EPA/600/8-88/058
August, 1989
HEALTH EFFECTS ASSESSMENT
FOR 2,4,5-TRICHLOROPHENOXY ACETIC ACID (2,4,5-T)
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
n
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with 2,4,5-T.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered preliminary and reflect limited resources
allocated to this project. Pertinent toxlcologlc and environmental data
were located through on-line literature searches of the TOXLINE, and the
CHEMFATE/DATALOG data bases. The basic literature searched supporting this
document 1s current up to May, 1986. Secondary sources of Information have
also been relied upon 1n the preparation of this report and represent large-
scale health assessment efforts that entail extensive peer and Agency review.
The following Office of Health and Environmental Assessment (OHEA) sources
have been extensively utilized:
U.S. EPA. 1981. Risk Assessment on (2,4,5-Trlchlorophenoxy)
Acetic Add, (2,4,5-T), 2,4,5-Trlchlorophenoxy Proplonlc Add,
2,3,7,8-Tetrachlorod1benzo-p-d1ox1n (TCDD). EPA 600/6-81-003.
NTIS PB 81-234825.
U.S. EPA. 1988. Integrated Risk Information System (IRIS).
Reference Dose for Oral Exposure for 2,4,5-Trlchlorophenoxy Acetic
Add (2,4,5-T). Online. (Verification date 01/20/88.) Environ-
mental Criteria and Assessment Office, Cincinnati, OH.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, the AIS or acceptable Intake subchronlc, Is an
estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure Is assumed. Animal data used for AIS estimates generally Include
exposures with durations of 30-90 days. Subchronlc human data are rarely
available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, Is similar 1n concept to the RfO
(reference dose). It 1s an estimate of an exposure level that would not be
expected to cause adverse effects when exposure occurs for a significant
portion of the llfespan [see U.S. EPA (1980) for a discussion of this
concept]. The AIC 1s route-specific and estimates acceptable exposure for a
given route with the Implicit assumption that exposure by other routes 1s
Insignificant.
111
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Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quan-
tities and the methodology for their development 1s explained In U.S. EPA
(1983).
For compounds for which there 1s sufficient evidence of carclnogenlclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer Is a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The data base for 2,4,5-T contained several subchronlc toxldty studies
and teratogen1dty/reproduct1ve effects studies, but there was relatively
IHtle useful chronic toxldty Information. There were, however, two long-
term studies using rats, a 2-year feeding study and a 3-generat1on reproduc-
tive effects study, that both defined a NOEL of 3 mg/kg. This value from
the 2-year dietary study using rats (Koclba et al., 1979) was used as the
basis for an oral RfD of 2 mg/day (U.S. EPA, 1988). The maximum CS that
could be calculated from chronic toxldty data was 28 and was derived from a
2-year feeding study using mice 1n which 12 mg/kg/day resulted In decreased
survival time (Muranyl-Kovacs et al., 1976). A subchronlc rat NOEL of 10
mg/kg/day (Gehrlng and Betso, 1978) was used as the basis for an RfD$ of
7.0 mg/day. The available Information was judged to be Inadequate for
evaluating the cardnogenldty of 2,4,5-T and Inhalation RfDs.
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS .
2.1. ORAL
2.2. INHALATION
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
1
4
4
4
5
5
5
6
6
6
7
w * w *
3.4.
i ui\n i UULIIAUI i i nnu u i mix ni.rnuvuui.ifL u i i
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
4. CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
8
18
18
19
19
19
19
19
19
20
21
21
5. REGULATORY STANDARDS AND CRITERIA 22
v1
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TABLE OF CONTENTS
Page
6. RISK ASSESSMENT 23
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 23
6.1.1. Oral 23
6.1.2. Inhalation 23
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 24
6.2.1. Oral 24
6.2.2. Inhalation 26
6.3. CARCINOGENIC POTENCY (q^) 26
7. REFERENCES 27
APPENDIX: Summary Table for 2,4,5-T 38
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LIST OF TABLES
No.
1-1
3-1
3-2
3-3
6-1
Title
Selected Physical and Chemical Properties and
Environmental Fate for 2,4,5-T
Studies on the Potential Teratogenlc Effects of 2,4,5-T
and Its Esters Administered to Mice by Gavage. ......
Studies on the Potential Teratogenlc Effects of Orally
Administered 2,4,5-T and Us Esters to Rats
Studies on the Potential Teratogenlc Effects of 2,4,5-T
1n Other Experimental Mammals Treated Orally
Composite Scores for the Tox1c1ty of 2,4,5-T by
Paae
2
9
12
14
Oral Exposure 25
V111
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LIST OF ABBREVIATIONS
CAS
CS
DHSO
DNA
E050
LOAEL
LOEL
NOAEL
NOEL
ppb
ppm
RBC
RfD
RfDj
RfD0
RfDS
RVd
RVe
SAP
SGPT
TLC
TLV
TWA
UV
Chemical Abstract Service
Composite score
Dimethyl sulfoxlde
Oeoxyr1bonucle1c acid
Dose effective to 50% of the recipients
Lowest-observed-adverse effect level
Lowest-observed-effect level
No-observed-adverse-effect level
No-observed-effect level
Parts per billion
Parts per million
Red blood cells
Reference dose
Inhalation reference dose
Oral reference dose
Subchronlc reference dose
Subchronlc Inhalation reference dose
Subchronlc oral reference dose
Dose-rating value
Effect-rating value
Serum alkaline phosphatase
Serum glutamlc pyruvlc transamlnase
Thin-layer chromatography
Threshold limit value
Time-weighted average
Ultraviolet
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and environmental fate of
2,4,5-T are presented In Table 1-1.
In the atmosphere, 2,4,5-T should exist partly In vapor form, and partly
as adsorbed matter on air-borne participates as a result of vapor phase
adsorption or wind erosion of treated soil (NorMs, 1981). 2,4,5-T has the
potential to undergo direct photolysis from UV adsorption at >290 nm
(PUmmer, 1972), reaction with photochemlcally generated HO radical (U.S.
EPA, 1986a) or physical removal by settling or washout 1n rainfall (NorMs,
1981). The atmospheric half-life listed In Table 1-1 1s based on the vapor
phase hydroxyl reaction rate constant of 4.59xlO~13 cm3/molecule/sec at
25°C and an ambient HO radical concentration of 8.0xl05 molecule/cm3
(U.S. EPA, 1986a). In water, photochemical decomposition and blodegradatlon
appear to be the dominant fate mechanisms. The aquatic near-surface
photolysis half-life during summer at latitude 40°N has been calculated to
be 15 days. The presence of humlc substances greatly enhances the photo-
reaction. In addle, weakly absorbing natural water, Iron and peroxides may
also catalyze the photoreactlon (Skurlatov et al.. 1983).
Data regarding the mlcroblal degradation of 2,4,5-T In soil suggest that
blodegradatlon may also contribute significantly to the degradation of
2,4,5-T In aquatic systems. Adsorption to suspended solids and sediments
may be significant since humlc adds found In almost all water and soil
systems have been shown to strongly adsorb 2,4.5-T from solution (Wershaw et
al., 1969). Bloaccumulatlon 1n aquatic organisms should not be significant.
0098h -1- 08/14/89
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TABLE 1-1
Selected Physical and Chemical Properties and
Environmental Fate for 2,4,5-T
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Mater solubility:
Log octanol/water
partition coefficient:
pKa:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives 1n
Air:
Water:
Soil:
93-76-5
halogenated phenoxy
add herbicide
255.5
NA
268 mg/l at 25°C
3.13
2.88
2-28 (estimated)
2.3
186
53-220
>1 day (estimated for
vapor phase)
<15 days (estimated)
10-208 days
Que Hee et al., 1981
Hansch and Leo, 1985
Que Hee et al., 1981
Kenaga, 1980; Garten
and Trabalka, 1983
Nked1-K1zza et al.,
1983
Kenaga, 1980
U.S. EPA, 19863
Skurlatov et al., 1983;
Lyman et al., 1982
McCall et al., 1981;
O'Connor and Wleranga,
1973; Altom and
StrHzke, 1973;
Bovey and Baur, 1972
NA = not available
0098h
-2-
08/14/89
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In soil, 2,4,5-T Is expected to blodegrade (Rosenburg and Alexander, 1980;
Byast and Hance, 1975). The persistence of 2,4,5-T 1n soil Is reported to
vary from 14-300 days depending upon climatic conditions and type of soil,
but usually does not exceed one full growing season regardless of the
application rate (McCall et al., 1981; O'Connor and Wleranga, 1973; A "I torn
and StrHzke, 1973; Bovey and Baur, 1972). Measured TLC Rf values of 0.17
for muck, 0.48 for clay, 0.54 for silt clay loam and 0.73-0.89 for sandy
loam (Helling, 1971) suggest that 2,4,5-T mobility would vary from highly
mobile In sandy soil to slightly mobile 1n muck (Relnbold, 1979).
0098h -3- 10/07/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
It has been reported that 2,4,5-T 1s rapidly and efficiently absorbed
from the gastrointestinal tract of mammals, <98-100X after small doses
(Erne, 1966; NRCC, 1978). Over 90X of single oral doses of 2,4,5-T
(0.04-200 mg/kg) were absorbed from the gastrointestinal tract of rats (Fang
et al., 1973; Piper et al., 1973). Eaton (1982) found that reabsorptlon of
biliary-excreted 2,4,5-T was almost complete. Ferry et al. (1982) reported
that two human volunteers who Ingested 1 mg of 2,4,5-T excreted 83.8 and
88.5X of the dose 1n the urine within 48 hours, suggesting that at least
that much had been absorbed from the gastrointestinal tract.
Gehrlng et al. (1973) conducted a pharmacoklnetlcs study 1n which oral
doses of 5 mg/kg were administered to five volunteers and essentially all of
the 2,4,5-T was absorbed from the gastrointestinal tract. Plasma 2,4,5-T
concentration appeared to be associated with first-order rates of absorption
and clearance. Applying a first-order model to the data, absorption
constants were calculated for each of the five subjects. These constants
ranged from 0.450*0.045 to 2.487^0.225 hour-1, corresponding to a t
of 0.75 hour.
On the basis of their low water solubility and by comparison with 2,4-0,
esters of 2,4,5-T would probably be absorbed less readily than the adds and
salts (Que Hee et al., 1981).
2.2. INHALATION
Burton et al. (1974) studied absorption of various herbicides from the
rat lung by administering them 1n Krebs-R1nger solution through a tracheal
cannula. The time necessary for 50% absorption of the administered 2,4,5-T
was 1.7 minutes. L1p1d solubility appeared to be the primary factor In
determining rate of absorption.
0098h 4- 01/27/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. A consideration In evaluating 2,4,5-T toxlclty data 1s that
the compound 1s usually formulated as a salt or ester In herbicides. These
salts and esters are rapidly hydrolyzed to the acid 1n animals, however, so
that their toxldty Is generally attributable to the parent add (Gehrlng
and Betso, 1978).
One of the major problems 1n assessing the effects of 2,4,5-T 1s the
contamination with varying amounts of 2,3,7,8-TCDO. Many Investigators were
unaware of the presence and amount of 2,3,7,8-TCDD 1n a sample and, there-
fore, this Information has gone unreported In many studies. Consequently,
whether the reported effects are attributable to 2,4,5-T alone, the
2,3,7,8-TCDD contaminant, a combination of both, or additional contaminants
such as the carrier of emulslfler Is not clear In many studies.
Results from several unpublished subchronlc oral toxlclty studies by Dow
Chemical Company have been reported In brief form. In 90-day rat studies,
monopropylene, dlpropylene and tMpropylene glycol butyl ether esters of
2,4,5-T at 186 and 62 mg/kg/day caused unspecified toxic effects, while no
toxic effects occurred at 18.6 mg/kg/day (Advisory Committee on 2,4,5-T,
1971; NAS, 1977). In another 90-day study, groups of Sprague-Dawley rats
were fed diets containing the acid form of 2,4,5-T that provided doses of 0,
3, 10, 30 or 100 mg/kg/day (Gehrlng and Betso, 1978). Depression In body
weight gain accompanied by decreased food Intakes, elevated SAP In both
sexes and SGPT In males and decreased RBC counts and blood hemoglobin
concentration In males, was observed at 100 mg/kg/day. Necropsy revealed
pale livers with hepatocellular swelling. At 30 mg/kg/day 2,4,5-T caused
Increased relative liver and kidney weights and elevated SGPT and SAP
0098h -5- 08/14/89
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levels. No adverse effects were reported at 10 and 3 mg/kg/day (Gehrlng and
Betso, 1978; MAS, 1977). In another 90-day rat study, 100 mg/kg/day 2,4,5-T
containing TCOO at 0.5 ppm caused decreased growth and changes In serum
enzyme concentrations, while no adverse effects were reported at 3, 10 and
30 mg/kg/day (Advisory Committee on 2,4,5-T, 1971). Further details were
not provided. The Weed Science Society of America (1979) reported 10
mg/kg/day as a 90-day NOEL for rats and dogs, but no details were given.
Drill and Hlratzka (1953) administered canned dog food containing
2,4,5-T 1n gelatin capsules to groups of 1-2 mongrel dogs/sex at 0, 2, 5, 10
or 20 mg/kg, 5 days/week for 90 days. Dogs receiving dally oral doses of 2,
5 or 10 mg/kg suffered no adverse effects, but four dogs receiving 20 mg/kg
died during the experiment. Dogs are much more sensitive to the effects of
orally-administered 2,4,5-T than rodents, probably because of a decreased
capacity for renal excretion of the compound.
3.1.2. Inhalation. Pertinent data regarding subchronlc toxldty of
2,4,5-T 1n Inhalation exposures could not be located In the available
literature.
3.2. CHRONIC
3.2.1. Oral. Koclba et al. (1979) conducted a 2-year study In which
groups of 50 male and 50 female Sprague-Dawley rats consumed diets contain-
ing 2,4,5-T that provided dosages of 3, 10 or 30 mg/kg/day. Parameters of
toxlclty that were evaluated Included appearance and behavior, food consump-
tion, body weight, mortality, hematology. clinical chemistries, urlnalysls,
and gross and microscopic pathology. Rats receiving the high dosage
experienced decreased body weight gain, increased relative kidney weight,
Increases In total urine volume, urinary coproporphyrlns and uroporphyrlns,
and morphological changes 1n kidneys, liver and lungs. Liver effects
0098h -6- 08/14/89
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Included an Increased Incidence of perlportal Inflammation, focal biliary
hyperplasla and Inflammation. M1ld kidney effects occurred at 10 mg/kg/day,
Including Increased urinary excretion of coproporphyrlns In males at 4
months and a mild Increase In the Incidence of mineralized deposits In the
renal pelvis of females after 2 years. No treatment-related effects
occurred at 3 mg/kg/day.
Muranyl-Kovacs et al. (1976) conducted a 2-year study In which two
strains of mice were fed 2,4,5-T (dloxln content <0.05 ppm). Male and
female XVII/G and C3Hf mice were provided with drinking water containing 100
mg/i (ppm) from 6 weeks of age for the next 2 months. From then until
death, 2,4,5-T was provided only 1n the diet at 80 ppm. According to the
authors, this resulted In a dosage of ~12 mg/kg/day. Effective numbers of
mice, those surviving >300 days or those developing a tumor at <300 days,
ranged from 19-44. Survival time of male C3Hf mice was decreased, but no
other toxic effects were reported.
3.2.2. Inhalation. There have been several ep1dem1olog1cal studies con-
cerning occupational exposure to 2,4,5-T, but most of these were concerned
with cancer Incidence and few threshold toxldty data were provided.
Susklnd and Hertzberg (1984) found an Increased Incidence of chloroacne
among 204 workers exposed to 2,4,5-T relative to 163 unexposed workers
(55.7% vs. 0%). There was also an association between exposure and history
of gastrointestinal tract ulcers. Pulmonary function values among exposed
workers who smoked were lower than those In unexposed workers who smoked.
There was no evidence of Increased risk of cardiovascular disease, hepatic
or renal disease, or nervous system problems. Exposures were not quantl-
tated and all of the workers 1n the study were currently or had been exposed
to other chemicals.
0098h -7- 07/14/89
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Chronic Inhalation bloassays with 2,4,5-T could not be located 1n the
available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Several studies concerning the teratogenldty of 2,4,5-T
are Included 1n Tables 3-1 to 3-3, but only studies that define thresholds
or address critical Issues are discussed In the text.
Several teratogenldty studies with mice are summarized 1n Table 3-1.
The most consistent teratogenetlc effect noted was cleft palate, which
occurred 1n the majority of the experiments (Neubert and DUlmann, 1972;
Roll, 1971; Courtney, 1977; Courtney et al., 1970a,b; Galnes et al., 1975;
Chernoff and Kavlock, 1982). TCDD, a common contaminant of 2,4,5-T, 1s a
known teratogen associated with the development of cleft palates 1n mice.
In order to estimate the contribution of TCDD to the Incidence of cleft
palate observed 1n 2,4,5-T-treated mice, Neubert and DUlmann (1972) con-
ducted teratogenldty studies with 2,4,5-T samples of different TCDD content
(samples A, B or C, Table 3-1) and with TCDD Itself. They calculated ED5Q
values for Incidence of cleft palate using the Utter as the experimental
unit and found that the ED values for 2,4,5-T samples A and B were much
lower than would be expected 1f TCDD alone were responsible for the terato-
genlc activity. The estimated ED5Q values, however, Indicated a more than
additive response, but H 1s not clear from these results If 2,4,5-T Itself
Is teratogenlc or 1f H synerglzes the teratogenlc action of TCDD. The
Induction of cleft palate has been demonstrated In three studies 1n which
relatively pure 2,4,5-T was used (TCDD content <0.05 ppm) (Neubert and
DUlmann, 1972; Roll, 1971; Courtney, 1977), suggesting that some terato-
genlc activity must be due to 2,4,5-T Itself or contaminants other than
TCDD. In these studies, the highest NOEL for cleft palate Induction was 30
mg/kg (Neubert and DUlmann, 1972) and the LOEL was 35 mg/kg (Roll, 1971).
0098h -8- 07/14/89
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The apparent NOEL might be an artifact resulting from the difficulties In
detecting statistically significant Increases In responses 1n small groups
of animals rather than a lack of teratogenlc activity at these doses.
Neubert and Dlllmann (1972) reported that doses as low as 8 mg/kg by gavage
had been shown to cause a significant decrease In fetal body weight In mice.
Several other studies Involved the use of 2,4,5-T samples containing
higher or unknown levels of TCOD contamination, making them less useful for
risk assessment; however, these studies pointed out that the teratogenlc
potency 1n mice varied with the strain of mice used, the dosing schedule,
and the vehicle. Based on data presented In Table 3-1 and on other data In
mice, 1t can be concluded. that 2,4,5-T was more teratogenlc 1n A/JAX mice
than 1n the other strains tested; that treatment on gestation days 11-14
produced a greater teratogenlc response than did treatment on gestation days
11-13 or 12-15 at the same or higher doses; and that administration as a
solution In DMSO led to a far greater response than did administration as a
suspension In sucrose solution.
The effect of the chemical form In which the 2,4,5-T was administered on
teratogenlc potency to mice was less clear. Frohberg et al. (1974) sug-
gested that the butoxyethyl ester 1s less potent than the add, but Neubert
and Dlllmann (1972) reported similar potencies for the acid and the butyl
ester. No firm conclusion can be drawn, however, because the TCDD content
of these esters was not reported.
Several studies with rats are presented in Table 3-2. A review of these
studies Indicates that at doses of >100 mq/kg/day, 2,4,5-T containing <0.5
ppm TCDD may cause maternal toxldty, fetotoxtcHy and skeletal anomalies.
In most cases these skeletal anomalies were relatively mild and Included
0098h -16- 07/14/89
-------
wavy Mbs, fused sternum, poor ossification and maligned sternebrae (Emerson
et al.. 1970, 1971; Khera and McKlnley, 1972; Khera et a!., 1971; Sparschu
et al., 1971). These data suggest that rats are less sensitive to the
teratogenlc effects of 2,4,5-T than mice, 1n which doses >35 mg/kg consis-
tently produced cleft palates. In the rat studies, a dosage of 25 mg/kg/day
on days 6-15 of gestation appears to be a NOEL for teratogenlc and fetotoxlc
effects.
Smith et al. (1981) conducted a 3-generat1on study 1n which 2,4,5-T
(TCDO content <0.03 ppb) was administered In the diet to groups of 10-16
male and 20-32 female SO rats at dosages of 0, 3, 10 and 30 mg/kg/day. Rats
were 4-6 weeks old Initially and were fed the diet for 90 days before
mating. The FI and F- rats were mated at the age of -130 days. No
treatment-related effects on food consumption, body weight gain, behavior,
appearance, organ weights, or hlstologlcal appearance of liver, kidneys and
thymus of weanllmjs were observed. There were no consistent treatment-
related effects on fertility Index, Utter size at birth, weanling body
weights or sex ratio of offspring. Reduced 21-day survival of pups was
observed 1n the 10 and 30 mg/kg/day groups. No adverse effects on reproduc-
tion occurred at 3 mg/kg/day. No treatment-related teratogenlc effects
occurred at any dosage.
Teratogenldty studies with other species were summarized In Table 3-3.
Collins and Williams (1971) studied teratogenlc effects of different 2,4,5-T
samples (TCDO content <0.1-4.5 ppm) In hamsters and found that Increasing
TCDD levels were associated with decreased fetal viability and Increased
Incidences of abnormalities/Utter. Highly purified 2,4,5-T still caused
abnormalities at doses of 100 mg/kg and caused decreased viability at 40
mg/kg. The studies with other species In Table 3-3 were essentially
0098h -17- 07/14/89
-------
negative for teratogenlc effects. Dougherty et al. (1973, 1975) and Wilson
(1971) did not observe teratogenlc effects 1n primates receiving doses <40
mg/kg.
3.3.2. Inhalation. Several studies have related exposure to 2,4,5-T to
Increases In birth defects and abortions In human populations. A positive
association was found In populations 1n Oregon (U.S. EPA, 1979), New Zealand
(Hanify et al., 1981) and Australia (Field and Kerr, 1979). No association
was found 1n Arkansas (Nelson et al., 1979), Hungary (Thomas, 1980), New
Zealand (Department of Health, New Zealand, 1980; McQueen et al., 1977;
Smith et al., 1982) and Australia (Aldred, 1978). These studies do not
demonstrate conclusively that 2,4,5-T 1s teratogenlc or fetotoxlc In humans.
Pearn (1985) concluded that no ep1dem1olog1cal data Indicate that 2,4,5-T
causes congenital malformations In humans. The normal problems with
ep1dem1olog1cal data are compounded by the difficulty 1n distinguishing
effects of 2,4,5-T from those of TCDD.
Only one animal study concerning Inhalation exposures to 2,4,5-T was
found, but It was available only as an abstract. In this study, the butoxy-
ethyl ester of 2,4,5-T caused unspecified malformations In NMRI mice at >216
mg/m3 (140.4 mg/kg/day; assuming a body weight of 30 grams and a contin-
uous exposure) (Frohberg et al., 1974).
3.4. TOXICANT INTERACTIONS
Although ep1dem1olog1c studies have been performed with the chloro-
phenoxy herbicides (Section 4 1.2.), these studies did not Investigate the
Interactive effects of these compounds. Neubert and Dlllmann (1972) Inves-
tigated the Interactions of TCDD and 2,4,5-T In teratogenesls In mice. It
was not clear 1f 2,4,5-T potentiated the teratogenlclty of TCDD or 1f
2,4,5-T was teratogenlc by Itself (see Section 3.3.1.).
0098h -18- 07/14/89
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4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. Data concerning cardnogenlclty of 2,4,5-T to humans from
oral exposure could not be located In the available literature.
4.1.2. Inhalation. There Is much data associating exposure to phenoxy
acid herbicides and the Incidence of cancer In humans. A detailed discus-
sion of this Information Is beyond the scope of this document, but reviews
and evaluations have been done by IARC (1982). Scandinavian ep1dem1o1og1c
studies summarized by IARC (1982) Indicated that occupational exposure to
phenoxy add herbicides was associated with an excess risk of the develop-
ment of soft-tissue sarcomas and malignant lymphomas. As was the case with
other ep1d1m1olog1cal data, It Is Impossible to separate effects of 2,4,5-T
from those of other phenoxy acid herbicides and TCDD; furthermore, the
lengths of exposure and exposure levels were unknown. Thus, these studies
are not useful for quantitative risk assessment.
4.2. BIOASSAYS
4.2.1. Oral. There are relatively few studies concerning cardnogenlclty
of 2,4,5-T 1n animals. In one study (B1onet1cs Research Laboratories, Inc.,
1968; Innes et a!., 1969), groups of 18 male and 18 female mice of each of
two strains (B6C3F1 and B6AKF1) received gavage doses of 21.5 mg/kg/day
2,4,5-T (TCDD content not specified) on days 7-28 of age, and then were fed
a diet containing 60 ppm 2,4,5-T for 18 months. There was an Increased
Incidence of hepatomas In treated male B6C3F1 mice relative to controls, but
this was not statistically significant. No other treatment-related effects
on tumor Incidence were observed.
0098h -19- 01/27/87
-------
Muranyl-Kovacs et al. (1976) exposed groups of C3HF and XVII/G mice to
2,4,5-T (TCOD content <0.05 ppm) In drinking water at 100 mg/l (19
mg/kg/day) for 2 months starting at 6 weeks of age and then 1n the diet at
80 ppm (15.2 mg/kg/day) until the mice died or were sacrificed when
moribund. Total tumor Incidence was Increased In treated C3HF mice, but
this Increase was statistically significant only In treated females.
Unusual types of tumors appeared relatively early In the life of the treated
C3HF mice compared with controls; the authors Interpreted this as an Indi-
cation of the cardnogenlclty of 2,4,5-T In mice. No specific target organ
was affected, but there was a generalized Increase 1n rare tumors 1n treated
C3HF mice.
Kociba et al. (1979) exposed groups of 50 male and 50 female SD rats to
2,4,5-T (TCDD content <0.33 ppb) 1n the diet that provided dosages of 3, 10
or 30 mg/kg/day for 2 years. The authors found no treatment-related
Increase In any type of tumor. A re-evaluation of the hlstologlcal samples
and statistical analyses, however, revealed a statistically significant
Increase In squamous cell carcinoma of the tongue In male rats receiving 30
mg/kg/day (U.S. EPA, 1981). U.S. EPA (1981) reviewed a similar or perhaps
the same study with rats receiving these doses 1n the diet and reported a
statistically significant Increase 1n testlcular tumors In treated rats, but
stated that these results were questionable. U.S. EPA (1981) concluded that
their re-evaluation of the Kociba et al. (1979) data provided "highly
suggestive" evidence of the cardnogenlclty of essentially pure 2,4,5-T;
however, no final judgement or quantitative cardnogenlclty risk assessment
was made because similar findings were not reported 1n other studies.
4.2.2. Inhalation. Inhalation cardnogenlclty bloassays could not be
located 1n the available literature.
0098h -20- 07/14/89
-------
4.3. OTHER RELEVANT DATA
B1onet1cs Research Laboratories, Inc. (1968) reported that single subcu-
taneous Injections of 215 mg/kg 2,4,5-T (98% pure) In dimethyl sulfoxlde at
28 days of age had no effect on tumor Incidence 1n groups of 18 male and 18
female B6C3F1 and BGAKF1 mice.
Negative results have generally been obtained with 2,4,5-T In bacterial
mutagenlclty assays. Results In other assays, Including yeast, DrosophHa.
mouse dominant lethal assays, and j_n vivo and In vitro mammalian mutagenlc-
lty assays were mixed (U.S. EPA, 1981).
4.4. WEIGHT OF EVIDENCE
IARC (1982) has classified 2,4,5-T and Us esters 1n Group 3, chemicals
that cannot be classified as to their cardnogenldty to humans, on the
basis of Inadequate evidence for cardnogenldty In humans and animals and
Inadequate evidence from short-term tests. It should be noted that IARC
(1982) classified occupational exposure to phenoxy add herbicides In Group
2B, probably carcinogenic to humans, on the basis of limited evidence for
cardnogenldty In humans. Overall, the evidence for cardnogenldty of
2,4,5-T to animals may most appropriately be considered "Inadequate." Using
the U.S. EPA (1986b) guidelines, 2,4,5-T would be placed In Group D, meaning
that current data are Inadequate for the assessment of the potential
cardnogenldty of 2,4,5-T.
0098h -21- 08/14/89
-------
5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (1988) recommended an RfD of 0.01 mg/kg/day for 2,4,5-T based
on a NOEL of 3 mg/kg/day In a 2-year rat feeding study (Koclba et al.. 1979)
and a 3-generatlon rat feeding study (Smith et al., 1981). The LOAEL In
both studies was 10 mg/kg/day, which caused Increased urinary copropor-
phyrlns and decreased neonatal survival, respectively.
NAS (1977) recommended an RfD of 0.1 mg/kg/day based on a NOAEL of 10
mg/kg/day In dogs. This NOAEL was based on the study by Drill and Hlratzka
(1953) 1n which mongrel dogs were fed capsules containing 2, 5, 10 or 20
mg/kg/day 2,4,5-T 5 days/week for 13 weeks. Mortality occurred at 20
mg/kg/day.
Both ACGIH (1986) and OSHA (1983) have recommended a TLV-TWA of 10
mg/m3 for occupational atmospheric exposures to 2,4,5-T. This value 1s
based on animal feeding studies and extensive use experience with the
compound (ACGIH, 1986).
0098h -22- 08/14/89
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral. Data from several subchronlc studies with 2,4,5-T suggest
that 10 mg/kg/day 1s a NOEL and a suitable basis for deriving an oral
RfD.Q. This dosage was a NOEL In the 13-week dog study by Drill and
Hlratzka (1953) 1n which no adverse effects were observed 1n dogs receiving
doses of 2.5 or 10 mg/kg/day, 5 days/week, while all dogs at 20 mg/kg/day
died. NAS (1977) reported 90-day rat NOELs of 10, 18.6 and 30 mg/kg/day
from various studies. Gehrlng and Betso (1978) described an unpublished
90-day study In which Sprague-Dawley rats receiving 30 mg/kg/day 1n the diet
experienced Increased liver and kidney weights and small but significant
Increases In SAP and SGPT levels, but no adverse effects occurred at 10
mg/kg/day. Although 10 mg/kg/day 1s not the highest NOEL below which no
adverse effects have been reported, 1t appears to provide the best basis for
RfDSQ derivation because the higher NOEL of 18.6 mg/kg/day for various
esters of 2,4,5-T (Advisory Committee on 2,4,5-T, 1971; NAS, 1977) 1s very
close to the 20 mg/kg/day level that was lethal to dogs (Drill and Hlratzka,
1953). The 10 mg/kg/day subchronlc NOEL In rats (Gehrlng and Betso, 1978)
Is the best basis for deriving an RfDso- If this value Is divided by an
uncertainty factor of 100 to account for Interspedes extrapolation and
differences 1n Individual sensitivity, the resulting RfDcn 1s 0.1
oU
mg/kg/day or 7 mg/day for a 70 kg human.
6.1.2. Inhalation. Subchronlc Inhalation data suitable for derivation of
an RfDo could not be located 1n the available literature.
0098h -23- 02/07/90
-------
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral. Several studies defined 3 mg/kg/day as a chronic oral NOEL.
In the 2-year rat study by Koclba et al. (1979), mild kidney effects
occurred at 10 mg/kg/day, but no adverse effects occurred at 3 mg/kg/day.
In the 3-generatlon rat study by Smith et al. (1981), 3 mg/kg/day was a NOEL
for reproductive and other toxic effects, while neonatal survival was
reduced at 10 and 30 mg/kg/day. Several other reproductlon/teratogenldty
studies 1n rats, mice and other species support 3 mg/kg/day as a NOEL for
these effects as well. Dividing the NOEL of 3 mg/kg/day from the Koclba et
al. (1979) study by an uncertainty factor of 300 to account for Interspecles
extrapolation, deficiencies 1n the chronic toxldty data base and differ-
ences 1n Individual human sensitivity results In an RfDQ of 0.01 mg/kg/day
or 0.7 mg/day for a 70 kg human.
CSs were calculated for several effects observed 1n the chronic toxlclty
and reproductive effects experiments with 2,4,5-T. Because of the rated
severity of teratogenlc and fetotoxlc effects relative to chronic toxldty
endpolnts such as hyperplasla and Increased organ weights, most of the
highest CSs could be obtained using data from teratogenlclty/reproductlve
effects studies. Because the contaminant TCDD Is also known to cause these
effects, however, only studies using 2,4,5-T samples of known low TCDD
content were considered appropriate for CS calculations. These calculations
are summarized 1n Table 6-1. The highest CS was obtained using data from
the 2-year feeding study by Muranyl-Kovacs et al. (1976) 1n which survival
time was significantly reduced 1n male C3HF mice receiving 80 ppm 1n the
diet, a level resulting In a dosage of ~12 mg/kg/day according to the
authors. The calculated RV. was 2.8, and the effect was assigned an RV
of 10, resulting 1n a maximum CS of 28 (see Table 6-1).
0098h -24- 08/14/89
-------
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0098h
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-------
6.2.2. Inhalation. The chronic Inhalation toxldty data reviewed 1n
Section 3.2.2. are not useful for quantitative risk assessment. In an
epidemiology study, Susklnd and Hertzberg (1984) observed decreased pulmo-
nary functions, ulcers of the gastrointestinal tract and an Increased
Incidence of chloracne 1n workers exposed to 2,4,5-T compared with controls,
but exposure levels and duration of exposure were not quantified. Experi-
ments with chronic exposure of laboratory animals could not be located 1n
the available literature.
6.3. CARCINOGENIC POTENCY (q^)
No quantitative estimates of carcinogenic potency have been made for
2,4,5-T because the Issue of Its cardnogenlcHy 1s still 1n doubt.
0098h -26- 02/07/90
-------
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0098h -27- 01/27/87
-------
Bovey, R.W. and J.R. Baur. 1972. Persistence of 2,4,5-T In grasslands of
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Chebotar, N.A. 1980. Cytogenetlc and morphological changes In cogenesls
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Courtney, K.D., D.W. Gaylor, M.D. Hogan and H.L. Falk. 1970a. Teratogenlc
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0098h -33- 01/27/87
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0098h -34- 01/27/87
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Roll, R. 1971. Studies of the teratogenlc effect of 2,4,5-T 1n mice. Food
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0098h -35- 01/27/87
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9-
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0098h -37- 08/14/89
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