August, 1987
820K88123
2,4,5-TRICHLOROPHENOXYACETIC ACID
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 acc-urately 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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2,4,5-Trichlorophenoxyacetic Acid
August, 1987
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 93-76-5
Structural Formula
-CHaCOOH
2,4,5-trichlorophenoxyacetic acid
Synonyms
0 2,4,5-T; Brush rhap; Brushtox; BCF-Bushkiller; Dacamine; Decamine 4T;
Ded-Weed; Dinoxol; Envert-T; Estercide t-2 and t-245; Esteron; Fence
rider; Forron; Forst U46; Fortex; Fruitone A; Inverton 245; Line
rider; Phortox; Reddon; Reddox; Spontox; Tippon; Tormona; Transamine;
Tributon; Trinoxol; Trioxon; Veon 245; Verton 2T; VEON; Weedar;
Weedone (Meister, 1983).
Uses
0 Salts and esters of 2,4,5-T are widely used to control woody plants
on industrial sites and rangeland. Amine formulations are used
extensively 'for weed control in rice (Meister, 1983).
Properties (BCPC, 1983; Meister, 1983; Windholz et al., 1983; Khan, 1985;
CHEMLAB, 1985)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (25°C)
Specific Gravity
Water Solubility (25°C)
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C8H503C13
255.49
Crystals
153°C
6.46 x 10~6 mm Hg
Solubility of acid is 150 g/L; amine
salts are soluble at 189 g/L (20°C);
esters are insoluble
3.00 (calculated)
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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Occurrence
0 2,4,5-T has been found in 5,009 of 24,516 surface water samples
analyzed and in 360 of 3,238 ground water samples (STORET, 1987).
Samples were collected at 3,967 surface water locations and 2,124
ground water locations, and 2,4,5-T was found in 45 states. The 85th
percentile of all nonzero samples was 0.1 ug/L in surface water and
1 ug/L in ground water sources. The maximum concentration found was
370 ug/L in surface water and 38 ug/L in ground water.
Environmental Fate
0 No information was found in the available literature on the environ-
mental fate of 2,4,5-T.
III. PHARMACOKINETICS
Absorption
0 In a study by Gehring et al. (1973), single oral doses of 5 mg/kg
2,4,5-T were ingested by five male volunteers. Essentially all
the 2,4,5-T was excreted unchanged via the urine, indicating that
gastrointestinal absorption was nearly complete.
* Fang et al. (1973) administered single doses of 14C-labeled 2,4,5-T
in corn oil by gavage to pregnant and nonpregnant female Wistar rats
at dose levels of 0.17, 4.3 or 41 mg/kg. Expired air, urine, feces,
internal organs and tissues were analyzed for radioactivity. During
the first 24 hours, an average of 75 ±7% of the radioactivity was
excreted in the urine, indicating that at least 75% of the dose had
been absorbed.
0 Piper et al. (1973) administered single oral doses of 14C-labeled
2,4,5-T in corn oil-acetone (9:1) to adult female Sprague-Dawley rats
at dose levels of 5, 50, 100 or 20 mg/kg, and to adult female beagle
dogs at 5 mg/kg. Fecal excretion was 3% at the lowest dose (5 mg/kg)
and increased to 14% at the highest dose (200 mg/kg) in rats. In
dogs given the 5 mg/kg dose, fecal excretion was 20%. These data
indicated that absorption was somewhat dose dependent, but was 80% or
higher at all doses.
Distribution
0 Gehring et al. (1973) administered single oral doses of 5 mg/kg of
2,4,5-T to five male volunteers. Essentially all the 2,4,5-T was
absorbed in the body; 65% of the absorbed dose resided in the plasma
where 98.7% was bound reversibly to protein. The volume of distribution
was 0.097 L/kg. Utilizing the kinetic constants from the single-dose
experiment, the expected concentrations of 2,4,5-T in the plasma
of individuals receiving repeated doses of 2,4,5-T were calculated.
From these calculations, it was determined that the plasma concentra-
tions would essentially reach a plateau value after 3 days. If the
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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daily dose ingested in mg/kg is AQ, the concentrations in the plasma
after attaining plateau would range from 12.7 AQ to 22.5 AQ ug/mL
(Gehring et al., 1973).
9 Fang et al. (1973) administered single oral doses of 1 4C-labeled
2,4,5-T to pregnant and nonpregnant female Wistar rats and internal
organs and tissues were analyzed for radioactivity. Radioactivity
was detected in all tissues, with the highest concentration found in
the kidney. The maximum concentration in all tissues was generally
reached between 6 and 12 hours after administration of the~dose
(0.17, 4.3 or 41 mg/kg) by gavage, and then started to decline rapidly„
Radioactivity also was detected in the fetuses and in the milk of the
pregnant rats. The average biological half-life of 2,4,5-T in the
organs was 3.4 hours for the adult rats and 97 hours for the newborn.
0 Piper et al. (1973) administered single oral doses of 5, 50, 100 or
200 mg/kg 2,4,5-T to Sprague-Dawley rats, and found that the apparent
volume of distribution increased with dose, indicating that distribution
of 2,4,5-T in the body was dose-dependent.
Metabolism
0 Gehring et al. (1973) administered single oral doses of 5 mg/kg •
2,4,5-T to human volunteers. Essentially all the chemical was
excreted in the urine as parent compound, indicating that there is
little metabolism of 2,4,5-T in humans.
0 Grunow et al. (1971) investigated the metabolism of 2,4,5-T in male
Wistar (AF/Han) rats after receiving single oral doses of 50 mg/kg.
The 2,4,5-T was dissolved in peanut oil and administered by gavage.
Urine was collected for 7 days after dosing and examined by gas
chromatography for 2,4,5-T and its conjugates and metabolites. From
45 to 70% of the administered dose was recovered in urine. In general,
about 10 to 30% of this was as acid-hydrolyzable conjugates, and the
remainder was unchanged 2,4,5-T. Three animals were given doses of
75 mg/kg, and their urine pooled. A metabolite isolated from this
pooled urine was identified as N-(2,4,5-trichlorophenoxy-acetyl)-
glycine.
0 Piper et al. (1973) administered single oral doses of 2,4,5-T to
female Sprague-Dawley rats at dose levels of 5, 50, 100 or 200 mi./kg.
A small amount of an unidentified metabolite was detected in urine at
the high doses, but not at the lower doses. In adult beagle dogs
given oral doses of 5 mg/kg, three unidentified metabolites were
detected in urine, suggesting a difference in metabolism between rats
and dogs.
0 In a study by Fang et al. (1973) in female Wistar rats, urinalysis
revealed that 90 to 95% of the radioactivity was unchanged 2,4,5-T.
The authors also found three unidentified minor metabolites, two of
which were nonpolar, in the urine.
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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Excretion
0 In a study by Gehring et al. (1973), single doses of 5 mg/kg 2,4,5-T
were ingested by five male volunteers. Hie concentrations of 2,4,5-T
in plasma and its excretion were measured at intervals after ingestion.
• The clearances from the plasma, as well as the body, occurred via
apparent first-order rate processes with half-lives of 23.1 and 29.7
hours, respectively. Essentially all the 2,4,5-T was excreted
unchanged via the urine.
0 In a study by Fang et al. (1973), 2,4,5-T labeled with 1 4c was orally
administered to pregnant and nonpregnant female Wistar rats at various
dosages, and expired air, urine and feces were analyzed for radio-
activity. During the first 24 hours, 75 ± 7% of the radioactivity
was excreted in the urine and 8.2% was excreted in the feces. No 14C
was found in the expired air. There was no significant difference in the
rate of elimination between the pregnant and nonpregnant rats, or
among the dosages used (0.17, 4.3 and 41 mg/kg). The average biological
half-life of 2,4,5-T in the organs was 3.4-hours for the adult rats
and 97 hours for the newborn.
0 Grunow et al. (1971) investigated the excretion of 2,4,5-T in male
Wistar (AF/Han) rats after single oral doses of 50 mg/kg. The 2,4,5-T
was dissolved in peanut oil and administered by gavage. From 45 to
70% of the administered dose was recovered in urine within 7 days.
0 Clearance of 14C activity from the plasma and its elimination from
the body of rats and dogs were determined after single oral doses of
labeled 2,4,5-T (Piper et al., 1973). The half-life values for the
clearance of radioactivity from the plasma of Sprague-Dawley (Spartan
strain) rats given doses of 5, 50, 100 or 200 mg/kg were 4.7, 4.2,
19.4 and 25.2 hours, respectively; half lives for elimination from
the body were 13.6, 13.1, 19.3 and 28.9 hours, respectively. Urinary
excretion of unchanged 2,4,5-T accounted for 68 to 93% of the radio-
activity eliminated from the body of the rats. Fecal excretion was
3% at 5 mg/kg, and increased to 14% at 200 mg/kg. These results
indicate that the excretion of 2,4,5-T is altered when large doses
are administered. In adult beagle dogs given doses of 5 mg/kg, the
half-life values for clearance from plasma and elimination from the
body were 77.0 and 86.6 hours, respectively. After 9 days, 11% of
the dose was recovered in urine and 20% was recovered in feces.
IV. HEALTH EFFECTS
Technical 2,4,5-T contains traces of the highly toxic compound
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an impurity (NAS, 1977).
Preparations of 2,4,5-T formerly contained TCDD at levels of 1 to 80
ppm, a concentration sufficiently high to cause toxic effects that
are characteristic of TCDD. It has not been feasible to completely
eliminate TCDD from technical 2,4,5-T, but NAS (1977) reported it to be
present in commercial 2,4,5-T at less than 0.1 ppm. In the following
sections, the purity of 2,4,5-T or the level of TCDD impurity is
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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given when known. When the generic term "dioxin" is used, no further
information was provided, and the 2,4,5-T is presumed to contain a
variety of dioxin species as well as other phenoxy compounds and
assorted intermediates and breakdown products.
Humans
Short-term Exposure
0 No clinical effects were observed in five volunteers who ingested
single oral doses of 5 mg/kg of 2,4,5-T (Gehring et al., 1973).
0 After an explosion in a chemical plant producing 2,4,5-T in 1949,
symptoms in exposed workers included chloracne, nausea, headache,
fatigue, and muscular aches and pains (Zack and Suskind, 1980).
Long-term Exposure
0 The mortality experience in a cohort of 1,926 men who had sprayed
2,4,5-T acid during 1955 to 1971 was followed prospectively from 1972
to 1980. Exposure was generally rather low because the duration of
work had mostly been less than 2 months. In the period 1972 to 1976,
mortality from all natural causes in this group was only 54% of the
expected value (based on age-specific rates for the general population),
and in the next 4-year period, 81% of the expected value. In the
assessment of cancer, mortality allowance was made for 10- and 15-year
periods of latency" between the first exposure and the start of the
recording of vital status during the followup. No increase in cancer
mortality was detected, and the distribution of cancer types was
unremarkable. No cases of death from lymphomas or soft tissue sarcomas
were found. It was noted, however, that the study results should be
interpreted with caution due to the small size of the cohort, the low
past exposure, and the brief followup period (Riihimaki et al., 1982).
0 An investigation of the rate of birth malformations in the Northland
region of New Zealand was analyzed with reference to the exposure in
the area to 2,4,5—T, which was applied as frequently as once a month
from 1960 to 1977. The chosen area was divided into sectors rated as
high, intermediate or low, based on the frequency of aerial spraying.
During this period, there were 37,751 babies born in the hospitals in
these sectors. It was estimated that well over 99% of all births
occur in hospitals in this Nortnland area. The epidemiological
analysis of the birth data gave no evidence that any malformation of
the central nervous system, including spina bifida, was associated
with the spraying of 2,4,5-T. Heart malformations, hypospadias, and
epispadias increased with spraying density, but the increases were
not statistically cignificant (p >0.05). The only anomaly that
increased in a statistically significant (p <0.05) manner with respect
to the spraying was,talipes (club foot) (Hanify et al., 1981).
0 The relationship between the use of 2,4,5-T in Arkansas and the
concurrent incidence of facial clefts in children was studied retro-
spectively. The estimated levels of exposure were determined by
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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categorizing the 75 counties into high, medium and low exposure groups
on the basis of their rice acreage during 6- to 7-year intervals
beginning in 1943. A total of 1,201 cases of cleft lip and/or cleft
palate for the 32 years (until 1974) was detected by screening birth
certificates and hospital records. Facial cleft rates, presented by
sex, race, time period and exposure group, generally rose over time.
No significant differences were found for any race or sex combination.
The investigators concluded that the general increase seen in facial
cleft incidence in the high- and low-exposure groups was attributable
to better case finding rather than maternal exposure to 2,4,5-T
(Nelson et al., 1979).
Ott et al. (1980) reported no effects in a survey of 204 workers
engaged in 2,4,5-T production at estimated airborne levels of 0.2 to
0.8 mg/m3 for 1 month to 10 years.
Numerous epidemiological studies on the relationship between exposure
to chlorophenoxyacetic acids and cancer induction are reviewed in
U.S. EPA (1985). The conclusion in this review is that there is
"limited" evidence for the carcinogenicity of chlorinated phenoxyacetic
herbicides and/or chlorophenols with chlorinated dibenzodioxin impuri-
ties, primarily based on Swedish case-control studies that associated
induction of soft-tissue sarcomas with exposure to these agents.
Animals
Short-term Exposure
0 The acute oral toxicity of 2,4,5-T was determined in mice, rats and
guinea pigs by Rowe and Hymas (1954) over a 2-week period. The LD^Q
values were 500 mg/kg for rats, 389 mg/kg for mice and 381 mg/kg for
guinea pigs.
0 Drill and Hiratzka (1953) investigated the acute oral toxicity of
2,4,5-T in adult mongrel dogs given single oral doses of 50, 100, 250
or 400 mg/kg by gelatin capsule. Animals were observed for 14 days,
at which time survivors were necropsied. The number of deaths at the
four dose levels were 0/4, 1/4, 1/1 and 1/1, respectively. The LDsg
value was estimated to be 100 mg/kg or higher. Marked changes were
not observed in animals that died, effects being limited to weight
loss, slight to moderate stiffness in the hind legs and ataxia (at
the highest doses).
0 Weanling male Wistar rats were fed diets containing 2,4,5-T for 3
weeks to investigate effects on the immune system (Vos et al., 1983).
2,4,5-T (>99% purity, TCDD content not specified) was fed at levels
of 200, 1,000 or 2,500 ppm (approximately 20, 100 or 250 mg/kg/day,
assuming 1 ppm equals 0.1 mg/kg/day in a younger rat by Lehman, 1959).
Following the 3-week feeding period, the animals were sacrificed and
the organs of the immune system, as well as other parameters of
general toxicity, were examined. Even at the lowest dose level of
200 ppm in the diet, 2,4,5-T caused a significant (p <0.05) decrease
in relative kidney weight and a significant (p <0.05) increase in
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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serum IgG level, the most sensitive indicators of its effects. In
this study, based on general toxicologic and specific immunologic
effects in the rat, the Lowest-Observed-Adverse-Effect-Level (LOAEL)
was 20 mg/kg/day.
Dermal/Ocular Effects
0 Gehring and Betso (1978) summarized the effects of 2,4,5-T on the skin
and the eye. The dry material is slightly irritating to the skin and
the eye. Highly concentrated solutions may burn the skin with
prolonged or repeated contact and can strongly irritate the eye and
possibly cause corneal damage. Preparations of 2,4,5-T formerly
contained 1 to 80 ppm 2,3,7,8-TCDD, a concentration high enough to
cause chloracne in industrial workers (NAS, 1977).
Long-term Exposure
0 Drill and Hiratzka (1953) investigated the subchronic toxicity of
2,4,5-T in adult mongrel dogs. One or two dogs of each sex per group
were fed capsules in food containing 0, 2, 5, 10 or 20 mg/kg 2,4,5-T,
5 days per week for 13 weeks. Animals were weighed twice weekly, and
blood was taken on days 0, 30 and 90. Upon death or completion of
the study, animals were necropsied with histological examination of
a number of tissues. No deaths occurred at doses of 10 mg/kg/day or
less, but 4/4 animals receiving 20 mg/kg/day died. No effects on
body weight, hematology and pathology were seen except in animals
that died. The No-Observed-Adverse-Effect-Level (NOAEL) was identified
as 10 mg/kg/day.
0 McCollister and Kociba (1970) examined the effects of 2,4,5-T admini-
stered in the diet for 90 days to male and female Sprague-Dawley rats
(Spartan strain). The 2,4,5-T (99.5% pure, <0.5 ppm dioxin) was
included in the diet at levels corresponding to doses of 0, 3, 10, 30
or 100 mg/kg/day. Five animals of each sex were used at each dose
level. At the conclusion of the study, necropsy, urinalyses, blood
counts and clinical chemistry assays were performed. There was no
mortality in any group. At 100 mg/kg, animals of both sexes had
depressed (p <0.05) body weight gain, a slight but significant
(p <0.05) decrease in food intake and elevated (p <0.05) serum alkaline
phosphatase (AP) levels. Necropsy revealed paleness and an accentuated
lobular pattern of the liver, with some inconsistent hepatocellular
swelling. Males (but not females) had slightly elevated serum glutamic-
pyruvic transaminase (SGPT) levels, and slight decreases in red blood
cell counts and in hemoglobin. Males given 100 mg/kg/day had increased
(p <0.05) kidney/body and liver/body weights. At the 30 mg/kg/day
dose level, males exhibited increased (p <0.05) liver/body, kidney/body,
and kidney weights. Females given 30 mg/kg/day had slightly but
significantly (p <0.05) elevated AP and SGPT levels, but the authors
felt that the clinical significance of these latter findings was
doubtful. No effects observed at the 3 or 10 mg/kg dose level were
considered to be related to the intake of 2,4,5-T. From this study,
a NOAEL of 10 mg/kg/day and a LOAEL of 30 mg/kg/day were identified.
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0 Groups of Sprague-Dawley rats (50/sex/level) were maintained on diets
supplying 3, 10 or 30 mg/kg/day of 2,4,5-T for 2 years (Kociba et al.,
1979). The 2,4,5-T was approximately 99% pure, containing 1.3% (w/w)
other phenoxy acid impurities. Dioxins were not detected, the limit
of detection for TCDD being 0.33 ppb. An interim sacrifice was
performed on an additionally included group of 10 animals of each sex
at 118 to 119 days. Control groups included 86 animals of each sex.
The highest dose level was associated with some degree of toxicity,
including a decrease in body weight gain (p <0.05 in females) and an
increase in relative kidney weight (p <0.05 in males). Increases
(p <0.05) in the volume of urine excreted and in the urinary excretion
of coproporphyrin and uroporphyrin were also observed at this dose
level. Increased (p <0.05) morphological changes were observed in the
kidney, liver and lungs of animals administered 30 mg/kg/day. The
kidney changes involved primarily the presence (p <0.05) of mineralized
deposits in the renal pelvis in females. Effects noted at the 10 mg/kg
dose level were primarily an increased (p <0.05) incidence of miner-
alized deposits in the renal pelvis in females. During the early
phase of the study there was an increase (p' <0.05) in urinary excretion
of coproporphyrin in males. At the lowest dose level (3 mg/kg),
there were no changes that were considered to be related to treatment
throughout the 2-year period. From this study in rats, a NOAEL of
3 mg/kg/day was identified.
Reproductive Effects
0 Male and female Sprague-Dawley rats (FQ) were fed lab chow containing
2,4,5-T (<0.03 ppb TCDD) to provide dose levels of 0, 3, 10 or 30
nig/kg/day for 90 days and then were bred (Smith et al., 1981). At
day 21 of lactation, pups were randomly selected for the following
generation (F-j) and the rest were necropsied. Subsequent matings were
conducted to produce F2, F3a and F3D litters, successive generations
being fed from weaning on the appropriate test or control diet.
Fertility was decreased (p <0.05) in the matings of the F^b litters in
the group given 10 mg/kg/day. Postnatal survival was significantly
(p <0.05) decreased in the F2 litters of the 10 mg/kg group and in the
F1, F2 and F3 litters of the 30 mg/kg group. A significant decrease
(p <0.05) in relative thymus weight was seen only in the F3t> generation
of the 30 mg/kg group, but the relative liver weights of weanlings
was significantly (p <0.05) increased in the F2» F3a and F^b litters
of this dosage group. Smith et al. concluded t^at dose levels of
2,4,5-T that were sufficiently high to cause signs of toxicity in
neonates had no effect on the reproductive capacity of the rats,
except for a tendency toward a reduction of postnatal survival at a
dose of 30 mg/kg. Reproduction was not impaired at the lowest dose
of 3 mg/kg. The apparent NOAEL with respect to reproductive capacity
and fetotoxic effects in this study is 3 mg/kg/day. Smith et al.
(1978) noted a significant (p <0.05) decrease in FT (10 and 30 mg/kg
on days 14 and 21) and F3 (3 mg/kg on day 14, and 10 and 30 mg/kg on
day 21) litters, and they concluded that there was no effect of
2,4,5-T on rat reproduction except for a tendency toward a reduction
in neonatal survival at 10 and 30 mg/kg.
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Developmental Effects
0 Sparschu et al. (1971) tested 2,4,5-T (commercial grade, 0.5 ppm TCDD)
at levels of 50 or 100 mg/kg/day in pregnant rats (strain not specified)
on either days 6 to 1 5 (50 mg/kg) or days 6 to 10 (100 mg/kg) of
gestation. The 2,4,5-T was administered by oral intubation in a
solution of Methocel, and controls were given an appropriate volume
of Methocel. At the 50 mg/kg dose, there was a slightly higher
incidence of delayed ossification of the skull bones, but this was
not considered a teratogenic response. The 100 mg/kg dose (administered
on days 6 to 10) was toxic to the dams and caused a high incidence of
maternal deaths (only 4 of the 25 pregnant rats survived). Of these,
three had complete early resorptions, and one had a litter of 13
viable fetuses that showed toxic effects (not further described) but
no terata. From these data for maternal effects, a NOAEL of 50 mg/kg
and a LOAEL of 100 mg/kg were identified. Also identified were a
NOAEL of 100 mg/kg for teratogenicity and a LOAEL of 50 mg/kg for
fetotoxicity.
0 A sample of 2,4,5-T (technical grade) containing 0.5 ppm TCDD as well
as other phenoxy compounds was administered to CD-1 rats by oral
intubation on days 6 through 15 of gestation at dose levels of 10,
21.5, 46.4 or 80 mg/kg/day (Courtney and Moore, 1971). Examination
of offspring revealed that the sample was not teratogenic at these
dose levels. There was a significant (p <0.05) increase in fetal
mortality at the 80 mg/kg/day dose levels (the maternal LD4Q). In
two 2,4,5-T-treated fetuses, mild gastrointestinal hemorrhages were
observed as a fetotoxic effect. Kidney anomalies were also slightly
increased with the effect most pronounced at the 80 mg/kg level, but
the number of litters examined was too small to evaluate this observa-
tion. In a separate study, rats were administered 50 mg/kg/day in an
identical protocol, but in this case they were allowed to litter, and
the neonates were examined and weighed on day 1 and followed for 21
days. Postnatal growth and development were comparable to that of
the control animals. A NOAEL of 46.4 mg/kg/day for both fetotoxicity
and teratogenicity in the CD-1 rat was identified from these data.
0 Sprague-Dawley rats (50/group) and New Zealand White rabbits (20/group)
were given oral doses (gavage for rats, capsules for rabbits) of
2,4,5-T (containing 0.5 ppm TCDD) during gestation (Emerson et al.,
1971). The rats received daily doses of 1, 3, 6, 12 or 24 mg/kg on
days 6 through 15, while the raobits were administered 10, 20 or 40
mg/kg on days 6 through 18 of gestation. In both species, animals
were observed daily, weighed periodically and subjected to Cesarean
section prior to parturition. Rabbit pups were kept for observation
for 24 hours and then sacrificed. There were no observable adverse
effects in dams of either species treated with the 2,4,5-T. Litter
size, number of fetal resorptions, birth weights and sex ratios all
appeared to be unaffected in the treated groups. Detailed visceral
and skeletal examinations were performed on the control and high-dose
groups for each species, and no embryotoxic or teratogenic effects
were revealed. A NOAEL for fetotoxic 'and maternal effects identified
from this study was 24 mg/kg/day for the rat and 40 mg/kg/day for the
rabbit.
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0 Several different samples of 2,4,5-T (containing <0.5 ppm TCDD) were
tested in pregnant Wistar rats by daily oral administration on days
6 through 15 of gestation at dose levels between 25 and 150 mg/kg/day
(Khera and McKinley, 1972). In some cases, fetuses were removed by
Cesarean section for examination; some animals were allowed to litter,
and the offspring were observed for up to 12 weeks. At doses of
100 rag/kg, there was an increase (p <0.05) in fetal mortality and an
increase (p <0.05) in skeletal anomalies; a visceral anomaly was noted
(dilatation of the renal pelvis), which was slightly increased over
the control level, but was not statistically significant (p >0.05).
The survival of the progeny was not affected up to doses of 100 mg/kg,
and in only one trial was there a low average litter size and viability.
This effect was not duplicated in a repeat test with the same sample.
At the 25 and 50 mg/kg dose levels, significant (p <0.05) differences
from controls were not apparent. With respect to fetotoxicity, this
study identified a NOAEL of 50 mg/kg/day in the rat.
0 The teratogenic effects of 2,4,5-T were examined in golden Syrian
hamsters after oral dosing (by gavage) on days 6 through 10 of gestation
at dose levels of 20, 40, 80 or 100 mg/kg/day (Collins et al., 1971).
Four samples of 2,4,5-T with dioxin levels of 45, 2.9, 0.5 or 0.1 ppm
were administered. Three samples, which had no detectable dioxin
(based on TCDD), were also tested. The 2,4,5-T samples induced fetal
death and terata. The incidence of effects increased with increasing
content of the TCDD impurity. 2,4,5-T with no detectable dioxin
produced no malformations below the 100 mg/kg dose level. Using the
data from the 2,4,5-T samples with no detectable dioxin, a NOAEL of
80 mg/kg/day for the hamster was identified.
0 Behavioral effects resulting from in utero exposure to 2,4,5-T were
examined in Long-Evans rats after single oral doses were administered
during gestation (Crampton and Rogers, 1983). The sample of 2,4,5-T
contained <0.03 ppm TCDD. Novelty response abnormalities were
detected after single doses as low as 6 mg/kg were administered on
day 8 of gestation. Examination of the brain in the affected offspring
failed to reveal any changes of a qualitative or quantitative structural
nature in various areas of the brain. With respect to behavioral
effects, the LOAEL for this study is 6 mg/kg.
0 The teratogenic effects of technical 2,4,5-T (TCDD content 0.1 ppm)
were studied using large numbers of pregnant mice of C57BL/6, C3H/He,
BALB/c and A/JAX inbred strains and CD-1 stock (Gaines et al., 1975).
Dose-response curves were determined for the incidence of cleft
palate, embryo lethality and fetal growth retardation. These deter-
minations were replicated 6 to 1 0 times for each inbred strain and
35 times for the CD-1. The number of litters studied ranged from 2J6
for BALB/c mice to 1,485 for CD-1 mice. Treatment was by gavage on
days 6 to 14 of pregnancy, and dose levels of 2,4,5-T ranged from 15
to 120 mg/kg/day. The lowest dose tested in the A/JAX was 15 mg/kg,
and this dose was teratogenic. The other strains and CD-1 demonstrated
teratogenicity at 30 mg/kg, the lowest dose tested. There were
significant (p <0.05) differences in sensitivities among the strains
for the parameters measured. Based on this study in the mouse, the
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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LOAEL for teratogenic effects is 15 mg/kg/day for the A/JAX strain
and 30 mg/kg/day for the other strains.
0 Neubert and Dillmann (1972) studied the effects of 2,4,5-T in pregnant
NMRI mice. Three samples of 2,4,5-T were utilized: one had <0.02 ppm
dioxin, and was considered "dioxin-free"; a_second sample had a dioxin
content of 0.05 i 0.02 ppm; and the third sample had an undetermined
dioxin content. The 2,4,5-T was administered by gavage on days 6
through 15 of gestation at dose levels from 8 to 120 mg/kg/day.
Fetuses were removed on day 18 and examined. Cleft palate frequency
exceeding (p <0.05) that of the controls was observed with doses
higher than 30 mg/kg with all samples. Reductions (p <0.05) in fetal
weight were observed with all samples tested at doses as low as 10 to
15 mg/kg. There was no clear increase in embryo lethality over that
of controls at these lower doses. With the purest sample of 2,4,5-T,
single oral doses of 150 to 300 mg/kg were capable of producing
significant (p <0.05) incidences of cleft palate. The maximal terato-
genic effect was seen when the 2,4,5-T was administered on days 12 to
13 of gestation. Based on the data obtained with the purest sample
of 2,4,5-T, the teratogenic NOAEL is 15 mg/kg/day and the fetotoxic
NOAEL is 8 mg/kg/day.
0 Roll (1971) examined the teratogenic effects of 2,4,5-T in NMRI-Han
mice after oral administration on days 6 to 15 of gestation at dose
levels of 0, 20, 35, 60, 90 or 130 mg/kg/day. The 2,4,5-T sample had
a purity of 99.6%, with a dioxin content of <0.01 ppm (measured by
the DOW method), or 0.05 ± 0.02 ppm (measured by the U.S. Food and
Drug Administration (FDA) method). Peanut oil was used as the vehicle.
Animals were sacrificed on day 18 and examined for defects. Fetal
weight was significantly (p <0.05) lower than control at all doses.
Resorptions were significantly (p <0.05) increased at 60 mg/kg and
above. The incidence of cleft palates was significantly (p <0.05)
higher at 35 mg/kg and higher, but there was no effect at 20 mg/kg.
There were also dose-dependent increases in ossification defects of
sternum and various other bones. The authors concluded that 2,4,5-T
alone (independent of TCDD contamination) was teratogenic in mice,
and that the teratogenic NOAEL in this strain was 20 mg/kg/day. In
view of the significantly (p <0.05) lower fetal weight at 20 mg/kg/day,
this level may also be considered the LOAEL for fetotoxicity.
0 No teratogenic effects were observed in the offspring of female
rhesus monkeys that were given oral doses of 0.05, 1.0 or 10.0 mg
2,4,5-T (containing 0.05 ppm TCDD)/kg/day in capsules during gestation
days 22 through 38. Neither was toxicity evident in the mothers
(Dougherty et al., 1976).
Mutagenicity
0 At 250 and 1,000 ppm 2,4,5-T (with no detectable TCDD), mutation
rate was significantly (p <0.05) increased at the higher dose in the
sex-linked recessive lethal test in Drosophila as carried out by
Majumdar and Golia (1974). The sex-linked test was not affected by
920 or 1,804 ppm of the sodium salt of 2,4,5-T at pH 6.8 in a study
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
-13-
carried out by Vogel and Chandler (1974). Although they found no
cytogenetic effects in Drosophila, Magnusson et al. (1977) concluded
that 1,000 ppm 2,4,5-T (<0.1 ppm TCDD) did cause an increase (p <0.05)
in the number of recessive lethals compared to the controls. Rasmusson
and Svahlin (1978) treated Drosophila larvae to food containing 100
and 200 ppm 2,4,5-T; survival was low at 200 ppm, but 2,4,5-T had
no observable effect on somatic mutational activity.
0 Anderson et al. (1972) found that neither 2,4,5-T nor its butyric
acid form showed any mutagenic action when tested on histidine—
requiring mutants of Salmonella typhimurium.
0 Buselmaier et al. (1972) found that intraperitoneal injection of
2,4,5-T (dioxin levels not given) had no effect in the host-mediated
assay (500 mg/kg) or in the dominant lethal test (100 mg/kg) with
NMRI mice. Styles (1973), likewise, found no increase in back mutation
rates with the serum of rats treated orally with 2,4,5-T in the
host-mediated assay with Salmonella typhimurium (dosages and purity
of the samples not given).
0 Shirasu et al. (1976) found that 2,4,5-T did not induce mitotic gene
conversion in a diploid strain of Saccharomyces cerevisiae. When the
pH of the treatment solution was less than 4.5, Zetterberg (1978)
found that 2,4,5-T was mutagenic in haploid, DNA-repair-defective
.§.• cerevisiae.
0 Jenssen and Renberg (1976) investigated the cytogenetic effects of
2,4,5-T in mice by examining the ability of the herbicide to induce
micronuclei formation in the erythrocytes of mouse bone marrow. CBA
mice were treated at 8 to 1 0 weeks of age (20 to 30 g) with a single
intraperitoneal injection of 100 mg/kg of 2,4,5-T (<1 ppm TCDD) dis-
solved in Tween 80 and physiological saline. Cytogenetic examination
at 24 hours and 7 days after treatment showed no detectable increase
in micronuclei in the erythrocytes compared to controls. A weak
toxic effect on the mitotic activity was indicated, as judged by a
decrease in the percentage of polychromatic erythrocytes.
Carcinogenicity
0 Innes et al. (1969) investigated the potential carcinogenic effects
of 2,4,5-T in two hybrid strains of mice derived by breeding SPF
C57BL/6 female mice to either C3H/Anf or AKR males. Beginning at
6 days of age, 2,4,5-T was administered by gavage in 0.5% gelatin to
a group of 72 mice at a dose level of 21.5 mg/kg/day. This was
reported to be the maximum tolerated dose. At 28 days of age, the
2,4,5-T was added to the diet at a level of 60 ppm, corresponding to
a dose of about 9 mg/kg/day (assuming that 1 ppm equals 0.15 mg/kg/day
in the diet from Lehman, 1959). This dose was fed for 18 months, at
which time the study was terminated. All animals were necropsied and
the tissues were examined both grossly and microscopically. There
were no significant (p >0.05) increases in tumors in either strain of
treated mice.
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2, 4, 5-Trichlorophenoxyacetic Acid August, 1987
-14-
* A lifetime study using oral administration of 2,4,5-T in both sexes
of two strains of mice, C3Hf and XVII/G, was performed by Muranyi-
Kovacs et al. (1976). The 2,4,5-T, which contained less than 0.05
ppm of dioxins, was administered in the water (1,000 mg/L) for 2
months beginning at 6 weeks of age, and thereafter in the diet at
80 ppm (12 mg/kg/day) until death or when the mice were sacrificed in
extremis. In the treated C3Hf mice there was a significant (p <0.03)
increase in the incidence of total tumors found in female mice and a
significant (p <0.001) increase in total nonincidental tumors in each
sex, which the authors interpreted as life-threatening. No signifi-
cant (p >0.05) difference was found in the XVII/G strain between the
treated and control mice. The authors felt that 2,4,5-T demonstrated
carcinogenic potential in the C3Hf strain, but that additional studies
in other strains and in other species of animals needed to be performed
before a reliable conclusion with respect to carcinogenicity could be
made.
0 Groups of Sprague-Dawley rats (50 each of males and females) were
maintained on diets supplying 3, 10 or 30 mg/kg/day of 2,4,5-T for 2
years (Kociba et al., 1979). The 2,4,5-T was approximately 99% pure,
containing 1.3% (w/w) other phenoxy acid impurities. Dioxins were
not detected, the limit of detection for TCDD being 0.33 ppb. An
interim sacrifice was performed on an additionally included group of
10 animals of each sex at 118 to 119 days. Control groups included
86 animals of each sex. At the end of the 2-year period, there was
no significant (p >0.05) increase in tumor incidence in any treated
group compared to the control for either male or female animals.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) X (BW) = /L ( /L)
(UF) x { L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
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2,4%5-Trichlorophenoxyacetic Acid August, 1987
' ?
-15-
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One-day HA value for 2,4,5-T. The study in humans
by Gehring et al. (1973) was not selected because observations of the subjects
were reported simply as clinical effects without further details. The
behavioral study in rats by Crampton and Rogers (1983) was not selected
because the interpretation of altered novelty response behavior in the absence
of other toxic signs needs further investigation before definitive conclusions
can be made. It is therefore recommended that the Ten-day HA value for a
10-kg child (0.8 mg/L, calculated below) be used at this time as a conservative
estimate of the One-day HA value.
Ten-day Health Advisory
The study by Neubert and Dillman (1972) has been selected to serve as
the basis for determination of the Ten-day HA value for 2,4,5-T. This
developmental study in rats identified a NOAEL of 8 mg/kg/day and a LOAEL
of 15 mg/kg/day, based on reduced body weights in pups from dams exposed on
days 6 to 15 of gestation. This LOAEL is supported by a number of other
developmental studies in rodents that identified LOAELs ranging from 15 to
100tmg/kg/day (Roll, 1971; Sparschu et al., 1971; Khera and McKinley, 1972;
Gaines et al., 1975). In the 21-day feeding study in rats by Vos et al.
(1983), a LOAEL of 20 mg/kg/day was identified based on effects on kidney
weight and the immune system. The 8 mg/kg/day NOAEL for fetal effects selected
from the Neubert and Dillman (1972) study may not be applicable to a 10-kg
child; however, the assumptions for a 10-kg child are used with this NOAEL
in this case since, although a NOAEL was not found in the 21-day study by
Vos et al. (1983) where the observed effects are applicable to a 10-kg child,
the LOAEL of 20 mg/kg/day is 2.5 times higher than the NOAEL used for the
Ten-day HA.
Using a NOAEL of 8 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = <8 mg/kg/day) (10 kg) = 0>8 /L (80Q /L)
(100) (1 L/day)
where:
8 mg/kg/day = NOAEL, based on absence of maternal or fetal effects in
rats exposed by gavage on days 6 to 15 of gestation.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
The reproduction study by Smith et al. (1981, 1978) has been selected
to serve as the basis for the Longer-term HA value for 2,4,5-T because the
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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reduction in neonatal survival over multiple generations is concluded to be
relevant to the Longer-term HA for a 10-kg child. The NOAEL identified was
3 mg/kg/day, and the LOAEL was 10 mg/kg/day. Other possible selections have
a higher NOAEL [10 mg/kg/day in the 90-day feeding study in rats by McCollister
and Kociba (1970) and the 90-day oral treatment study in dogs by Drill and
Hiratzka (1953)].
Using a NOAEL of 3 mg/kg/day, the Longer-term HA for a 10-kg child is
calculated as follows:
Longer-term HA * (3 mg/kg/day) (10 kg) = 0.3 mg/L (300 ug/L)
(100) (1 L/day)
where:
3 mg/kg/day = NOAEL, based on absence of adverse effects in neonatal rats
in the three-generation reproduction study in rats given
2,4,5-T in the diet.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (3 mg/kg/day) (70 kg) -LOS mg/L (1,050 ug/L)
(100) (2 L/day)
where:
3 mg/kg/day = NOAEL, based on absence of adverse effects in neonatal rats
in a three-generation reproduction study in rats given
2,4,5-T in the diet.
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 sf.dy.
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
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2,4,5-Trichlorophenoxyacetic Acid « August, 1987
-17-
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, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The study by Kociba et al. (1979) has been selected to serve as the
basis for the Lifetime HA value for 2,4,5-T. In this study, rats were fed
2,4,5-T in the diet for 2 years. Based on observations of effects of 2,4,5-T
on various biochemical parameters in addition to gross and microscopic obser-
vations related to general toxicity in the rats, this study identified a
NOAEL of 3 mg/kg/day and a LOAEL of 10 mg/kg/day. This study is supported by
the three-generation rat study (Smith et al., 1981, 1978) that identified a
NOAEL of 3 mg/kg/day.
Using this study, the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = j.3.0 mg/kg/day) = 0>003 mg/kg/day
(100) (10)
where:
3.0 mg/kg/day = NOAEL, based on absence of adverse effects on the
kidneys, liver and lungs of rats exposed to 2,4,5-T
in the diet for 2 years.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
10 = modifying factor used by U.S. EPA Office of Pesticide
Programs to account for data gaps (chronic feeding
study in dogs) which does not make it possible to
establish the most sensitive end point for 2,4,5-T.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0-003 mg/kg/day) (70 kg) = 0.., 05 mg/L {, Q
(2 L/day)
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2,4,5-Trichlorqphenoxyacetic Acid August, 1987
-18-
where:
0.003 mg/kg/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 = (0.105 mg/L) (20%) = 0.021 mg/L (21 ug/L)
where:
0.105 mg/L = DWEL.
20% = assumed relative source contribution from water,
Evaluation of Carcinogenic Potential
0 Chronic feeding studies with 2,4,5-T in Sprague-Dawley rats (Kociba
et al., 1979) and C57BL/6 x C3H/Anf, C57BL/6 x AKR and XVII/G strains
of mice (Innes et al., 1969; Muranyi-Kovacs, et al; 1976) were
negative for carcinogenic effects. A chronic feeding study with
2,4,5-T in C3Hf mice was inconclusive (Muranyi-Kovacs et al., 1976).
'• IARC (1982) concluded that the carcinogenic!ty of 2,4,5-T is indeter-
minant (Group 3, inadequate evidence in animals and humans).
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), 2,4,5-T may be classified in
Group D: not classified. This category is for agents with inadequate
animal evidence of carcinogenicity.
0 The Carcinogen Assessment Group (CAG) of the U.S. EPA classified
chlorophenoxyacetic acids and/or chlorophenols containing 2,3,7,8-TCDD
in IARC category 2A (probably carcinogenic in humans on the basis
of limited evidence in humans), but a quantitative cancer risk estimate
only for 2,3,7,8-TCDD itself was made. The CAG considered the human
evidence for the carcinogenicity of 2,3,7,8-TCDD alone to be "inadequate"
because of the difficulty in attributing observed effects solely to
the presence of 2,3,7,8-TCDD, which occurs as an impurity in the
phenoxyacetic acids and chlorophenols (U.S. EPA, 1985).
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The U.S.- EPA/Office of Pesticide Programs has calculated a Provisional
Acceptable Daily Intake (PADI) value of 0.003 mg/kg/day, based on the
results of a rat chronic oral NOAEL of 3 mg/kg/day with an uncertainty
factor of 1,000 (used because of data gaps).
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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0 The National Academy of Sciences (NAS, 1977) has calculated an ADI
of 0.1 mg/kg/day, using a NOAEL of 10 mg/kg/day (identified in a
90-day feeding study in dogs) and an uncertainty factor of 100. A
chronic Suggested-No-Adverse-Effeet-Level (SNARL) of 0.7 mg/L was
calculated based on the ADI of 0.1 mg/kg/day.
0 The American Conference of Governmental Industrial Hygienists (ACGIH,
1981) has recommended a Threshold Limit Value-Time-Weighted Average
(TLV-TWA) of 10 mg/m3 and a Threshold Limit Value-Short-Term Exposure
Limit (TLV-STEL) of 20 mg/m3.
0 The ADI recommended by the World Health Organization is 0 to
0.03 mg/kg (Vettorazzi and van den Hurk, 1983).
VII. ANALYTICAL METHODS
0 Determination of 2,4,5-T is by a liquid-liquid extraction gas
chromatographic procedure (U.S. EPA, 1978; -Standard Methods, 1985).
Specifically, the procedure involves the extraction of chlorophanoxy
acids and their esters from an acidified water sample with ethyl
ether. The esters are hydrolyzed to acids, and extraneous organic
material is removed by a solvent wash. The acids are converted to
methyl esters that are extracted from the aqueous phase. Separation
and identification of the esters is made by gas chromatography.
Detection and measurement are accomplished by an electron-capture,
microcoulometric or electrolytic conductivity detector. Identifica-
tion may be corroborated through the use of two unlike columns. The
detection limit is dependent on the sample size and instrumentation
used. Typically, using a 1-L sample and a gas chromatograph with
an electron-capture detector results in an approximate detection
limit of 10 ng/L for 2,4,5-T.
VIII. TREATMENT TECHNOLOGIES
Available data indicate that granular-activated carbon (GAC) and
powdered-activated carbon (PAC) adsorption will effectively remove
2,4,5-T from water.
0 Robeck et al. (1965) experimentally determined adsorption isotherms
for the butoxy ethanol ester of 2,4,5-T on PAC. Based on these
results, it was calculated that 14 mg/L PAC would be required to
remove 90% of 2,4,5-T, while 44 mg/L PAC would be required to remove
99% of 2,4,5-T (Pershe and Goss, 1979; Robeck et al., 1965).
0 Robeck et al. (1965) reported the results of a GAC column operating
under pilot plant conditions. At a flow rate of 0.5 gpm/ft3, 99+%
of 2,4,5-T was removed. By comparison, treatment with 5 to 20 mg/L
PAC removed 80 to 95% of the same concentration of 2,4,5-T.
0 in a laboratory study conducted with an exchange resin, Rees and Au
(1979) reported 89±2% removal efficiency of 2,4,5-T from contaminated
water by adsorption onto synthetic resins.
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
-20-
Conventional water treatment technique of coagulation with alum,
sedimentation and sand filtration removed 63% of the 2,4,5-T ester
present in spiked river water (Robeck et al., 1965).
Treatment technologies for the removal of 2,4,5-T from water are
available and have been reported to be effective. However, selection
of individual or combinations of technologies to attempt 2,4,5-T
removal from water must be based on a case-by-case technical evaluation,
and an assessment of the economics involved.
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2,4,5-Trichlorophenoxyacetic Acid August, 1987
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IX. REFERENCES
ACGIH. 1981. American Conference of Governmental Industrial Hygenists.
Threshold limit values for chemical substances and physical agents in
the workroom environment. Cincinnati, OH: ACGIH, p. 27.
Anderson, K.J., E.G. Leighty and M.T. Takahashi. 1972. Evaluation of
herbicides for possible mutagenic properties. J. Agric. Food Chem.
20:649-656.
BCPC. 1983. British Crop Protection Council. The pesticide manual. A
world compendium, 7th ed. (C. R. Worthing, ed.). 2,4,5-T, p. 11120.
Buselmaier, W., G. Roehrborn and P. Propping. 1972. Mutagenicity investi-
gations with pesticides in the host-mediated assay and the dominant
lethal test in mice. Biol. Zentralbl. 91:311-325.
CHEMLAB. 1985. The chemical information system. CIS, Inc., Bethesda, MD.
Collins, T.F.X., G.H. Williams and G.C. Gray. 1971. Teratogenic studies
with 2,4,5-T and 2,4-D in the hamster. Bull. Environ. Contain. Toxicol.
6(6):559-67.
Courtney, K.D. and J.A. Moore. 1971. Teratology studies with 2,4^5-tri-
chlorophenoxyacetic acid and 2, 3, 7,8-tetrachlorodibenzo-p-dioxin.
Toxicol. Appl. Pharmacol. 20:396-403.
Crampton, M.A. and L.J. Rogers. 1983. Low doses of 2,4,5-trichlorophenoxy-
acetic acid are behaviorally teratogenic in rats. Experientia. 39:891-2.
Dougherty, W.J., F. Coulston and L. Golberg. 1976. The evaluation of the
teratogenic effects of 2,4,5-trichlorophenoxyacetic acid in the Rhesus
monkey. Environ. Qual. Saf. 5:89-96.
Drill, V.A. and T. Hiratzka. 1953. Toxicity of 2,4-dichlorophenoxyacetic
acid and 2,4,5-trichlorophenoxyacetic acid. A report on their acute and
chronic toxicity in dogs. Arch. Ind. Hyg. Occup. Med. 7:61-67.
Emerson, J.L.., D.J. Thompson, R.J. Strebing, C.G. Gerbig and V.B. Robinson.
1971. Teratogenic studies on 2,4,5-trichlorophenoxyacetic acid in the
rat and rabbit. Food Cosmet. Toxicol. 9:395-404
Fang, S.C., E. Fallin, M.L. Montgomery and V.H. Freed. 1973. Metabolism and
distribution of 2,4,5-trichlorophenoxyacetic acid in female rats. Toxicol.
Appl. Pharmacol. 24(45:555-563.
Gaines, T.B., J.F. Holson, C.J. Nelson and H.J. Schumacher. 1975. Analysis
of strain differences in sensitivity and reproducibility of results in
assessing 2,4,5-T teratogenicity in mice. Toxicol. Appl. Pharmacol.
33:174-175. Abstract No. 30.
Gehring, P.J. and J.E. Betso. 1978. Phenoxy acids: Effects and fate in
mammals. Ecol. Bull. 27:122-133.
-------
2,4,5-Trichlorophenoxyacetic Acid ,..,,-, August, 1987
-22-
Gehring, P.J., C.G. Krammer, B.A. Schwetz, J.Q. Rose, V.K. Rowe and J.S. Zimmer.
1973. The fate of 2,4,5-trichloropfienoxyacetic acid (2,4,5-T) following
oral administration to man. Toxicol. Appl. Pharmacol. 25(3):441.
'Gfunpw, W., C. Bohme and B. Budczies. 1971. Renal excretion of 2,4,5-T by
rats. Food Cosmet. Toxicol. 9:667-670.
Hanify, J.A., P. Metcalf, C.L. Nobbs and K.J. Worsley. 1981. Aerial spraying
' o"f 2,4,5-T and human birth malformation: An epidemiological investigation.
Science. 212(44925:349-351.
: IARC. 1982. International Agency for Research on Cancer. IARC monographs
on the' evaluation of carcinogenic risk of chemicals to man. Lyon, Frances
IARC, *Suppl. 4.
Iriries, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein, E.R. Hart,
"'•" ~" A.jVPallotta:, R.R. Bates, H.L. Falk, J.J. Gart, M. Klein, I. Mitchell
and J. Peters'. 1969. Bioassay of pesticides and industrial chemicals
for tumorigenicity in mice: A preliminary note. J. Natl. Cancer Inst.
Jenssen, D. and L. Renberg. 1976. Distribution and cytogenetic test of
2,4,-D and 2,4,5-T phenoxyacetic acids in mouse blood tissues. Chem.
' : " Biol.-Interact. 14(3-4):291-299. . s
Khan, M.A.Q.. 1985* Personal communication to Environmental Criteria and
- Assessment Office, U.S,,, Environmental Protection Agency, Cincinnati, OH.
January.
Khera, K.S. and W.P. McKinley. 1972. Pre- and postnatal studies on 2,4,5-
* * trichlordphenoxyacetic acid, 2,4,-dichlorophenoxyacetic acid and their
"' • derivatives' in rats. Toxicol. Appl. Pnarmacol. 22:14-28.
Kociba, R.J., D.J. Keyes, R.W. Lisowe, R.P. Kalnins, D.D. Dittenber, C.E. Wade,
S.J. Gorzinski, N.H. Mahle and B.A. Schwetz. 1979. Results of a two-year
: • chronic" toxicity and oncogenic study of rats ingesting diets containing
" " "2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Food Cosmet. Toxicol.
- r : ' 17:205-221.
Lehman, A.j. 1959. Appraisal of the safety of chemicals in foods, drugs and
~- cosmetics. Association of Food end Drug Officials of the United States.
Magnusson, J., C. Ramel and' A.~ Eriksson. 1977. Mutagenic effects of chlori-
nated phenoxyacetic acids in Drosophila melanogaster. Hereditas.
'
Majumdar, S.K. and J.K. Golia. 1974. Mutation test of 2,4,5-trichlorophen-
oxyacetic acid on Drosophila melanogaster. Can. J. Genet. Cytol.
'--'-•'• 16(2): 465-466; '
McCollister, S.B. and R.J. Kociba. 1970. Results of 90-day dietary feeding
"c c -study on 2,4>5-trichlorophenoxyacetic acid. Unpublished study by Dow
'-* ''•' ChemicaK 'MRID 6&092151.
-------
2,4,5-Trichlorophenoxyacetic Acid August, 1987
' -23-
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH:, leister
Publishing Company. ' V",
Muranyi-Kovacs, I., G. Rudali and J. Imbert. 1976. Bioassay of 2,4,^5-tri-
chlorophenoxyacetic acid for carcinogenicity in mice. Br. J. dancer.
33:626-633.
HAS. 1977. National Academy of Sciences. Drinking water and }ieal!th,~ Vol. 1.
Washington, DC: National Academy Press. .',,'•
Nelson, C.J., J.F. Holson, H.G. Green and D.W. Gaylor. 1979. Retrospective
study of the relationship between agricultural use of 2,4',S-T arid cleft
palate occurrence in Arkansas. Teratology. 19: (3 )377-384".
j ,
Neubert, D. and I. Dillmann. 1972. Embryotoxic effects in mice treated,with
2,4, 5-trichlorophenoxyacetic acid and 2, 3, 7, S-tetrachlorodJibehzo-p-dioxin.
Naunyn-Schmiedeberg's Arch. Pharmacol.^ 272:243-264V '~ ",' ','.'.
* o • - , •" , T
Ott, M.G., B. B. Holder and R.D. Olson. 1980. A mortality analysisJof
employees engaged in the manufacture of 2,4,5-trichlorophenbxyacetic
acid. J. Occup. Med. 22(1):47-50. ,.,.,,-. ..
Pershe, E.R. and J. Goss. 1979. Uses of powdered, and gjranuj.arj" activated
carbon in water treatment. J. New Eng". Water* Works'Assbc'. Y9):254-286.
Piper, W.N., J.Q. Rose, M.L. Leng and P.J. Gehring. 1973.'.The 'fate 'of
2, 4, 5-trichlorophenoxyacetic acid (2,4/%-T") following "oral adnunistra-
tion to rats and dogs. Toxicol. Appl. Pharmacol. 26:339-351.'
Rasmusson, B. and H. Svahlin. 1978. Mutagenicity tests^pf .2., 4-dichioro-
phenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid in genetically
stable and unstable strains of Drosophila melanogaster. Ecol. Bull.
27:190-192. .. %
Rees, G.A.V. and L. Au. 1979. Use of XAD-2~macroreticuia.rJ re^sin for the
recovery of ambient trace levels of pesticides and^ industrial organic
pollutants from water. Bull. Environ. Contain. Toxicol. 22(4/5): 561-566.
Riihimaki, V., S. Asp and S. Hernberg. 1982. . Mortality of 2,4-dichloro-
phenoxyacetic acid and 2,4, S-trichlorophenoxyacetic acid, hejtbicide
applicators in Finland: first report of ah ongoing prospective cohort
study. Scand. 0. Work Environ. Health. 8.(1):3,7-42. . .. t.
* , . -' \' *. i • -. L
'•' ,")„", ' .. • , " . ~ • - " ".; ^ " , "'.
Robeck, G.G., K.A. Dostal, J.M. Cohen and J.F. Kreissl. 1965. Eff-ectiveness
of water treatment processes in pesticide removal. J. Am. Water Works
Assoc. (2):181-199.
. ' ' 1 V.-
Roll, R. 1971. Studies of the teratogenic effect of 2,4,5,rT., i.n pipe. Food
Cosmet. Toxicol. 9(5):671-676.
Rowe, V.K. and T.A. Hymas. 1954. Summary of toxicplogical-informa-jtion on
2,4-D and 2,4,5-T type herbicides and an evaluation ,of the, hazards to
livestock associated with their use. Am. J. Vet. Res. 15:622-629.
-------
T2j*,r5TTEicMorophenoxyacetic AcigJ t-". > - -^-^.y- August, 1987
ShiraSu, Y., M. Moriya, K. Kate, A. Furuhaahi andTt,Kada. 1976. Mutagenicity
tn-. t.jtr: _ screening of pesticides in the- micr-obiaL system. Mutat. Res. 40:19-30.
Smith, F.A., B.A. Schwetz, F.J. Murray, A.A. Crawford, J.A. John, R.J. Kociba
.. .T:< .. aad-'CftiJs . Humiston. 1978. Three-gener.ation. .study of rats ingesting
2,4,5-trichlorophenoxyacetic acid in the diet. . .Tpxicol. Appl. Pharmacol.
45:293 (Abst.).
Smith, F.A., F.J. Murray, J.A. John, K.D. Nitschke, R.J. Kociba and B.A.
Schwetz. 1981. Three-generation reproduction study of rats ingesting
2,4,5-trichlorophenoxyacetic acid in the diet. Food Cosmet. Toxicol.
19:41-45.
Sparschu, G.L., F.L. Dunn, R.W. Lisowe and V.K. Rowe. 1971. Study of the
effects of high levels of 2,4,5-trichlorophenoxyacetic acid on fetal
development in the rat. Food Cosmet. Toxicol. 9:527-530.
Standard Methods. 1985. Method 509B, chlorinated phenoxy acid herbicides.
Standard Methods for the Examination of Water and Wastewater, 16th ed.
APHA, AWWA, WPCF.
STORET. 1987.
Styles, J.A. 1973. Cytotoxic effects of various pesticides in vivo and in
vitro. Mutat. Res. 21(1):50-51.
U.S. EPA. 1978. U.S. Environmental Protection Agency. Method for chloro-
phenoxy acid herbicides in drinking water. Methods for organochlorine
pesticides and chlorophenoxy acid herbicides in drinking water and raw
source water. Office of Drinking Water. Washington, DC. Interim
draft, July.
U.S. EPA. 1985. U.S. Environmental Protection Agency. Health assessment
document for polychlorinated dibenzo-p-dioxins. Office of Health and
Environmental Assessment. Cincinnati, OH. EPA/600/8-84/014F.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for car-
cinogen risk assessment. Fed. Reg. 51(185):33992-34003. September 24.
Vettorazzi, G. and G.W. van den Hurd, eds. 1985. Pesticides reference index.
J.M.P.R. p. 41.
Vogel, E. and J.L.R. Chandler. 1974. Mutagenicity testing of cyclamate and
some pesticides in Drosophila melanogaster. Experientia. 30(6):621-623.
Vos, J.G., E.I. Krajnc, P.K. Beekhof and M.J. van Logten. 1983. Methods for
testing immune effects of toxic chemicals: Evaluation of the immunotoxicity
of various pesticides in the rat. Pestic. Chem.: Hum. Welfare Environ.,
Proc. 5th Int. Congr. Pestic. Chem. 3:497-504.
Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein,,eds. 1983. The
Merck index—an encyclopedia of chemicals and drugs, 10th ed. Rahway, NJs
Merck and Company, Inc.
-------
2,4,5-Trichlorophenoxyacetic Acid jl August-,
»
+
Zack, J.A. and R.R. Suskirid* <980.' -ftie mortality experience of vworkers-;,
exposed to tetrachlxjVc&lbenzoiJSr^iri in a trichlorophenol "proeess accident.
J. Occup. Med. 22O):11-14.
Zetterberg, G. 1978. 'Gen^ti'c 'effects''of phenoxy acids on microorganisms.
Ecol. Bull. 27:193-204. r ; l
, " OC-'' - f,v ; -112.
•.'- '„..-_:• i , r. r
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