g/L at 25°C in acetone);  picloram potas-
sium and amine salts are highly soluble in water (greater than 4UO g/L at 25°C)
(WSA, 1967; NRCC, 1974).  The chemical and physical properties of  picloram  are
summarized in Table II-l.
     Picloram is manufactured from o-picoline in a series of reactions begin-
ning with AlC^-catalyzed chlorination, followed by selective amination and
hydrolysis (NRCC, 1974).  Picloram is widely used as a broad spectrum  herbicide
for the control of broadleaf and woody plants in rangelands, pastures, and
rights-of-way for power  lines and highways.  It is commercially available under
the trade name Tordon* in a variety of concentrations and formulations (Table
11-2), some containing 2,4-dlchlorophenoxyacetic acid (2,4-D),  "Agent White,"
a mixture of picloram and 2,4-0, was widely used as a defoliant in Vietnam.  In
1982, it was reported that U.S. production of picloram was 0.3 million pounds
per year (CEH, 1985).
     Dilute solutions of picloram are stable in water, but picloram is subject
to photochemical degradation  with a half-life  of 2 to 7 days in water depend-
ing  on the concentration of humic substances,  light intensity, and pH (Plimmer,

    Table  II-l.   Physical  and  Chemical  Properties of Picloram
Chemical Abstracts  Service
(CAS) Registry Number

Registry of Toxic Effects of
Chemical Substances  (RTECS)

Chemical formula

Molecular weight

Physical state and color

Boiling point

Melting point

Vapor pressure

Absorption spectrometry

Solubility (at 25°C)

   Free acid in water
   Free acid in acetone
   Potassium salt in water

Amdon; 4-amino-3,5,6-
trichloro-2-picolinic acid;
ATCP; Borolin; K-PIN;
Tordon (see Table II-2)

Unite powder


215°C (decomposes)

6.2 x 10-7 nimHg  at 25°C
1.07 x 10-6 mmHg at 45°C

Max 223.5 nm in H20
285 nm in 6 N HC1
0.4 g/L
19.8 g/L
400 g/L
SOURCE:  Adapted from NIOSH (198U); Sittig (1981); Dow (1983a).

                  Table  II-2.  Available Picloram Formulations
 Active ingredients
(percent equivalent)
Tordon 101*
Mixture weed
and brush
Tordon K*
Tordon 22K«
Weed killer
Tordon 2K«

Tordon 10K*

Tordon 101«
Tordon RTU»
6.5% picloram as
salt; 23.9% 2,4-D as
tri i sopropanolami ne

2.3% as potassium

23.3% picloram as
potassium salt
2% picloram as
potassium salt

10% picloram as
potassium salt

3.2% picloram as
tri i sopropanol ami ne
salt; 11.9% 2,4-D as

3.2% picloram as
tri i sopropanolami ne
salt; 11.9% 2,4-D as
tri i sopropanolami ne
Contains a glycol derivative
sequesterant and glycol
wetting agent along with
alcohol and water
Contains glycol and sorbitol
ester-type wetting agents
along with alcohol and water

Ethylene glycol
Ethylene glycol
SOURCE:  Adapted from Dow (1983a); NRCC (1974)

 1970; Mulllson,  1982; Skurlatov et al., 1983).  Picloram also undergoes concen-
 tration-dependent autocatalytic hydrolysis  (Haas et al., 1971).  Picloram is
 relatively persistent in soil, with a half-life ranging from 30 to 400 days,
 depending on conditions  {Bovey et al., 1969; Foy, 1976).  Picloram is removed
 from soil primarily by leaching, but photodegradation and aerobic bacterial
 degradation also contribute to reductions in soil concentrations (Mullison,  1982;
 Meikle et al., 1974).


     Picioram has been found in 359 of 653 surface water samples analyzed and
 in 5 of 77 groundwater samples analyzed (STORE!, 1987).  Picloram was found  in
 seven States in which samples were collected at 124 surface water locations  and
 49 groundwater locations.  The 85th percent!le of all nonzero samples was 0.13
 ug/L in surface water samples and 1.00 ug/L in groundwater samples.   The
maximum concentration found was 4.6 ug/L in surface water and 1.00 ug/L in


     The main processes for dissipation of picloram in the environment are
photodegradation and aerobic degradation in soil.  Field tests conducted in
Texas with a liquid formulation of picloram have indicated that approximately
 74% of the picloram originally contained in the test ecosystems, which included
the soil, water, and vegetation,  dissipated within 28 days  after application
 (Scifres, 1977).

     Photodegradation of picloram occurs rapidly in water (Hamaker,  1964;
 Redemann, 1966; Youngson, 1968; Youngson and Goring, 1967), but is somewhat
 slower on a soil surface {Bovey et al., 1970;  Merkle et al., 1967; Youngson  and
 Goring, 1967).  Hydrolysis of picloram is very slow (Hamaker, 1976).

      Laboratory studies  have shown that under aerobic conditions in soil, tne
half-life of picloram  is  dependent upon the concentration, the temperature, and
the moisture content of the soil.  The major degradation product is COg, with
other metabolites present in insignificant amounts (McCall and Jefferies, 1978;
Merkle et al., 1967; Meikle et al., 1970, 1974; Meikle, 1973; Hamaker, 1975).
In the absence of light and under anaerobic conditions in soil or water, pic-
loram degradation is extremely slow (McCall and Jefferies, 1978).

      Following normal  agricultural, forestry, and industrial applications of
picloram, long-term accumulation of picloram in the soil  generally does not
occur.  In the field,  dissipation of picloram will occur at a faster rate in
hot,  wet areas compared with cool, dry locations (Hamaker et al., 1967).  The
half-life of picloram  under most field conditions is a few months (Youngson,
1966).  The potential for picloram to move off treated areas in runoff water is
typically very small (Fryer et al., 1979).  Although picloram is considered to
have moderate mobility in soil  (Helling, 1971a,b), leaching is generally
limited to the upper portions of most soil profiles (Grover, 1977).  Instances
of picloram entering the yroundwater are largely limited  to cases involving
misapplication or unusual soil  conditions (Frank et al.,  1979).


                              III.  TOXICOKINETICS

     Except for one human study (Nolan et al., 1984) on absorption  and excre-
tion of picloram administered to human volunteers, all  data in  this  section  are
derived from animal studies.
     Picloram (1,400 mg/kg)  was rapidly and almost completely absorbed (80 to
84%) from the GI tract of rats after 48 hours (Nolan et al., 1980).  Fisher et
al. (1965) administered one Holstein cow (weight, approximately 500 kg; food
consumption, 22.7 kg/day) 5 ppm picloram in feed for 4 days (estimated to equal
0.23 mg/kg/day).  Ninety-eight percent of the total dose was excreted in the
urine, demonstrating nearly complete absorption.  Similar results were observed
in three male CDF Fischer rats receiving l^C-picloram (dose not specified),
where 95% of the dose was absorbed (Dow, 1983b).  Nolan (1984) reported that
results of an oral metabolism study on human volunteers indicated that picloram
was rapidly absorbed (half-life, 20 minutes) from the gastrointestinal tract.
An average of 93.8% of the total radioactivity was excreted in the urine after
72 hours postdose as unchanged picloram.
     Picloram appears to be distributed throughout the body, with the highest
concentration in the kidneys.   In rats  (species,  age, sex not specified) admin-
istered a single dose of 14c-labeled picloram (20  ppm) in food, radioactivity
was found in abdominal fat, liver, muscle, and kidneys, with peak levels occur-
ring 2 to 3 hours after  dosing  (Redemann,  1964).

      Hereford-Hoi stein  steers,  fed daily picloram doses of 200 to 1,600 ppm
 {2.6  to  23 mg/kg/day) for 2 weeks, had tissue concentrations of 0.05 to 0.32
 mg/kg in muscle, 0.06 to 0.45 mg/ky in fat, 0.12 to 1.6 mg/kg in liver, 0.18 t<
 2.0 mg/kg in blood, and 2 to 18 mg/kg in kidney (Kutschinski and Riley, 1969).
 In a  similar study, two steers  (species not specified) fed 100 or 200 ppm
 picloram (3 or 6 mg/kg/day) for 31 days had kidney levels of 4 or 10 mg/kg,
 while concentrations in other tissues {muscle, omentum fat, heart, liver, and
 brain) were less than 0.5 mg/kg (Leasure and Getzander, 1964).


      Picloram administered to rats, dogs,  or cattle was excreted in urine in
 unaltered form (Fisher et al., 1965; Nolan et al., 1980; Dow, 1963, 1983b),
and no 14C02 was detected in expired air of rats given 14C-picloram (Redemann,
 1964; Nolan et al., 1980;  Dow, 1983b).   These studies  indicated that picloram
 is not significantly metabolized in mammals (Kedemann, 1964; Fisher et al.,
1965; and Nolan et al., 1980).

     Picloram is excreted primarily in  the urine of experimental  animals
(Fisher et al., 1965;  Nolan et al., 1980;  and Redemann, 1964).  Rats (male
Fischer 344), administered a single oral  dose of 1,400 mg/kg bw,  excreted 80 to
84% of the dose in the urine (within 48 hours); 15% in the feces; less than
0.5% in the bile; and  virtually no measurable amount as expired C02 (Nolan et
al., 1980).  Similar results were observed in dogs (Dow, 1963).  Two beagles
 (one male and one female)  received 100  ppm unlabeled picloram (the ammonium salt:
of 4-amino-3,5,6-trichloropicolinic acid)  in the diet for 1 week followed
by 14c-picloram in the diet for 5 days.   The dogs  were then returned to a diet

containing unlabeled picloram until no more radioactivity was excreted in the
urine or feces.  Approximately 90% of the total dose was excreted in the urine
within 48 hours after the last radioactive feeding, and L to 2% was  excreted
in the feces.  One Holstein cow fed 5 ppm (approximately 0.23 mg/kg/day based
on a body weight of 500 kg and food consumption of 22.7 kg/day) .picloram in
feed for 4 days excreted over 971 of the dose in the urine (Fisher et al.,
1965).  In male Fischer 344 rats orally administered 10 mg/kg bw, clearance  of
picloram from the plasma was biphasic, showing half-lives of 29 and  228 minutes.
When administered the same dose intravenously, biphasic clearance occurred with
half-lives of 6.3 and 128 minutes {Nolan et al., 1980).  Two sheep (strain and
sex not specified) fed 200 ppm picloram (8.8 mg/kg/day) for 7 days cleared the
picloram from their plasma within 96 hours, corresponding to a half-life of
about 21 hours (McCollister and Leng, 1969).
     Cattle also excrete picloram primarily in the urine (Fisher et  al., 1965},
but small amounts may also appear in milk (Kutschinski, 1969).  In Holstein
cows fed picloram for 6 to 14 days at doses of 2.7 mg/kg/day or less, no pic-
loram could be found in milk; while cows fed picloram at doses of 5.4 to 18
mg/kg/day had milk levels up to 0.28 mg/L (Kutschinski, 1969).  This corre-
sponds to only about 0.02% of the ingested dose.  When picloram feeding was
discontinued, milk levels of picloram were undetectable within 58 hours.
     Nolan et al. (1984) studied the fate of picloram in humans.  Six male
volunteers (40 to 51 years old) ingested single oral doses of 5 or 0.5 mg/kg in
approximately 100 ml of grape juice.  Picloram was rapidly absorbed.  Over 75?.
of the dose was excreted (unchanged) in the urine within 6 hours (tyg s 2*9
hours), and the remainder was eliminated with an average half-life of 27 hours.
A total of more than 90% of the administered dose was recovered.  Thus, excretion

of picloram in humans may be biphasic, as has been demonstrated in rats (Nolan
et al., 1980).


     Although picloram is readily absorbed from the gut, its rapid excretion in
urine prevents marked accumulation in the body.  Kutschinski and Riley (1969)
administered picloram {23 mg/kg/day)  to steers for 14 days and measured tissue
levels in animals killed immediately or 3 days after the last dose.  Initial
values of 18 mg/kg in the kidneys and 0.05 to 2 mg/kg in other tissues fell  to
0.06 mg/kg in the kidneys and less than 0.05 mg/kg in other tissues by the end
of 3 days.


     Picloram is readily absorbed from the gastrointestinal tract of mammals.
It distributes throughout the body, with the highest accumulation in the kid-
neys.  Picloram is not significantly  metabolized, and is excreted unchanged,
primarily in the urine.  Low levels may appear in the milk.  When exposure
ceases, picloram is rapidly depleted  from blood and tissues without significant

                              IV.  HUMAN EXPOSURE

     Humans may be exposed to chemicals such as picloram from a variety  of
sources including drinking water, food, ambient air,  and occupational  settings.
This analysis of human exposure to picloram is limited to drinking water,  food,
and ambient air, since these media are sources common to all  individuals.
     Information concerning the occurrence of and exposure to picloram in  the
environment is presented in another document entitled "Occurrence of  Pesticides
in Drinking Water, Food, and Air" (Johnston et al., 1984).  Data obtained  on
levels of picloram in drinking water, food, and ambient air presented in the
document were not sufficient to determine the intake of picloram from any  of
those sources.  In addition, tolerances for picloram in and on raw agricultural
products and in foods (Table IV-1) cannot be used to estimate typical  dietary

                      Table IV-1.  Tolerances for Picloram
                  Food or commodi ty
^Excluding flour.
^Excluding kidney and liver.

SOURCE:  Adapted from U.S. EPA (1979,  1981).
Tolerance (ug/kg)
Barley, milled fractios*
Oats, milled fractions*
Wheat, milled fractions*
Raw agricultural commodities
Green forage
Meat by-productsb
Eggs /mi Ik /poultry
Grasses, forage





                         V.  HEALTH EFFECTS IN ANIMALS


1.   Lethality

     Lethal doses of picloram have been estimated In a number of species,  and
the results are summarized in Table V-l.  LDso values range from approximately
1,500 rag/kg bw in mice to 8,200 mg/kg bw in rats (NIOSH,  198U; Dow,  1983b).

     The acute oral toxicity of XRM-4716 herbicide formulation (greater than
32% butoxy ethyl ester of triclopyr and 17% picloram) to  groups of six male  and
six female Fischer 344 rats was determined.  The rats were administered doses
of 630, 1,300, 2,500, 3,200 mg/kg {males only), 4,000 mg/kg (males only),  or
5,000 mg/kg and observed for 2 weeks.  The LDjQ values were estimated at 3,383
and 2,526 mg/kg for males and females, respectively.  The following  clinical
signs of toxicity were observed:  diarrhea (630, 1,300, 4,000, 5,000 mg/kg);
shallow breathing (2,500, 5,000 mg/kg); palpebral closure and/or watery eyes
(2,500, 5,000 mg/kg); lethargy (2,500 to 5,000 mg/kg); and unconsciousness
(5,000 mg/kg) (Carreon et al., 1983b).
     Hayes et al. (1986) administered, by gavage, a single dose of 500 to  1,250
mg/kg of aqueous potassium picloram to groups of five male Sprague-Oawley  rats.
Five female rats were administered doses ranging from 600 to 850 mg/kg. Animals
were observed for toxicity for  14 days.  The acute oral LDsg was 954 (95%  con-
fidence limit, 812 to 1,120) my/kg for males and 686 (95% confidence limit,  599
to 786) mg/kg for females.  Females appeared to be more sensitive to acute
toxicity than males.  Depression, prostration, ataxia, tremors, and convulsions
preceded death.  In this study, the pH of me dosing solution was greater than
11, and the authors reported that attempts to neutralize the  solution resulted

       Table V-l.  Acute Oral Toxicity of Picloram
 LD50 (mg/kg)
Guinea pig
686 (females)
954 (males)
2,525 (females)
3,383 (males)
8,200 (females)
2,000 to
4,000 (females)
3,000 (females)
6,000 (males)
Hayes et al. (1986)

Carreon et al.
NIOSH (1980)
Dow (1983b)
NIOSH (1980)
Dow (1983b)

NIOSH (1980),
Dow (1983b)
NIOSH (1980),
Dow (1983b)
NIOSH (1980)
Dow (19835)

in precipitation of picloram.  Therefore,  the animals  received  the dosing
solution unneutralized.  The LDgg values obtained from this  study were  low
compared to the values in rats obtained by other investigators.  This was
probably due in part to the extreme alkalinity of the  dosing solution.
Therefore, the LDso values obtained from this study were considered to  be
2.   Other Effects
     Six Fischer 344 rats/sex were administered, by gavage,  a  single  dose  of
5,000 mg/kg of undiluted XRM-47U3 (4-amino-3,5,6-trichloropicolinic 26.9%,
3,6-dichloropicolinic acid 19.8%) and observed for 2 weeks.   All  animals sur-
vived the observation period, gained weight, and exhibited no toxic signs
(Carreon et al., 1983a).
     Hayes et al. (1986) noted that there were no consistent biologically
significant compound-related effects on fluid consumption, body weight, mortality,
hematology, clinical chemistry, urinalysis, or organ weights in rats  that
received 60, 190, or 600 mg/kg/day potassium picloram in the drinking water for
14 days.  A NOAEL of 600 mg/kg/day, the highest dose tested, was  identified.
     In a range-finding study in dogs (Dow, 1981b), two female beagles (one
animal/dose) received gelatin capsules containing approximately 400 or 800
mg/kg/day of picloram (adjusted for a purity of 79.1%) for 7 consecutive days.
A third female  received picloram at 1,600 mg/kg/day for 4 consecutive days.
All dogs were observed a total of  14 days.  Acute toxicity evidenced  by loss of
body weight, inactivity, and listlessness was noted in the dogs receiving  800
or 1,600 mg/kg/day during the entire observation period.  A NOAEL of  400 mg/kg/
day was suggested by this study.

     In a subsequent short-term feeding study, beagles (one animal/dose)
received approximately 200, 400, or 800 mg/kg/day (adjusted for a purity  of
79.4%) of picloram in the diet for 7 days.  An additional  dog received picloram'i
in the diet at 400 my/kg/day for 14 days.  A sharp decrease in food consumption
resulting in weight loss was noted in dogs fed 400 or 800  mg/kg/day.   However,
no control was used in this study and, therefore, the decreases in  food
consumption and body weight noted in treated dogs could not be compared to the
food consumption and body weight gains of untreated dogs.   A NOAEL  of 200
mg/kg/day was identified in this study (Dow, 1981c).
     Dow (1980) conducted a feeding study in mice in which groups of six
mice of each sex received 0, 90, 270, 580, 900, or 2,700 mg/kg/day picloram
(adjusted for a purity of 89%) in the diet for 32 days.  Significantly increased
(p <0.05) relative liver weights (g/100 g body weight) were noted in females
receiving picloram at 2,700 mg/ky/day.  The NOAEL for this study was 900 mg/kg/\
day.                                                                           '

     Jackson (1966) administered picloram (as either the acid or the potassium
salt) in single oral doses  (method not specified) to 16 yearling sheep and 6
calves (strain and sex not specified).  The sheep (16 to 49 kg) received doses
at levels of 288, 432, 576, or 720 mg/kg bw (three to six animals/group).  The
calves (123 to 195 kg) received doses of 144, 216, 360, or 540 mg/kg (one to
two animals/group).  No signs of toxicosis were observed in any of the animals.
In an additional experiment, four sheep were given a daily acid picloram dose
of 18 mg/kg bw for 33 days; 10 sheep were given potassium picloram for 30 days
at a daily dose of 72 mg/kg (no other experimental details reported).  Body
weight of the treated sheep was comparable to that of the untreated controls.
Again, no adverse effects were reported.

     The clinical signs of picloram poisoniny are similar in most animals  and
include CNS toxicity as evidenced by ataxia, tremors and convulsions,  weakness,
diarrhea, and weight loss.  Palmer and Radeleff (1969)  attempted to calculate
the level at which signs of picloram poisoning occurred in cattle, sheep,  and
chickens orally administered picloram for 1U days.  Three cattle were  9 to 16
months old and of mixed breeding and sex.  Six sheep were primarily Delaine
ewes and wethers (age not specified).  Five chickens were White Leghorn
6-week-old cockerels.  Body weights were not reported.   There was a control
group for the chickens only (one or two animals).  The  cattle and sheep were
dosed, respectively, by drenching, and by balling gun and capsule.  The chickens
were dosed either by gavage or gelatin capsule.  A maximum of 10 daily doses of
picloram were administered at 10U, 250, or 500 mg/kg.  The cattle exhibited
toxic signs after 8 doses at the 500-mg/kg dose level,  and the sheep after 10
doses at 250 mg/kg.  Toxic signs included weakness, depression, and anorexia in
cattle and sheep.  Hemorrhagic lymph nodes, congested lung mucosa, and swollen
livers were observed at necropsy in one cow and one sheep.  After 10 days  at
each dose level, the only adverse effect noted in chickens was a significant
(p value not reported) decrease in average weight gain  (32 to 38%) as  compared
to the control group.  The NOAEL for sheep and a Lowest-Observed-Adverse-
Effects Level (LOAEL) for chickens was 100 mg picloram/kg bw.  The 250 mg/kg
concentration represents a NOAEL for cattle.
     Thompson et al. (1972) dosed groups of 35 pregnant Sprague-Dawley-derived
rats by gavage at levels of 500, 750, or 1,000 mg picloram/kg on gestation days
6 through 15.  At the 750- and 1,000-mg/kg/day concentrations, mild diarrhea
and hyperesthesia were observed after one to four treatments; 14 maternal  deaths
occurred between days 8 and 17 of gestation in these groups.  There were no
toxic signs at the 500-my/kg dose level.

3.   Dermal/Ocular Effects

     Most  formulations of picloram have been studied for their potential  to
produce skin sensitization reactions in humans.  Dow (1981) reported that
Tordon* 22K was not a sensitizer following an application as a 5% solution.  A
formulation of Tordon* 101 containing 6% picloram acid and 2,4-0 acid as  a 5%
aqueous solution was not a sensitizer in humans (Gabriel and Gross,  1964).
When the triisopropanolamine salts of picloram and 2,4-D (Tordon* 101)  were
applied as a 5% solution, sensitization occurred in several individuals;  how-
ever, when applied alone, the individual components were not reactive.


     B6C3Fi mice were administered 0, 1,000, 1,400, or 2,000 mg picloram/kg/day
in the diet for 13 weeks (Tollett et al., 1980).  Each dose group contained 10
mice/sex/dose.  Liver weights were significantly increased (no p value  reported)
in females at all dose levels, and in males at the 1,400- and 2,000-mg/kg con-
centrations.  These changes were accompanied by morphological alterations of
hepatocytes in the same groups.  No other treatment-related changes  were  noted.
Thus, based on the observed liver effects, 1,000 mg/kg/day represented  a  LOAEL
with a NOAEL of <1,000 mg/kg estimated from this study.

     In another subchronic (13-week) study, CDF Fischer 344 rats (15/sex/dose)
were fed 0, 15, 50, 150, 300, or 500 mg picloram/kg/day.  Body weights  were not
affected by the exposure to picloram.  Significant (p 
function were observed.  A dose of 5U mg picloram/kg/day  was  stated  to  be  the
NOAEL  (Gorzinski et al., 1982).
     Hayes et al. (1986) found similar toxicological  manifestations  when 60,
190, 600, or 1,070 mg potassium picloram/kg/day was administered  in  the drinking
water for 90-days to 20 Sprague-Oawley rats/sex in the low- and mid-dose groups
and to 10 rats/sex in the high-dose group.   Animals received  fresh drinking
solutions twice weekly, and consumption was measured at each change. Mortality
was dose-dependent: mortality was 9/10 (males) and 7/10 (females) at the highest
dose (1,070 mg/kg/day) and 4/20 (males) and 2/20 (females)  at the 600 mg/kg
dose.  Mild kidney lesions (primarily in the tubular epithelium)  were noted  in
male rats receiving 60, 190, and 600 mg/kg, and were more prominent  at  the
600-mg/kg level.  Also noted were an increased incidence  of mononuclear liver
foci in male rats receiving 190 or 600 mg/kg and in females receiving 600
mg/kg.  No other compound-related lesions were seen.  A IOAEL of  60  mg/kg  is
derived for this study.
     A 6-month study was conducted with beagle dogs that received daily doses
of 0, 7, 35, or 175 mg picloram/kg bw (six/sex/dose) in the diet  (Dow,  1982).
Statistically significant  (p  <0.05) increased  absolute and relative  liver
weights, decreased body weights and body weight gains, decreased  food consump-
tion, and changes in  liver enzymes were observed at the highest dose (175
mg/kg) for both males and females, and statistically significant  increased
absolute and relative  liver weights were seen  at the intermediate dose  (35
mg/kg) for males only.  The 7-mg/kg/day dose  level was considered to be the
     Symptoms observed  in Osborne-Mendel rats  (50/sex/group) given picloram in
the  diet in time-weighted  average  doses of  7,437 or  14,875 ppm (equivalent to
370  or 740 mg/kg/day  calculated using  Lehman,  1959}  for 80 weeks included rou^n
hair coats, pale mucous  membranes,  dermatitis, alopecia, tachypnea,  discolored

urine, diarrhea, abdominal distention, and vaginal bleeding (NCI, 1978).  After
2 years, renal disease was also observed in rats receiving 370 to 740 mg/kg/day .<
in the diet, although it  is not clear if this was a consequence of picloram-    M
induced toxicity or the natural aging process.  Parathyroid hyperplasia was
also observed in this study, but this phenomenon has been shown to occur in
end-stage renal disease when decreased renal  phosphate clearance occurs (Chevilla,
1976).  Other changes of  uncertain significance observed in the picloram-treated
rats and mice include polyarteritis, thyroid hyperplasia, and adenoma.  There
were apparent increases in testicular atrophy in male rats fed picloram.
Incidences of 14 and 28% were noted in the 370- and 740-mg/kg/day group,
respectively.  However, this lesion was also noted in 5 of 10 control rats
examined.  Therefore, the increases noted in picloram-treated rats did not
appear to be treatment related.

     Landry et al. (1986) administered 0, 20, 60, or 200 mg/picloram (93%
pure)/kg bw in the diet to Fisher 344 rats (50 rats/sex/dose) for 2 years.      j
Interim sacrifices were performed on 10 rats/sex/dose at study months 6 and 12.
No overt signs of toxicity and no biologically significant effects on body
weight, food consumption, or clinical laboratory parameters were observed in
these animals.  Relative  liver weights were increased in both sexes at the
60-mg/kg/day dose level  at 6 months and at the 200 rag/kg/day level at both 6
and 12 months.  Slight increases in the size and pallor of centrilobular hepato-
cytes were observed at 6 months in_.these two dose groups.  This effect did not
increase 1n severity from 6 to 12 months and was not accompanied by overt
hepatocellular degeneration or necrosis.
     There were no overt signs of toxicity in terminal survivors.  Further-
more, there were no treatment-related effects on mortality, body weight, food

consumption, clinical  pathology parameters,  or gross pathological  findings.  A
statistically significant (p <0.05) increase in the incidence of minimally
increased size and altered tinctorial  properties of the centrilobular  hepato-
cytes that was attributable to treatment was observed in rats of both  sexes
receiving 6U and 200 mg/kg/day.  Males were  apparently more sensitive  than
females, since the changes were more pronounced in males.  Picloram ingestion
did not induce hepatocellular necrosis (Landry et al., 1986).  A NOAEl of
20 mg/kg/day was identified.


     Picloram (at least 90% pure) was  administered in the diet to Osborne-
Mendel rats and B6C3Fi mice (NCI, 1978) for 80 weeks, with rats observed for an
additional 33 weeks and mice for 10 weeks.  Thus, terminal sacrifices  were  at
113 weeks for rats and 90 weeks for mice.  Groups of 50 male and 50 female
rats received time-weighted average doses of plcloram at 7,437 or 14,875 ppm
(equivalent to 37U or 740 my/kg/day based on Lehman, 1959) in the diet.  Matched
controls consisted of 10/sex with pooled control groups of 30/sex.  In pic-
loram-exposed rats, a relatively high incidence of follicular hyperplasia,
C-cell hyperplasia, and C-cell adenoma of the thyroid was observed in both
sexes.  However, the incidence of thyroid adenoma was not statistically signif-
icant.  An increased incidence of hepatic neoplastic nodules {considered to be
beniyn tumors) was observed in treated rats.   In male rats, the lesion appeared
in only three animals of the low-dose treatment group and was not significant
when compared to controls.  However,  a significant dose-related trend was ob-
served in females  (p • 0.016).  The incidence  in the high-dose  female group was
significant  (p * 0.014) when compared with  that  of  the  pooled  control group.
The  incidences of  liver foci composed  of  eosinophilic  and/or clear hepatocytes

were  0/10, 8/5U, and  18/49  in matched controls,  low-dose, and high-dose female
rats,  respectively, and  0/10, 12/49, and 5/49 in matched controls, low-dose,
and high-dose male  rats,  respectively.  The  NCI  considered that the data were
suggestive of the induction of benign neoplastic nodules in the livers of
female rats.  Subsequent  laboratory review by the National Toxicology Program
(NTP)  has questioned  the  findings of this study because animals exposed to
known  carcinogens were placed in the same room with the study group, and
cross-contamination might have occurred.

      In the NCI (1978) study with mice, groups of 50 male and 50 female B6C3Fi
mice  received time-weighted average doses of 2,531 or 5,062 ppm (equivalent to
380 or 759 mg/kg/day based on Lehman, 1959) picloram in the diet.  No statisti-
cally  significant treatment-related increase in tumors was found.  It was
concluded that picloram was not carcinogenic in mice.

     No evidence for  carcinogenicity was observed by Landry et al. (1986)  in
a study in which male and female Fischer 344 rats received 2U to 200 my pic-
loram/kg bw in the diet for 2 years; while no increase in tumors was seen, a
statistically significant decrease in pituitary adenomas of male rats was


     There is little evidence to suggest that the oral administration of
picloram results in teratogenicity, developmental toxicity, or reproductive
toxicity in rats, mice, or rabbits.

     Groups of 4 male and 12 female rats were fed diets containing 0, O.U3,
0.1, or 0.3% (0, 15, 50, or 150 mg/kg/day based on Lehman, 1959) Tordon*
(95% picloram) through a  three-generation (two litters per generation) reproduc
tion and teratology study (McCollister et al., 1S67).  The rats were 11 weeks

old at the start of the study and were maintained on the test diets  throughout
the entire three-generation period.  After 1 month on the experimental  diet,
the animals were bred to produce the F^a generation.  Records were kept of
numbers of pups born live, born dead, OP killed by the dam;  litter size was
culled to eight pups after 5 days.  At 21 days of age, the pups were weaned  and
weighed.  After 7 to 1U days, the dam was bred for the F^ generation.   The
second generation (Fga and f^} was derived from F2b animals aged 110 days.   Two
weanlings per sex per level of both litters of each generation were  examined
for gross pathology.  Gross pathology was also performed on.all parent  rats  and
all females that did not become pregnant.  Five male and five female, weanlings
from each group of the f^b litter were randomly selected for gross and  microscopic
examination of the lung, heart, liver, kidneys, adrenals, pancreas,  spleen,  and
gonads.  Picloram reduced fertility by 42% in the F^ females of the 150-mg/kg/day
dose group, but this effect was judged as spurious since it was not  seen in
subsequent generations.  No other reproductive effects were noted.   A NOAEL
of 15U my/kg/day, the highest dose tested, was identified in this study.
     In the study described above {HcCollister et al., 1967), the Flc,  F2c,
and F3C litters were used to study the teratogenic potential of picloram.  The
dams were sacrificed on day 19 or 20 of gestation; offspring were examined for
skeletal and soft tissue anomalies, and  placentas were examined for  fetal
deaths or resorptions.  No teratogenic effects were observed at any  dose level.
     Hayden et al.  (1963) demonstrated that picloram had no effect on fertility
of female mice (strain and number not specified) when compared to an oral
contraceptive  (Enovida) containing norethynodril  (progestin)-and mestranol
(estrogen) in a ratio of 66:1.  Both picloram and the contraceptive  were fed to
fertile mice in the diet at approximate  dose  levels of 15 mg/kg/day.  The
female mice receiving the contraceptive  became  infertile during the treatment


 period,  whereas  female mice  receiving picloram  continued to  be fertile during
 the  treatment period.
      Sprague-Dawley  rats were  administered picloram by gavage on days 6 to 15  ''^
 of gestation at  dose levels  of 0,  500, 750, or  1,000 mg/kg/day (Thompson et
 al.,  1972).  Twenty-five females  in each  group  were killed on day 20, and their
 litters  were delivered by cesarean section; 10  additional dams per group were
 allowed  to deliver and wean  their  pups.   Mild diarrhea, hyperesthesia, and
 mortality were noted in the  dams  receiving 750  or 1,000 mg/kg.  Uterine find-
 ings  and postnatal evaluations revealed no toxic effects of  picloram; however,
 statistically significant increases (p <0.05) in unossified  fifth sternebrae
 indicated delayed fetal growth in  all picloram-treated groups.  In addition,
 increased incidences of accessory  ribs also reflected developmental  toxicity at
 1,000 mg/kg.  A  developmental LOAEL of 500 mg/kg/day, based  on the incidence of
 unossified sternebrae, was obtained in this study.
      — 	 	_ .	 „		„,. ,,.„.„.	 r	--.-.„ -„., „.,
 gestation days 6 though 18 at oral doses  of 0,  40, 200, or 400 my acid equivalent/
kg/day (John-Greene et al.,  1985).  Maternal  weight loss during the first 3
days of  treatment indicated  maternal toxicity at the 200- and 400-mg/kg dose
 levels.  Uterine implantation data, fetal weights, and fetal examinations,
 however, did not indicate developmental toxicity at any of these dose levels.
A NOAEL  for maternal toxicity of 4U mg/kg/day and a developmental NOAEL of
400 mg/kg/day (the highest dose tested) were identified.

     Japanese quail  fed technical picloram for  14 days (100 mg/kg feed, esti-
mated to equal  a daily dose  of 12.b mg/kg bw) showed no reduction in egg pro-
duction  or egg hatchability  (Kenaga, 196*).  A  higher daily dose (1,000 mg/kg
 feed, 12b my/kg  bw)  resulted in a  5U% decrease  in egg fertility during the

first week; however, egg fertility returned to normal  during  the  second week.
Quail fed a diet originally containing 100 rng/kg feed, and  then increased  over
1 year to 10,000 mg/kg feed, did not show any signs of reproductive  impairment.
     In studies on chicken and pheasant eggs, picloram in combination  with
2,4-dichlorophenoxyacetic acid (2,4-0) at use levels (10.2% picloram and  39.6%
2,4-0, applied at the maximum rate of 93.3 L/hectare,  Somers  et al., 1974c)
applied to fertile eggs prior to incubation, produced no detrimental effects  on
eyg hatchability or chick weights.  No increase in the incidence  of  teratogenic
effects was reported.  An additional study using chicken eggs exposed  to  pic-
loram technical at day 0, 4, and 18 of incubation produced  no adverse  effects
(Somers et al., 1974a,b,c).  Subsequent studies, utilizing hens and  cockerels
raised from eggs exposed to picloram and artificially inseminated, demonstrated
no detrimental effects in the offspring (Somers et al., 1978b).   Some  fertile
eggs from the treated parents were treated with picloram prior to incubation,
and no adverse effects were observed.  Picloram was detected  in the  tissues  of
the developing embryo in these studies, demonstrating that  it had penetrated
the egg shell.
     In the 2-year feeding study by NCI (1978) described previously, testicular
atrophy was observed in male Osborne-Mendel rats receving picloram at  370 or
74U mg/kg/day.  However, this lesion was also observed in control animals and,
therefore, was probably not due to picloram administration.
     The  limited number of genetic toxicology assays that have been  performed
with picloram are categorized into  gene mutation assays  (category 1),  chromo-
some aberration assays (category 2),  and studies that assess  other mutagenic

                                   Table V-2.   Genotoxicity of Picloram
Mortal mans
et al.
et al.
et al.
S. typnimurium
TA1535, TA1537,
TA97, TA98,
5 nonreported
doses +/- rat
and hamster S9
S. typhimurium     NRa
T8 his- strains)
                           Bacteriophage       NR
S. typhimurium     99.9%
TA1535, TA1536,
TA1S37, TA1538
                           200 ug/plate
                           (spot test)
                                                     detailed  priotc
                                                     for 270 coded
                                                     compounds ;!;al 1
                                Table V-2.   (continued)

et al.

et al.

et al.
et al .

endpoint Organism Purity
Gene Chinese hamster 93.4%
mutation ovary CHO/HGPRT

Sex-linked D. melanogaster NR

Chromosome Male and female 89%
aberration: rat bone marrow

Micronucleus Male and female 92%
induction mouse bone
Chromosome D. mel anogast_e_r Commercial
loss: grade
partial and

range Response
5 doses
(125 to 750
ug/mL -S9;
5 doses
(250 to 1,250
ug/mL +S9)
5,000 ppm
(3 days adult

1,000 ppm
Oral gavage:
20, 200,
2,000 mg/kg

Oral gavage:
171, 514,
1,543 mg/kg
650 ppm
(3 days adult

assayed to a
cytotoxic dos<

assay of 53 c-;
compounds ;
appropriate d<

maximum tola re
dose (MTO) riot
achieved; mite
cycle not ful "
numerous techf
Acceptable fo-
late stages ot
sperm cycle;
assayed to a
cytotoxic lev;


mechanisms (category 3).  The findings from the studies are discussed below and
summarized in Table V-2.

1.   Gene Mutation Assays (Category 1}

     a.  Mutation In microbial systems

     Picloram was tested by the National  Toxicology Program (Mortelmans  et al.,
1986) in an evaluation of 270 coded compounds in the preincubation modification
of the Salmonella/mammalian microsome assay (Ames test).  Each compound  was
investigated in two independent trials with S^. typhimurium TA1535, TA1537,
TA97, TA98, and TA100 in the absence OP presence of a S9-cofactor mix (S9 liver
fraction) derived from Aroclor 1254-induced rats or hamsters.  At least  five
doses, up to a cytotoxic level, the limit of solubility, or a maximum of 1U
mg/plate were assayed; concurrent negative and positive controls were included
in all tests.  Negative results were obtained with picloram (greater than 97*.).
Although no details of the assays with picloram were reported, it can be assume
that the test material was assayed to an acceptable high dose with no indica-
tion of a mutagenic effect.  The earlier study of Andersen et al. (1972), which
surveyed 110 herbicides, reported that an unspecified dose of picloram was
negative in spot tests with eight unidentified histidine-requiring S_. typhi-
murium mutant strains.  The same authors presented data showing that 6,000 ug
of picloram did not increase the reversion of the transitional bacteriophage
AP72 mutant to wild type (T4).  Carere et al. (1978) also performed the Ames
syot test with picloram (99.9%).  Based on the findings of three independent
experiments, picloram at 200 ug/plate, the dose reported by the authors  as
being not excessively cytotoxic, was not mutagenic in S_. typhimurium TA153S,
TA1536, TA1537, and TA1S38 either with or without 59 activation.

     From the results of a nonactivated Ames test with S_. typhimurium TA1S35
and  TA1538, Rashid  (1974) concluded that picloram (99%) assayed over a noncyto-
toxic dose range (1 to 325 ug/plate) was a doubtful  mutagen.  This conclusion
was  based on an effect that was neither dose related nor approached a twofold
increase in mutant colonies at any tested concentration.

     In contrast to the negative Ames tests, Ercegovich and Rashid (abstract,
1977) reported picloram as a weak mutagen; however, no details were given.

     Carere et al.  (1978) investigated the potential of picloram (99.9%) to
induce streptomycin resistance in Streptotnyces coelicolor and found that 200
ug (the only dose reported) caused an approximately fortyfold increase in
mutant colonies.  The authors did not indicate if other doses were assayed or
if the effect was dose related; however, the finding was reported as being
confirmed in independent experiments.

     b.  Gene mutation in mammalian cells

     Results of an unpublished Chinese hamster ovary (CHO) HGPRT forward muta-
tion assay (Linscombe and Gollapudi, 1987), conducted with five nonactivated
doses (125 to 750 ug/mL and five S9-activated doses (250 to 1,250 ug/mL),
indicated that a 93.4% preparation of picloram, tested to a cytotoxic level,
was not mutagenic.  The study was well controlled and provides acceptable
evidence of a negative response.

     c.  Sex-linked recessive lethal mutations in Drosophila melanogaster

     Woodruff et al. (1985) investigated picloram as part of the NTP evaluation
of 63 coded compounds in Drosophila mutagenicity testing.  Prior to performance
of the sex-linked recessive lethal assay, preliminary palatibility and toxicity
tests were conducted to select doses for the mutation study.

      For the  full  study,  adult male  flies  were  fed  a  solution  containing 5,000
 ppm picloram  for  3 days  and  individually  mated  with untreated  females through
 three sequential  matings  timed to  correspond with different stages of spermato- •
 genesis.  The FI  progeny  were permitted one  round of  brother-sister mating, and
 the resulting progeny  (F2) were scored for lethal mutations.   The percent
 lethals  for the test group was 0.2%  (12 lethals in  5,911 tests} as compared to
 0.1%  (6/6,014) in  the  solvent control group.  Due to  the negative result,
 picloram was  retested  by  adult injection.  Males were injected with 0.2 to 0.3
 uL  of  a  freshly prepared  1,000-ppm solution of picloram.  Following a 24- to
 48-hour  recovery  period,  males were  mated  and F£ progeny were  scored as des-
 cribed for the feeding study.  The 0.03% lethal mutation frequency (2/5,790)
 in  the treatment group was less than the control frequency, 0.09% (5/5,871).
 The results of this well-controlled  study  show that appropriate doses were
 assayed  and that picloram was not mutagenic.

 2.   Chromosome AberrationAssays  (Category ZY
     a.   Somatic cells

     Mensik et al. (unpublished study, 1976) administered 20,  200, and 2,000
mg/kg picloram (89%) by oral  gavage to five male and  five female rats in a  bone
 marrow cytogenetic assay.  Animals were sacrificed  21 hours posttreatment,  bone
 marrow cells were  collected, and 5U metaphases per animals were scored for
 abnormal  chromosomes.  Picloram was neither toxic,  cytotoxic,  nor clastogenic;
 however,  the entire mitotic cycle was not sampled and a maximum tolerated dose
 (MTD) was not achieved.  The study does not provide acceptable data to support
 a negative conclusion.

     The unpublished mouse micronucleus assay (Gollapudi et al., 1985),  con-
 ducted with three  oral gavage administrations of 92%  picloram  (171 to 1,543

mg/kg), failed to provide conclusive evidence of a negative  response  because
severe technical deficiencies compromised the study.
     b.  Germinal cells (chromosome loss in 0. melanogaster)
     Two independent trials were performed by Woodruff et al. (1983)  to deter-
mine the ability of a commercial preparation of picloram to  induce  chromosome
breaks as determined by complete or partial chromosome losses in £. melanoyas-
ter males.  Adult males were fed a 650-ppm solution of picloram for 3 days.
Twenty-four percent of the flies did not survive treatment;  survivors were
mated with a DNA-repair-deficient mutant strain of untreated females  (MUS-302)
for 3 days, and the f\ male progeny were scored for chromosome losses.  Results
from both trials, analyzed separately or in combination, showed that  the fre-
quency of complete or partial chromosome loss in the picloram-treated group  was
slightly lower than that recorded for the negative control.   The  reported
negative conclusion was based on assaying picloram to a toxic dose  and evaluat-
ing approximately 11,000 f\ males per group.  However, since only one round  of
mating followed treatment, the negative conclusion applies only to  germ cells
that were primarily sperm at the time of exposure.
3.   Other Mutagenic Mechanisms (Category 3)
     No studies were available  for this category of genetic endpoints.
4-.   Conclusions
     No compelling evidence of  a mutagenic effect in relevant biological sys-
tems was uncovered.   Although  picloram at a  single reported dose was mutagenic
                  the weight of evidence from well-conducted microbial (Ames
test), mammalian cell, and DrosopMla mutayenicity studies tends to support the

 conclusion  that picloram does not possess mutagenic activity.  The single jn_
 vivo  somatic cell  cytogenetic assay with picloram was unacceptable.  The £.
 melanogaster X or  Y chromosome  loss assay, although technically sound, was
 incomplete  because only the  late stages of spermatogenesis were sampled.
      No  assays were found to fulfill testing in the third category of genetic
 endpoints (i.e., DNA damage/repair, aneuploid induction, or if[ vivo cell trans-
 formation).  The reviewed studies are, therefore, not sufficient to establish a
 complete genetic toxicology profile for picloram.


      Single oral doses of picloram are slightly toxic to most animals, with
 LDso  values ranging from about 1,500 mg/kg bw in mice to 8,000 mg/kg bw
 in rats.  General  signs of acute intoxication include CNS toxicity (ataxia,
 convulsions, tremors), weakness, diarrhea, and weight loss.  Liver enlargement
 is a  frequent consequence of longer term picloram ingestion, but the mechanism
 of this  change is  not known.  Kidney effects are also observed (particularly in
 male  rats).  Obvious injuries to other tissues are not usually observed.  An
 increase in the incidence of benign neoplastic liver nodules was observed in
 female rats.  However, there was no evidence of carcinogenicity in a con-
 currently run study in mice.  The results of this one study are suggestive of
 the induction of benign liver tumors in female rats.  This conclusion has not
 been  substantiated by other studies.  Mutagenic tests in microorganisms have
yielded  mostly negative (but a few weakly positive) results, indicating that
 picloram has low mutagenic potential.  Picloram appears to have very little
 effect on reproduction and is not teratogenic.

                         VI.  HEALTH EFFECTS IN HUMANS

     No adverse effects were reported by Nolan et al. (1984) after the oral
administration of picloram to six human volunteers (described in Section III).
In addition, no adverse effects were observed when a dermal  dose of 2 mg/kg
(in 1% ethyl alcohol) was applied to the skin of the six volunteers.  The
authors reported that only 0.18% of the total dermal dose applied to human
skin was excreted 72 hours after dosing.  Because picloram is quickly cleared
from the blood stream and excreted in the urine 48 hours after oral
administration, the authors concluded that very little is absorbed through
the skin.  A number of picloram formulations tested in humans produced no
sensitization (Dow, 1983b).


                          VII.  MECHANISMS OF TOXICITY


     There are no published studies regarding the mechanism of picloram toxi-
city in mammals.  .Because picloram induces hepatomegaly in rats and dogs (Dow,
1983b; Thompson et al., 1972), it might be speculated that picloram is  an  enzyme
inducer (as are many other chlorinated hydrocarbons) (Neal, 1980).   Whether
this could account for any of the toxic effects is not clear.


     The herbicidal effects of picloram result from its ability to  function as
an auxin, producing rapid and inappropriate growth, distortion of growing
tissues, and curvatures of leaves and stems (NRCC, 1974).

     Picloram has been reported to display mild synergism with 2,4-dichlorophen-
oxyacetic acid in sheep, using lethality as an index of effectiveness (Jackson,
1966).  However, no synergistic activity was found with 2,4-0  on hatchability
and posthatching development  in chickens or pheasants  (Somers  et al., 1974a,c;
1978a,b).  In addition, no synergistic activity of picloram and 2,4,5-trichloro-
phenoxyacetic acid (2,4,5-T)  in honeybees was demonstrated (Moffett et al.,

     The mechanism of  action  of picloram in animals is not known.  In plants,
picloram functions as  an auxin,  resulting  in  formation of  abnormal and malformed
plants.  Mild synergism with  2,4-0 rtas been noted  in sheep, but not in other



      The  quantification of toxicological effects of a chemical consists of
 separate  assessments of noncarcinogenic and carcinogenic effects.  Chemicals
 that  do not produce carcinogenic effects are  believed to have a threshold dose
 below which no adverse, noncarcinogenic health effects occur, while carcinogens
 are assumed to act without a threshold.


 1.    Noncarcinogenic Effects

      In the quantification of noncarcinogenic effects, a Reference Dose (RfD,
 formerly  called the Acceptable Daily Intake (ADI)) is calculated.  The RfD is
 an estimate (with an uncertainty spanning perhaps an order of magnitude) of a
 daily exposure of the human population (including sensitive subgroups) that is
 likely to be without an appreciable risk of deleterious health effects during
 a lifetime.  The RfD is derived from a No-Observed-Adverse-Effect Level (NOAEL),
 or Lowest-Ubserved-Adverse-Effect Level  (LOAEL), identified from a subchronic
 or chronic study, and divided by an uncertainty factor(s).  The RfO is calculated
 as follows:
       RfD =   (NOAEL or LOAEL)
             Uncertainty factorys)
	 mg/kg bw/day
     Selection of the uncertainty factor to be employed in the calculation of
the RfD is based on professional judgment while considering the entire data
base of toxicoloyical effects for the chemical.  To ensure that uncertainty
factors are selected and applied in a consistent manner, the Office of Drinking
Water (UOW) employs a modification to the guidelines proposed by the National
Academy of Sciences  (MAS, 1977, 1980) as follows:

      o   An  uncertainty  factor of  10 is generally used when good chronic or
         subchronic  human exposure data identifying a NOAEL are available and
         are supported by good chronic or subchronic toxicity data in other

      o   An  uncertainty  factor of 100 is generally used when good chronic
         toxicity data identifying a NOAEL are available for one or more animal
         species (and human data are not available), or when good chronic or
         subchronic  toxicity data identifying a LOAEL in humans are available.

      o   An  uncertainty  factor of 1,000 is generally used when limited or
         incomplete  chronic or subchronic toxicity data are available, or when
         good chronic or subchronic toxicity data identifying a LOAEL, but not
         a NOAEL, for one or more animal species are available.

     The uncertainty factor used for a specific risk assessment is based prin-
cipally on  scientific judgment rather than scientific fact and accounts for     (•
possible intra- and interspecies differences.  Additional  considerations,  which
may necessitate the use of an additional  uncertainty factor of 1 to 10, not
incorporated in the NAS/ODW guidelines for selection of an uncertainty  factor
include the use of a less-than-lifetime study for deriving an RfO, the  signifi-
cance of the adverse health effect,  pharraacokinetic factors,  and the counter-
balancing of beneficial  effects.
     From the RfD, a Drinking Water  Equivalent Level  (DWEL) can be calculated.
The DWEL represents a medium-specific (i.e., drinking water) lifetime exposure,
at which adverse,  noncarcinogenic nealth  effects are not anticipated to occur.
The DWEL assumes 100% exposure from drinking water.  The DWEL provides  the non-
carcinogenic health effects basis for estaolishing a drinking water standard.

For ingestion data, the DWEL is derived as follows:

     OWEL =    RfD x (body weight In kg)    .  	mg/l_ (	ug/L)
            Qrinlciny water volume in L/day
               Body weight = assumed to be 70 kg for an  adult.
     Drinking water volume * assumed to be 2 L per day for  an  adult.
     In addition to the KfD and the DWEL, Health Advisories (HAs)  for exposures
of shorter duration (One-day, Ten-day, and Longer-term)  are determined.
The HA values are used as informal  guidance to municipalities  and  other  organi-
zations when emergency spills or contamination situations occur.  The HAs are
calculated using an equation similar to the RfD and DWEL; however, the NOAELs
or LOAELs are identified from acute or subchronic studies.   The HAs are  derived
as follows:
     HA = (NOAEL or LOAEL) x (bw) = 	mg/L (	Ug/L)
            (UF) x (    L/day)
     Using the above equation, the following drinking water HAs are developed
for noncarcinogenic effects:
     1.  One-day HA for a 10-kg child ingesting 1 L water per day.
     2.  Ten-day HA for a 10-kg child ingesting 1 L water per day.
     3.  Longer-term HA for a 10-kg child ingesting 1 L water per day.
     4.  Longer-term HA for a 70-kg adult ingesting 2 L water per day.
     The One-day HA calculated for a 10-kg child assumes a single acute expo-
sure to the chemical and is generally derived  from  a  study of less than 7 days
duration.  The Ten-day HA assumes a limited  exposure period of  1 to 2 weeks and

is generally derived from a study of less than 30 days duration.  The Longer-
term HA is derived for both a 10-kg child and a 70-kg adult and assumes  an
exposure period of approximately 7 years (or 1U% of an individual's  lifetime),  i
The Longer-term HA is generally derived from a study of subchronic duration
(exposure for 10% of an animal's lifetime).

2.   Carcinogenic Effects

     The EPA categorizes the carcinogenic potential  of a chemical, based  on
the overall  weight of evidence, according to the following scheme:

     o  Group A:   Human Carcinogen.  Sufficient-evidence exists from  epidemiology
                  studies to support a causal association between  exposure to
                  the chemical  and human cancer.

     o  Group B:   Probable Human Carcinogen.  Sufficient evidence  of  carcino-
                  genicity in animals  with limited  (Group 81)  or inadequate
                  (Group B2) evidence in humans.
     o  Group C:   Possible Human Carcinogen.  Limited evidence of  carcinogeni-
                  city in animals in the absence of human data.

     o  Group D:   Not Classified as to Human Carcinogenicity.   Inadequate human
                  and animal evidence of carcinogenicity or for which no  data
                  are available.

     o  Group E:   Evidence of Noncareinogeniclty  for Humans.   No evidence of
                  carcinogenicity in at least two adequate animal  tests  in
                  different species or in both adequate epidemiologic and
                  animal  studies.

     If toxicological evidence leads to the classification of  the contaminant
as a known, probable, or possible human carcinogen, mathematical  models  are
used to calculate the estimated excess cancer risk associated  with the  inges-
tion of the contaminant in drinking water.  The data used in these estimates
usually come from lifetime exposure studies in animals.   To predict the  risk
for humans from animal data, animal doses must be converted to equivalent  human
doses.  This conversion includes correction for noncontinuous  exposure,  less-
than-lifetime studies, and for differences in size.  The factor that compen-
sates for the size difference is the cube root of the ratio of the animal  and
human body weights.  It is assumed that the average adult human body weight  is
70 kg, and that the average water consumption of an adult human is 2 liters  of
water per day.
     For contaminants with a carcinogenic potential, chemical  levels are cor-
related with a carcinogenic risk estimate by employing a cancer potency {unit
risk) value together with the assumption for lifetime exposure via ingestion of
water.  The cancer unit risk is usually derived from a linearized multistage
model with a 95% upper confidence limit providing a low dose estimate;  that  is,
the true risk to humans, while not identifiable,  is not likely to exceed the
upper limit estimate and, in fact, may be lower.  Excess cancer risk estimates
may also be calculated using other models such as the one-hit, Weibull, logit,
and probit.  There is little basis in the current understanding of the  biologi-
cal mechanisms involved in cancer to suggest that any one of these models is
able to predict risk more accurately than any others.  Because each model  is
based on differing assumptions, the estimates that are derived for each model
can differ by several orders of magnitude.
     The scientific  data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and

 random errors in  scientific measurement.   In most cases, only studies using
 experimental animals  have  been  performed.  Thus, there is uncertainty when the
 data  are extrapolated to humans.  When developing cancer risk rate levels,     \
 several other areas of  uncertainty exist,  such as the incomplete knowledge
 concerning the health effects of contaminants in drinking water; the impact of
 the experimental  animal's  age,  sex, and species; the nature of the target organ
 system(s) examined; and the actual rate of exposure of the internal  targets in
 experimental animals  or humans.  Dose-response data usually are available only
 for high levels of exposure, not for the lower levels of exposure closer to
 where a standard  may  be set.  When there is exposure to more than one contami-
 nant, additional  uncertainty results from a lack of information about possible
 synergistic or antagonistic effects.

 1.   One-day Health Advisory.

     No information was found in the available literature that was  suitable for1
calculation of the One-day HA for picloram.  It is therefore recommended that
the Ten-day HA for a lu-kg child (2U mg/L, calculated below)  be used at this
time as a conservative estimate of the One-day HA value.
2.   Ten-day Health Advisory
     Two studies were considered for calculation of the Ten-day HA for picloram..
In the study reported by Hayes et a1. (1986), no consistent compound-related
effects were seen in rats administered 60, 190, or 600 mg/kg/day of potassium
picloram for 14 days.  The NUAEL was 600 mg/kg/day, the highest dose tested.

     In the second study (Dow, 1981c), beagles received 0, 200, 400, or 800
mg/ky/day of picloram for 7 to 14 days.  Toxicity in the form of reduced body  l\

weight and food consumption was observed in dogs administered picloram at 400
or 800 mg/kg/day, and a NOAEL of 200 mg/kg/day was identified.

     The dog study by Dow (1981c) was selected to serve as the basis  for the
Ten-day HA because a dose response was demonstrated, and dogs appear  to be the
species most sensitive to picloram toxicity.

     The Ten-day HA for a 10-kg child is calculated as follows:

     (200 mg/kg/day)(1U kg) = 20 mg/L (20,000 ug/L)
        (1 I/day)(100)

     200 mg/kg/day * NOAEL, based on the absence of reduced body weight and
                     feed intake in beagle dogs exposed to picloram for 7 to 14
             10 kg * assumed body weight of a child.
               100'~ uncertainty factor, chosen in accordance with  NAS/ODW
                     guidelines in which a NOAEL from an animal  study is
           1 L/day » assumed daily water consumption of a 10-kg  child.

3.   Longer-term Health Advisory

     Two studies were considered as the basis for the Longer-term HA  value for
picloram.  In a study reported by Hayes et al. (1986), aqueous potassium pic-
loram was administered to 20 Sprague-Oawley rats/sex/dose at concentrations of
60, 190, or 600 my/kg/day in drinking water for 90 days.  Mild kidney lesions
(primarily in the tubular epithelium) were noted in all treated  male  rats at
all dose levels, especially at the 60U-mg/kg level.  Also observed  was increased
incidence of mononuclear liver foci in male rats at the 190- and 600-mg/kg/day
dose levels, and in females that received 600 mg/kg/day.  No other  compound-
related effects were seen.  A LOAEL of 60 mg/kg, based on kidney lesions in

 males,  is  therefore  derived  for  this study.  A  NOAEL was not identified in this

      The second study considered was reported by Dow (1982).  In this study,
 beagles received doses of 0, 7,  35, or 175 mg/kg/day of picloram in the diet
 for  6 months.  Reduced body  weight  gain,  food consumption, and alanine trans-
 aminase levels and increased alkaline phosphatase levels, and absolute and
 relative liver weights were  observed in males and females ingesting 175 mg/kg/
 day  of picloram.  Increases  in absolute and relative liver weight were noted in
 males at 35 mg/kg/day.  The  NOAEL for this study was identified as 7 mg/kg/day.

      The dog study reported  by Dow  (1982) was selected for derivation of the
 Longer-term HA because the dose  levels were appropriately chosen to demonstrate
 a No-Observed-Adverse-Effect Level, and dogs appear to be the species most
 sensitive to picloram toxicity.

     The Longer-term HA for a 10-kg child is calculated as  follows:            (
     (7 mg/kg/day)(10 kg) * 0.7 mg/L (7UO ug/L)
       (1 L/day)(100)
     7 mg/kg/day * NOAEL, based on the absence of relative and absolute liver
                   weight changes.
           10 kg = assumed body weight of a child.
             100 * uncertainty factor, chosen in accordance with NAS/OOW
                   guidelines for use with a NOAEL from an animal study.
         1 L/day » assumed daily water consumption of a 10-kg child.
     The longer-term HA for a 70-kg adult is calculated as follows:

      (7 mg/kg/day)(7Q kg) = 2.45 mg/L (2,000 ug/L)
       (2 L/day)(100)
7 mg/kg/day
                   NOAEL, based on the absence of relative and absolute liver
                   weight changes.
           70 kg » assumed body weight of an adult.
             100 = uncertainty factor, chosen in accordance with NAS/ODW
                   guidelines for use with a NOAEL from an animal study.
         2 I/day a assumed daily water consumption of an adult.

4.   Reference Dose and Drinking Water Equivalent Level
     Tne study by Dow (1982) has been chosen to calculate the reference dose
for picloram because dogs have been shown to be the species most sensitive to
picloram.  In this study, picloram was fed for 6 months to beagle dogs (six/
sex/group) in the diet at dose levels of 0, 7, 35, or 175 mg/kg/day.  At 175
mg/kg/day, the following adverse effects were observed in both male and female
dogs: decreased body weight gain, food consumption, and alanine transaminase
levels; and increased alkaline phosphatase levels, and absolute and relative
liver weights.  At 35 mg/kg/day, increased absolute and relative liver weights
were noted in males.  No compound-related effects were detected in females at
35 mg/kg/day or in males or females at 7 mg/kg/day.  Based on these data, 7
mg/kg/day was identified as the NOAEl for dogs for a 6-month exposure.  Using
this value, the DWEL is derived as follows:

Step 1:  Determination of the Reference Dose (RfD)
     RfO * (? mdayi * °'07
*The U.S. EPA Office of Pesticide Programs has set an RfD for picloram at 0.07
 mg/kg/day (U.S. EPA, 1986).

      7 mg/kg/day
NOAEl, based on the absence of relative and absolute liver
weight changes,
uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal  study.
Step 2:  Determination of the Drinking Water Equivalent Level  (DUEL)

     UWEL = (0.07 mg/kq/day)(70 kg) s 2.45 mg/L (2,000 ug/L)
                 (2 L/day)

     0.07 mg/kg/day > RfD.
              70 kg = assumed body weight of an adult.
            2 L/day * assumed daily water consumption of an adult.


     The National Cancer Institute conducted studies on the carcinogenic poten-
tial of picloram 1n rats and mice  (NCI, 1978).  An increase in malignant tumors
was not observed in male rats or in male or female mice with dietary  exposures
of 370 to 7by mg/kg/day for 80 weeks.  However, a statistically significant
increase in neoplastic nodules in the liver was observed in female  rats.  The
study was considered to provide limited evidence of card"nogenicity in that
there was an increase in the incidence of benign tumors only in a single

     Landry et al. (1986) did not report any statistically significant treat-
ment-related increase in tumor incidence in rats that received 20 to 200 mg
picloram/kg body weight in the diet for 2 years.

     The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of picloram.
     Based on the weight-of-evidence criteria in EPA's Guidelines  for Carcino-
gen Risk Assessment (U.S. EPA, 1986), picloram is classified in Group 0:  Not
Classified as to Human Carcinogenicity.   This classification is generally
used for chemicals with inadequate evidence of carcinogenicity in  humans  and
animals or for which no data are available.  There is no supporting evidence,
e.g., mutagenicity, for carcinogenic potential.  On this basis, no risk assess-
ment for carcinogenicity will be performed.
     Table VIII-1 summarizes the HA and  DWEl values recommended in this

 Table VIII-1.  Summary of Quantification of Toxicological Effects for Picloram

One-day HA for lu-kg child
Ten-day HA for 10-kg child
Longer-term HA for 10-kg child
Longer-term HA for 70-kg adult
OWEL (1UU% from drinking water)
Excess cancer risk (10~6)
Drinking water
Dow (1981c)
Dow (1981c)
Dow (1982)
Dow (1982)
Dow (1982)

aThe Ten-day HA value for a 10-kg child is used as a conservative estimate
 of the One-day HA value.

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