August, ^987
PICLORAM
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 1918-02-01
Structural Formula
NH2
It
C^L ^
^sN^
'Cl
f)
'C-OH
(4-amino-3,5,6-trichloropicolinic acid)
Synonyms
0 Amdon; ACTP? Borolin? K-PIN; Tordon (Meister, 1987).
Uses
0 Broad-spectrum herbicide for the control of broadleaf and woody plants
in rangelands, pastures and rights-of-way for powerlines and highways
(Meister, 1987).
Properties (Meister, 1987)
Chemical Formula
Molecular Weight
Physical State (Room Temp.)
Boiling Point
Melting Point
Density
Vapor Pressure (25°C)
Specific Gravity
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conveision Factor ~
Occurrence
0 Picloram has been found in 359 of 653 surface water samples analyzed
and in 5 of 77 ground water samples (STORET, 1987). Samples were
collected at 124 surface water locations and 49 ground water locations,
and picloram was found in 7 states. The 85th percentile of all
nonzero samples was 0.13 ug/L in surface water and 1.00 ug/L in
ground water sources. The maximum concentration found was 4.6 ug/L
in surface water and 1.00 ug/L in ground water.
241.6
White powder
Decomposes
215°C (decomposes)
6.2 x 10~7 mm Hg
0.043 g/100 mL (free acid)
40 g/100 mL (salts)
(Chlorine-like)
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Picloram August, 1987
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Environmental Fate
0 The main processes for dissipation of picloram in the environment are
photodegradation and aerobic soil degradation. 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, was
dissipated within 28 days after application (Scifres et al., 1977).
0 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).
0 Laboratory studies have shown that under aerobic soil conditions, the
half-life of picloram is dependent upon the applied concentration,
and the temperature and moisture of the soil. The major degradation
product is CC^; other metabolites are 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 under
anaerobic soil and aquatic conditions, picloram degradation is extremely
slow (McCall and Jefferies, 1978).
0 Following normal agricultural, forestry and industrial applications
of picloram, long-term accumulation of picloram in the soil generally
does not occur. In the field, the dissipation of picloram will occur
at a faster rate in hot, wet areas compared, to cool, dry locations
(Hamaker et al., 1967). The half-life of picloram under most field
conditions is a few months (Youngson, 1966). There is little potential
for picloram to move off treated areas in runoff water (Fryer et al.,
1979). Although picloram is considered to have moderate mobility
(Helling, 1971a,b), leaching is generally limited to the upper portions
of most soil profiles (Grover, 1977), Instances of picloram entering
the ground water are largely limited to cases involving misapplications
or unusual soil conditions (Frank et al., 1979).
III. PHARMACOKINETICS
Absorption
0 Picloram is readily absorbed from the gastrointestinal (GI) tract of
rats (Nolan et al., 1980). Within 48 hours after dosing rats with
1400 rag/kg body weight (bw), 80 to 84% of the dose was found in
urine.
0 A 500-kg Holstein cow was administered 5 mg/kg picloram in the feed
for 4 days (approximately 0.23 mg/kg/day). Ninety-eight percent of
the total dose was excreted in the urine, demonstrating nearly
complete absorption (Fisher et al., 1965).
0 Similar results were observed in three male Fischer CDF rats receiving
14c-picloram (dose not specified), where 95% of the dose was absorbed
(Dow, 1983).
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Distribution
0 Picloram appears to be distributed throughout the body, with the
highest concentration in the kidneys (Redemann, 1964). In rats
(strain, age and sex not specified) administered a single 20 mg/kg
dose of 1^C-labeled picloram in food, radioactivity was found in
abdominal fat, liver, muscle and kidneys with maximum levels occurring
2 to 3 hours after dosing.
0 Hereford-Holstein steers fed picloram at daily doses of 3.2 to 23 mg/kg
for 2 weeks had tissue concentrations of 0.05 to 0.32 mg/kg in
muscle, 0.06 to 0.45 mg/kg in fat, 0.12 to 1.6 mg/kg in liver, 0.18
to 2.0 mg/kg in blood and 2 to 18 mg/kg in kidney (Kutschinski and
Riley, 1969).
0 In a similar study, two steers (strain not specified) fed 100 or 200 mg
picloram (3 or 6 mg/kg bw/day) for 31 days had picloram concentrations
of 4 or 10 mg/kg, respectively, in the kidneys, while concentrations
in other tissues (muscle, omentum fat, heart, liver, brain) were less
than 0.5 mg/kg (Leasure and Getzander, 1964).
Metabolism
8 Picloram administered to rats or cattle was excreted in the urine in
unaltered form (Fisher et al., 1965; Nolan et al., 1980; Dow, 1983),
and no ^ ^CO^ was detected in expired air of rats given ' ^-carbon-
labeled picloram (Redemann, 1964; Nolan et al., 1980; Dow, 1983).
These studies indicate that picloram is not metabolized significantly
by mammals.
Excretion
Picloram administered to rats is excreted primarily in the urine
(Redemann, 1964; Nolan et al., 1980; Fisher et al., 1965).
Male (F344) rats that were administered a single oral dose of picloram
at 1,400 mg/kg bw, within 48 hours excreted 80 to 84% of the dose in
the urine, 15% in the feces, less than 0.5%. in the bile and virtually
no measurable amount as expired CC>2 (Nolan et al., 1980).
One Holstein cow administered 5 ppm picloram in feel for 4 consecutive
days excreted more than 98% of the dose in the urine (Fisher et al.,
1965).
In male F344 rats administered picloram at 10 mg/kg bw orally, 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).
Cattle excrete picloram primarily in the urine (Fisher et al., 1965),
although small amounts may appear in the milk (Kutschinski and Riley,
1969). In Holstein cows fed picloram for 6 to 14 days at doses of
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Picloram
August, 1987
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2.7 mg/kg/day or less, no picloram could be found in the milk, while
cows fed picloram at doses of 5.4 to 18 mg/kg/day had milk levels up
to 0.28 mg/L. This corresponds to 0.02% of the ingested dose. When
picloram feeding was discontinued, picloram levels in milk became
undetectable within 48 hours.
Nolan et al. (1983) investigated the excretion of picloram in humans.
Six male volunteers (40- to 51-years old) ingested picloram at 0.5 or
5 mg/kg in approximately 100 mL of grape juice. Seventy-six percent
of the dose was excreted unchanged in the urine within 6 hours (half-
life of 2.9 hours). The remainder was eliminated with an average
half-life of 27 hours. The authors did not report observations, if
any, of adverse effects. Thus, excretion of picloram in humans was
biphasic as had been demonstrated in rats by Nolan et al. (1980).
IV. HEALTH EFFECTS
Humans
No information on the health effects of picloram in humans was found
in the available literature. In the excretion study by Nolan et al.
(1983), described above, the authors did not address the presence of
toxic effects in human volunteers ingesting picloram at 0.5 or 5 mg/kg.
Animals
Short-term Exposure
0 The acute oral toxicity of picloram is low. Lethal doses have been
estimated in a number of species, with LD50 values ranging from
2,000 to 4,000 mg/kg (NIOSH, 1980; Dow, 1983).
0 In a 7- to 14-day study .by Dow (1981), beagle dogs (number per group
not specified) were administered picloram (79.4% Tordon) at dose
levels of 0, 250, 500 or 1000 mg/kg/day. Based on 79.4% active
ingredient, actual doses administered were 200, 400 or 800 mg/kg/day.
The No-Observed-Adverse-Effect-Level (NOAEL) was determined to be
200 mg/kg/day, the lowest dose tested, based on the absence of reduced
food intake.
0 In a 9-day feeding study by Dow (1980a), picloram was fed to dogs
(one/dose) at dose levels of 400, 800 or 1,600 mg/kg bw/day. Picloram
was acutely toxic to female dogs at the higher doses and not toxic
at 400 mg/kg/day (the lowest dose tested), which was identified as
the NOAEL.
0 In a 32-day feeding study by Dow (1980b), picloram was administered
to mice at dose levels of 0, 90, 270, 580, 900 or 2,700 mg/kg/day.
The NOAEL was 900 mg/kg/day, and the Lowest-Observed-Adverse-Effect-
Level (LOAEL) was 2700 mg/kg/day, based on increased liver weight.
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Picloram August, 1987
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Dermal/Ocular Effects
0 Most formulations of picloram have been evaluated for the potential
to produce skin sensitization reactions in humans. Dow (1981) reported
in summary data 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-D acid was not a sensitizer as a 5% aqueous
solution in humans (Gabriel and Gross, 1964). However, when the
triisopropanolamine salts of picloram and 2,4-D (Tordon 101) were
applied as a 5% solution, sensitization occurred in several individuals;
however, when applied alone, the individual components were nonreactive,
Long-term Exposure
0 Subchronic studies with picloram have been conducted by Dow (1983)
using three species (dogs, rats, mice) over periods of 3 to 6 months.
A 6-month study was conducted with beagle dogs that received picloram
at daily doses of 0, 7, 35 or 175 mg/kg/day (six/sex/dose group)
(Dow, 1983). Increased liver weights were observed at the highest
dose (175 mg/kg/day) for males and females, and at the intermediate
dose (35 mg/kg/day) for males. Therefore, the 7-mg/kg/day dose level
was considered to be a NOAEL.
0 In a 13-week feeding study, CDF Fischer 344 rats (1 5/sex/dosage group)
were fed picloram in their diet at dose levels of 0, 15, 50, 150, 300
or 500 mg/kg/day (Dow, 1983). Liver swelling was observed in both
sexes at the 150- and 300-mg/kg/day dose levels. The NOAEL in this
study was identified as 50 mg/kg/day.
0 Osborne-Mendel rats receiving picloram at 370 or 740 mg/kg/day in the
diet for 2 years had renal disease resembling that of the natural
aging process (NCI, 1978). Increased indices of parathyroid hyperplasia,
polyarteritis, testicular atrophy and thyroid hyperplasia and adenoma
were observed. Polyarteritis may be indicative of an autoimmune
effect.
0 Ten male and female B6C3F-J mice were administered picloram in their
diet at dose levels of 0, 1,000, 1,400 or 2,000 mg/kg/day for 13 weeks
(Dow, 1983). Liver weights were increased significantly (p values not
reported) in females and males at all dose levels tested.
Reproductive Effects
0 As described above in the 2-year feeding study by NCI (1978), testicular
atrophy was observed in male Osborne-Mendel rats receiving picloram at
370 or 740 mg/kg/day.
0 Groups of 4 male and 1 2 female rats were maintained on diets containing
0, 7.5, 25 or 75 mg/kg/day of Tordon (95% picloram) through a -three-
generation (two litters per generation) fertility, reproduction,
lactation and teratology study (McCollister et al., 1967). The rats
were 11-weeks old at the start of the study and were maintained on
the test diets for 1 month prior to breeding to produce the F-|a
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Picloram August, 1987
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generation. Records were kept of numbers of pups born live, born
dead or killed by the dam; litter size was culled to eight pups after
5 days. Lactation continued until the pups were 21-days old, when
they were weaned and weighed. After a 7- to 10-day rest, the dam was
returned for breeding the FIJ., generation. The second generation (?2a
and F3b) was derived from F2b animals after 110 days of age. Two
weanlings per sex per level of both litters of each generation were
observed for gross pathology. Gross pathology was also performed on
all parent rats and all females not becoming pregnant. Five male and
five female weanlings from each group of the F^ litter were selected
randomly for gross and microscopic examination (lung, heart, liver,
kidney, adrenals, pancreas, spleen and gonads). Picloram reduced
fertility in the 75 mg/kg/day dose group. No other effects were
noted. Based on these results, a NOAEL of 25 mg/kg/day was identified.
Developmental Effects
0 In the McCollister et al. (1967) study described above, the F1c, F2c
and F3c litters were used to study the teratogenic potential of
picloram. The dams were sacrificed on day 19 or 20 of gestation, and
offspring were inspected for gross abnormalities, including skeletal
and internal structures, and placentas were examined for fetal death
or resorptions. None were observed at any dose level. Picloram
reduced fertility in the 75-mg/kg/day dose group. Based on these
results, a NOAEL of 25 mg/kg/day was identified.
0 Thompson et al. (1972) administered picloram in corn oil to pregnant
Sprague-Dawley rats on days 6 to 15 of gestation. Four groups of 35
rats (25 for the teratology portion and 10 for the postnatal portion
of the study) received picloram at 0, 500, 750 or 1,000 mg/kg/day by
gavage. Rats were observed daily for signs of toxicity. Prebreeding
and gestation day 20 body weights were obtained on teratology rats
and prebreeding and postpartum day 21 body weights were obtained for
signs of maternal toxicity, while rats given 750 or 1,000 mg/kg/day
developed hyperesthesia and mild diarrhea after 1 to 4 days of treatment;
and 14 maternal deaths occurred between days 8 and 17 of gestation in
these dose groups. Evidence of retarded fetal growth, as reflected
by an increase in unossified fifth sternebrae, was observed in all
treatment groups but not in a dose-related manner; i.e., the occurrence
of bilateral accessory ribs was increased significantly in fetuses of
dams given 1,000 mg/kg for 10 days during gestation. At this dose
level, there was maternal toxicity and, therefore, no NOAEL was
determined. The LOAEL was 500 mg/kg, the lowest dose tested.
Mutagenicity
0 The mutagenic activity of picloram has been studied in a number of
microbial systems. Ames tests in several Salmonella typhimurium
strains indicated that picloram was not mutagenic with or without
activation by liver microsomal fractions (Andersen et al., 1972;
Torracca et al., 1976; Carere et al., 1978).
0 One study using the same system as above found picloram to be weakly
mutagenic (Ercegovich and Rashid, 1977).
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Picloram August, 1987
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0 Picloram was shown to be negative in the reversion of bacteriophage
AP72 to T4 phenotype (Andersen et al., 1972), but positive in the
forward mutation spot test utilizing Streptomyces coelicolor (Carere
et al., 1978).
0 Irrespective of a weak mutagenic response in the Salmonella typhimurium
test (Ercegovich and Rashid, 1977) and a positive forward mutation,
the authors take the position that picloram is not mutagenic. This
view is supported by studies in male and female Sprague-Dawley rats
fed picloram at dose levels of 20, 200 or 2,000 mg/kg/day in which no
cytological changes in bone marrow cells were observed (Mensik et
al., 1976).
Carcinogenicity
0 Picloram (at least 90% pure) was administered by diet to Osborne-
Mendel rats and B6C3F1 mice (NCI, 1978; also reviewed by Reuber,
1981). Pooled controls from carcinogenicity studies run in the same
laboratory (and room, at the Gulf South Research Institute) and over-
lapping this study by at least 1 year were used. Fifty male rats
were dosed with picloram at 208 or 417 mg/kg/day and 50 female rats
were dosed at 361 or 723 mg/kg/day. During the second year, rough
hair coats, diarrhea, pale mucous membranes, alopecia and abdominal
distention were observed in treated rats. In addition, a relatively
high incidence of follicular hyperplasia, C-cell hyperplasia and
C-cell adenoma of the thyroid occurred in both sexes. However, the
statistical tests for adenoma did not show sufficient evidence for
association of the tumor with picloram administration. An increased
incidence of hepatic neoplastic nodules (considered to be benign tumors)
was observed in treated animals. 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, the trend was signifi-
cantly dose-related in females (p = 0.016). The incidence in the
high-dose group was significant (p = 0.014) when compared with that
of the pooled control group. The incidences of foci of cellular
alteration of the liver were: female rats - matched controls 0/10,
low-dose 8/50, high-dose 18/49; male rats - matched controls 0/10,
low-dose 12/49, high-dose 5/49. Thus, there is evidence that picloram
induced benign neoplastic nodules in the livers of rats of both
sexes, but especially those of the females. Subsequent laboratory
review by the National Toxicology Program (NTP) has questioned the
findings of this study because animals with exposure to known carcinogens
were placed in the same room with these animals and cross-contamination
might have occurred. In the same study, NCI (1978), 50 male and
50 female mice received picloram at 208 or 417, and 361 or 723 mg/kg/day,
respectively. Body weights of mice were unaffected, and no consistent
clinical signs attributable to treatment were reported during the
first 6 months of the study, except isolated incidences of tremors
and hyperactivity. Later, particularly in the second year, rough
hair coats, diarrhea, pale mucous membranes, alopecia and abdominal
distention occurred. No tumors were found in male or female mice or
male rats at incidences that could be significantly related to treatment.
It was concluded that picloram was not a carcinogen for B6C3F-) mice.
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Picloram , « August, 1987
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Dow (1986) retested picloram (93% pure) in a 2-year chronic feeding/
oncogenicity study in Fisher 344 rats. Rats (50/sex/dose) were fed
20, 60 or 200 mg/kg/day. Oncogenic effects above those of controls
were absent in this study.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = or LOAEL ) x (BW) = _ mg/L ( _ Ug/L)
(UP) x ( _ L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 1 00 or 1,000), in
accordance with NAS/ODW guidelines.
_ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One-day HA value for picloram. It is, therefore,
recommended that the Ten-day HA value for a 10-kg child (20 mg/L, calculated
below) be used at this time as a conservative estimate of the One-day HA value,
Ten-day Health Advisory
The 7- to 14-day study in dogs by Dow (1981) has been selected to serve
as the basis for the Ten-day HA value for picloram because dogs appear to be
the most sensitive species. Ooses of 200, 400 or 800 mg/kg/day were used and
the dose of 200 mg/kg/day was identified as the NOAEL for short-term exposures
based on reduced food intake. Other short-term studies include a 9-day study
in dogs by Dow (1980a) with a NOAEL of 400 mg/kg/day and a 32-day study in
mice by Dow (1980b) with a NOAEL of 900 mg/kg/day.
Using a NOAEL of 200 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = (200 mg/kg/day ) (10 kg) = 2Q mg/L (20,000 ug/1)
(100) (1 L/day)
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Picloram , August, 1987
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where:
200 mg/kg/day « NOAEL based on the absence of reduced feed intake in
beagle dogs exposed to picloram for 7 to 14 days.
1 0 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
The study by Dow (1983) has been selected to serve as the basis for the
Longer-term HA value 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, increased alkaline phosphatase
levels, absolute liver weight and relative liver weight. 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 study, the Longer-term HA for a 10-kg child is calculated as
follows:
Longer-term HA = ^ffiffl*^1)0* - 0.7 "g/L (700 ug/L)
where:
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/OCW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (7 mg/kg/day) (70) = 2.45 mg/L (2,450 ug/L)
(100) (2 L/day)
where:
7 mg/kg/day = NOAEL, based on the absence of relative and absolute
liver weight changes.
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Picloram August, 1987
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70 kg * assumed body weight of an adult.
100 » uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is-an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The study by Dow (1983), chosen for the Longer-term Health Advisory has
also been chosen to calculate the Lifetime HA value for 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, increased
alkaline phosphatase levels, absolute liver weight and relative liver weight.
At 35 mg/kg/day, increased absolute and relative liver weights were noted in
males, io 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. Therefore, the
Lifetime HA for picloram is determined as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (7 mg/kg/day) = 0<07 mg/kg/day
(100)
where:
7 mg/kg/day = NOAEL, based on the absence of relative and absolute
liver weight changes.
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Picloram August, 1987
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100 « 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 (DWEL)
DWEL = (0.07 mg/kg/day) (70) . 2.45 /L (2450 /L)
(2 L/day)
where:
0.07 mgAg/day «= RfD.
70 kg - assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (2.45 mg/L) (20%) = 0.49 mg/L (490 ug/L)
where:
2.45 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 The National Cancer Institute conducted studies on the carcinogenic
potential of picloram in rats and mice (NCI, 1978; this study
was also reviewed by Reuber, 1981). In the study with mice, there
was no indication of an oncogenic response from dietary exposure
which included levels of more than 5,000 ppm picloram (723 mg/kg/day)
for the greater part of their lifetime. The rat study, however, was
negative for oncogenic effects in males, while female rats exhibited
a statistically significant increase in neoplastic nodules in the
liver. On a time-weighted average, exposures ranged up to 14,875 ppm
(743 mg/kg/day) picloram in the diet.
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of picloram.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986b), picloram may be classified
in Group D: not classified. This group is generally used for sub-'
stances with inadequate human and animal evidence of carcinogenicity
or for which no data are available.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The U.S. EPA Office of Pesticide Programs has set an RfD for picloram
at 0.07 mg/kg/day (U.S. EPA, 1986b).
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Picloram August, 1987
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* Tolerances have been established for picloram in or on raw agricultural
commodities (U.S. EPA, 1986c).
0 The National Academy of Sciences (HAS, 1983) has calculated a chronic
Suggested-No-Adverse-Response-Level (SNARL) of 1.05 mg/L for picloram.
An uncertainty factor of 1,000 was used because the issue of carcino-
genicity had not yet been resolved and also because the Johnson (1971)
study used by NAS does not provide enough information for a complete
judgment of its adequacy.
VII. ANALYTICAL METHODS
0 Analysis of picloram is by a gas chromatographic (GC) method applicable
to the determination of certain chlorinated acid pesticides in water
samples (U.S. EPA, 1986d). In this method, approximately 1 liter of
sample is acidified. The compounds are extracted with ethyl ether
using a separatory funnel. The derivatives are hydrolyzed with
potassium hydroxide and extraneous organic material is removed by a
solvent wash. After acidification, the acids are extracted and
converted to their methyl esters using diazomethane. Excess reagent
is removed, and the esters are determined by electron-capture gas
chromatography. The method detection limit has not been determined
for picloram.
VIII. TREATMENT TECHNOLOGIES
0 The manufacture of this compound has been discontinued (Meister,
1987). No information was found on treatment technologies capable of
effectively removing picloram from contaminated water.
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Picloram August, 1987
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Confidential Business Information submitted to the Office of Pesticide
Programs.
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