United States
Environmental Protection
Agency
Drinking Water Health Advisory
For Dacthal and Dacthal
Degradates:
Tetrachloroterephthalic acid (TPA)
and Monomethyl
Tetrachloroterephthalic acid (MTP)
April, 2008
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Drinking Water Health Advisory
For Dacthal and Dacthal Degradates: Tetrachloroterephthalic Acid (TPA)
and Monomethyl Tetrachloroterephthalic Acid (MTP)
Prepared by:
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC 20460
http://www.epa.gov/waterscience/
Document Number: 822-R-08-011
April, 2008
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Dacthal and Dacthal Degradates
TABLE OF CONTENTS
Page
ACKNOWLEDGMENTS VII
LIST OF ABBREVIATIONS IX
1.0 INTRODUCTION 1
2.0 GENERAL INFORMATION AND PROPERTIES 3
2.1 Chemical and Physical Properties 3
2.2 Uses 4
3.0 OCCURRENCE/EXPOSURE 5
3.1 Air 5
3.2 Food 5
3.3 Water 6
3.4 Soil 6
4.0 HEALTH EFFECTS DATA 9
4.1 Human Studies 9
4.1.1 Short-term Exposure 9
4.1.2 Long-term Exposure 9
4.1.3 Reproductive and Developmental Effects 9
4.1.4 Carcinogenicity 9
4.2 Animal Studies 10
4.2.1 Short-term Exposure 10
4.2.2 Long-term Exposure 11
4.2.4 Reproductive and Developmental Effects 13
4.2.5 Genotoxicity 14
4.2.6 Carcinogenicity 14
4.3 Proposed Mode of Action 15
4.3.1 Noncancer Effects 15
4.3.2 Cancer Effects 16
5.0 QUANTIFICATION OF TOXICOLOGICAL EFFECTS 17
5.1 One-day Health Advisory 19
iii
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Dacthal and Dacthal Degradates
5.2 Ten-day Health Advisory 19
5.3 Longer-term Health Advisory 20
5.4 Lifetime Health Advisory 22
5.5 Evaluation of Carcinogenic Potential 23
6.0 OTHER CRITERIA, GUIDANCE, AND STANDARDS 25
7.0 ANALYTICAL METHODS 27
8.0 TREATMENT TECHNOLOGIES 29
9.0 REFERENCES 31
IV
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Dacthal and Dacthal Degradates
LIST OF TABLES
TABLE 1. Chemical and Physical Properties of Dacthal, TPA, and MTP
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Dacthal and Dacthal Degradates
VI
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Dacthal and Dacthal Degradates
ACKNOWLEDGMENTS
This document was prepared by Oak Ridge National Laboratory, Oak Ridge, Tennessee, work
assignment 2006-002-2, under the U.S. EPA IAG Number DW-89-92209701. The Lead EPA
Scientist is Joyce Morrissey Donohue, Ph.D., Health and Ecological Criteria Division, Office of
Science and Technology, Office of Water, U. S. Environmental Protection Agency.
Vll
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Dacthal and Dacthal Degradates
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Dacthal and Dacthal Degradates
LIST OF ABBREVIATIONS
a.i. active ingredient
atm atmosphere
BMD benchmark dose
BMDL lower confidence bound on the Bench Mark Dose
CAS Chemical Abstracts Service
EPA Environmental Protection Agency
g gram
gd gestation day
Hg mercury
HSDB Hazardous Substances Data Bank
kg kilogram
Koc organic carbon partition coefficient
Kow octanol-water partition coefficient
L liter
LEL lowest effect level
LOAEL lowest observed adverse effect level
LOEL lowest observed effect level
m meter
m3 cubic meters
Hg microgram
mg milligram
min minute
mL milliliter
mm millimeter
mM millimolar
mol mole
MRL minimum reporting level
NAWQA National Water Quality Assessment
NOAEL no observed adverse effect level
NOEL no observed effect level
OPP Offi ce of Pe sti ci de Program s
OGWDW Office of Ground Water and Drinking Water
OST Office of Science and Technology
OW Office of Water
ppm parts per million
PWS Public Water Systems
RED Reregi strati on Eligibility Decision
RfD reference dose
RSC relative source contribution
SDWA Safe Drinking Water Act
UCM unregulated contaminant monitoring
IX
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1.0 INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Water (OW), provides
information on the environmental properties, health effects, analytical methods, and treatment
technologies for regulated and unregulated drinking water contaminants. HAs establish
nonregulatory concentrations of drinking water contaminants at which adverse health effects are
not anticipated to occur over specific exposure durations (one-day, ten-days, several years, and a
lifetime). HAs serve as informal technical guidance to assist Federal, State and local officials,
and managers of public or community water systems in 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.
The Registration Eligibility Decision (RED for dacthal or DCPA (U.S. EPA, 1998a:
htt|i^/wwj^^ is the peer reviewed health risk assessment
that supports the HA. A comprehensive summary of the data that support this HA is included in
the OW Health Effects Support Document for Dacthal and its degradates:
http_:/J_www.eQa,go^
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Dacthal and Dacthal Degradates
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Dacthal and Dacthal Degradates
2.0 GENERAL INFORMATION AND PROPERTIES
2.1 Chemical and Physical Properties
Dacthal is a pre-emergence herbicide. Tetrachloroterephthalic acid (TPA) and monomethyl
tetrachloroterephthalic acid (MTP) are its environmental degradates; they are formed through
hydrolysis of the methyl ester groupings in dacthal. TPA is the terminal hydrolytic dacthal
degradate. The chemical structures of dacthal and of its two major metabolites, MTP and TPA
are shown below. Another degradate,!,2,4,5-Tetrachlorobenzene can be formed in the
environment by photolysis.
C
O
c
ci
Dacthal
MTP
TPA
Synonyms: Dacthal (registered trade name): chlorthal-dimethyl, dimethyl
tetrachloroterephthalate; 1,4-benzenedicarboxylic acid, 2,3,5,6-tetrachloro-, dimethyl ester; DAC
893; dacthalor; and DCPA (U.S. EPA, 2006a; ChemFinder 2004; HSDB, 2005).
MTP: monomethyl tetrachloroterephthalic acid; chlorthal-monomethyl; monomethyl 2,3,5,6-
tetrachloroterephthalate; 1,4-benzenedicarboxylic acid, 2,3,5,6-tetrachloro-, monomethyl ester
(U.S. EPA, 2006a; ChemFinder 2004; HSDB, 2005).
TPA: tetrachloroterephthalic acid; chlorothal; chlorthal; perchloroterephthalic acid; 1,4-
benzenedicarboxylic acid, 2,3,5,6-tetrachloro- (U.S. EPA, 2006a; ChemFinder 2004; HSDB,
2005)
Dacthal is an odorless crystalline solid. Its physical and chemical properties are presented in
Table 1. No data were found on the physical and chemical properties of the degradates. The
properties of both degradates are expected to have many similarities in common with the parent
dacthal. Their aqueous solubility is predicted to be higher than dacthal, because one or two of the
ester functional groups have been hydrolyzed releasing methanol and increasing solubility in
water. However, both compounds are still expected to be relatively insoluble in water based on
the low solubility of terephthalic acid (2.8 g/L, IPCS, 1994). The vapor pressures of the acid
derivatives are predicted to be lower than that of the parent (U.S. EPA 2006b).
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Dacthal and Dacthal Degradates
TABLE 1. Chemical and Physical Properties of Dacthal, TPA, and MTP
Property
CAS Registry No.
Formula
Molecular Weight
Color/Physical State
Odor
Boiling point
Melting point
Density
Vapor pressure @ 25°C:
Solubility in Water @ (25°C):
in Organic Solvents® (25°C):
Partition coefficients:
Log Kow
Log Koc
Conversion factors*
(at 25°C, 1 atm)
Dacthal
1861-32-1
C\(figC\4O4
331.97
Colorless crystals
Odorless
365°C
155°C
1.70
2.5xl0^mmHg
0.5 mg/L
70-250 mg/L
4.40
3.77-4.28
1 ppm= 13.6 mg/m3
1 mg/m3 = 0.07 ppm
TPA
2136-79-0
C8H2C1404
303.91
~
~
~
~
~
~
~
1 ppm = 12.4 mg/m3
1 mg/m3= 0.08 ppm
MTP
887-54-7
C^MziClziO '4
317.94
~
~
~
~
~
~
~
1 ppm = 12.9 mg/m3
1 mg/m3 = 0.07 ppm
Source: ChemFinder 2004; HSDB, 2005
*Calculated as follows: ppm = mg/m3 x (24.45/molecular weight); mg/m3 = ppm x (molecular weight/24.45)
2.2 Uses
Dacthal is used as a selective, pre-emergence herbicide to control annual grasses and some
annual broad-leaved weeds in turf, ornamentals, herbs, strawberries, garden vegetables, beans,
and alfalfa (Meister, 1998; U.S. EPA, 1998a, U.S. EPA, 2004). Depending on crop and time of
treatment, application rates generally range between 10-15 Ib a.i./acre (U.S. EPA 1998a). There
are many registered products with dacthal as an active ingredient. Some uses, particularly on
vegetable crops, have been voluntarily terminated by the registrant in response to EPA concerns
regarding the contamination of ground water with dacthal and TPA (U.S. EPA, 1998a, 2005a).
Dacthal is registered for both residential and commercial use.
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Dacthal and Dacthal Degradates
3.0 OCCURRENCE/EXPOSURE
3.1 Air
Dacthal is not expected to be found in air except in areas of recent application where it is likely
to exist in both the vapor and particulate phases. In the vapor phase, it reacts slowly with
hydroxyl radicals with an estimated half-life of 36 days (Meylan and Howard, 1993).
Particulate-phase dacthal may be removed physically from air by wet and dry deposition.
There are limited data on measurements of dacthal in ambient indoor or outdoor air; no data
were identified for the degradates. Indoor, outdoor, and personal air samples were collected
seasonally in Jacksonville, Florida, and Springfield/Chicopee, Massachusetts by Whitmore et al.
(1994), to assess non-occupational exposure to dacthal. Residents from Jacksonville had low
exposures (not detected to 0.6 ng/m3). The Springfield/Chicopee residents were exposed to
higher levels (not detected to 2.6 ng/m3). In both cases the highest concentrations were those
collected by personal samplers. In 1970-1971 the arithmetic mean airborne pesticide
concentration of dacthal in the United States was minimal; 0.49% of the samples were positive
and the maximum dacthal concentration was 2.1 ng/m3 (Lee, 1977; Kutz et al., 1976).
3.2 Food
Dacthal is registered and labeled for use on alfalfa, succulent and snap beans, beets, garden
cress, kale, mustards, turnips, tomatoes, yams and other vegetables. Accordingly it may be
present as residues in foods, especially vegetable produce. Use of dacthal on beans, peppers,
squash, lettuce, soybeans, corn, and rutabagas has been terminated (U.S. EPA, 1998a, 2005a),
reducing concern for these crops in the future. At present, no tolerances exist for residues of
dacthal in animal commodities but tolerances have been established for a variety of vegetables,
fruits, and herbs (U.S. EPA, 2004a).
When produce samples from 1989-1990 were tested for the presence of dacthal (n = 6,970;
approximately 80% domestic, 20% foreign), 50 samples (0.7%) were positive for dacthal at a
detection limit of 0.125 ppm. In the 1991-2001 FDA Total Diet Study, dacthal residues were
detected in a variety of produce. The most frequent detections were found in leafy vegetables
(spinach and collard greens) and root vegetables (radish and turnip). Green beans had a low
incidence of detection but relatively high mean concentrations, whereas black olives had a high
frequency of detection but a low average residue level (FDA, 2003). In market basket surveys
conducted in the early 1980's, estimates of dacthal intake from foods ranged from 1.1 to 2.4
ng/kg/day (Gartrell et al., 1986a, 1986b; Gunderson, 1988). Leafy vegetables appeared to be the
major source of exposure. No reissue data were identified for the dacthal degradates.
In a 1993 aquaculture survey, eight catfish samples out of 308 samples contained 10-90 ug/kg
DCPA (FDA, 1993). The USGS measured the concentrations of dacthal in whole fish from 1310
sites over the period from 1992-2001 as part of the NAWQA survey described in Section 3.3.
Detections were infrequent (1.9 -5% of samples) with the highest value reported for an
agricultural area. The average and 95th percentile concentrations were below the method
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Dacthal and Dacthal Degradates
reporting limit of 5 |ig/kg wet weight in tissue; the highest level reported was 33.7 ug/kg fish
tissue (Nowell, 2003). The bioconcentration factor for dacthal in fish was estimated at 1,300
L/kg based on its Kow value (HSDB, 2005).
3.3 Water
Under U.S. EPA's Unregulated Contaminant Monitoring Rule (UCMR 1, 1999) monitoring for
dacthal degradates (combined) was conducted by all large Public Water Systems (PWSs) and a
statistical, nationally representative sample of small PWSs; there was no requirement for
monitoring of dacthal. The analytical method for detection of TPA and MTP does not distinguish
between the two compounds, therefore, results are reported as those for combined dacthal
degradates.
Dacthal degradates were detected by 2.13% of small PWSs at a minimum reporting level of >1
|ig/L. Among large systems 5.14% had detections. Most detections for both small and large
systems were from ground water systems. The largest number of systems with detections
(15.1%-42% of PWSs) were seen in Arizona, Delaware, Nebraska, New Jersey, Rhode Island,
and Guam. There appeared to be a cluster of states with detections that ranged from 5% to 15%
of samples in the Northeast and the states surrounding the Great Lakes. The maximum
concentration detected was 39 jig/L for the large systems and 190 jig/L for small systems;
median concentrations were about 2 |ig/L for both small and large systems.
Occurrence data for dacthal and MTP, but not TPA, were collected from 1992 to 2001 under the
United States Geological Survey's (USGS) National Water Quality Assessment (NAWQA)
program. Detection limits varied, but did not exceed 0.003 |ig/L for dacthal and 0.070 |ig/L for
MTP (Martin et al., 2003). Dacthal was found in ambient surface water at frequencies ranging
from 6.34% of samples in undeveloped areas to 21.78% of samples in urban areas at 95
percentile concentrations that were less than 0.007 jig/L for all locations evaluated. In
agricultural settings, 11.46% of samples were positive for dacthal along with 15.4% of samples
in mixed land use settings. The highest concentration (40 |ig/L) was found at an agricultural site.
MTP was only detected in surface water samples ( 0.18%) from agricultural settings at a
maximum concentration of 0.430 |ig/L. The high frequency of detections in urban and mixed use
areas may reflect applications to lawns and golf courses.
In untreated ground water, dacthal detection frequencies ranged from not detected in
undeveloped settings to 1.18% in agricultural settings. Dacthal was not detected in >95% of the
samples from all settings. The highest ground water concentration, (10 |ig/L) was found at an
agricultural site (Kolpin and Martin, 2003). MTP was only detected in ground water samples
from agricultural settings (0.08 %) and at maximum concentration of 1.1 |ig/L (Kolpin and
Martin, 2003).
3.4 Soil
Based on an estimated high Koc of 5900, dacthal is expected to bind strongly to organic matter
resulting in almost complete immobility in soil. During a 21-day period, 36%-52% of the total
measured dacthal loss from soil was accounted for by volatilization and 26% by breakdown in
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Dacthal and Dacthal Degradates
soil. Photodegradation on soil surfaces may occur with a half-life of 5 hours; reaction products
include MTP, TPA, and 1,2,4,5-tetrachlorobenzene (HSDB, 2005). In soil, biodegradation of
dacthal into TPA is slow. TPA is extremely mobile and persistent in the environment and will
leach to ground water wherever dacthal is used, regardless of soil properties.
TPA and MTP, and to a lesser degree, dacthal, may be present in runoff and can leach to
groundwater (U.S. EPA, 1998a; Wettasinghe and Tinsley, 1993)..
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4.0 HEALTH EFFECTS DATA
MTP and TPA are present in the environment as degradates of the pesticide dacthal. They are
also metabolites of dacthal in humans and animals. Thus, this document presents a summary of
the available data on the health effects of the parent pesticide and its two degradates. Dacthal
appears to be poorly absorbed from the gastrointestinal tract in humans (Tusing, 1963) and
animals (Skinner and Stallard, 1963). In rat metabolism studies, the absorption of a 1 mg/kg
dose was 79% but only 8 for a 1000 mg/kg (U.S. EPA, 1998a). Low solubility (0.5 mg/L) in
aqueous media would contribute to its poor intestinal uptake. Metabolically, dacthal is
converted first to MTP and then TPA (Hazleton and Dieterich, 1963; Skinner and Stallard, 1963;
Tusing, 1963) most likely by nonspecific esterases. The solubility of the degradates is likely to
be greater than that for dacthal since acids tend to be more soluble than esters.
Little is known about the distribution of dacthal or its metabolites. The target organs for dacthal
suggest distributions to the liver, kidney, thyroid and lungs. Limited data from animal studies
indicate that there is distribution of the metabolites to the liver and kidney; parent compound has
been detected in adipose tissue. Most orally ingested dacthal is excreted in the feces,
unabsorbed; TPA and MTP have been identified in the urine of humans and animals treated with
dacthal (Skinner and Stallard, 1963; Tusing, 1963); the levels of MTP far exceed those of TPA.
There have been no toxicokinetic studies of MTP or TPA. TPA does not degrade in living
systems based on the projections of the META metabolism and biodegradation modeling
program (Klopman et al., 1996).
4.1 Human Studies
4.1.1 Short-term Exposure
Pure dacthal, administered as single 25 mg or 50 mg oral dose to volunteer subjects (3 subjects at
each dose), did not cause any observable effects based on assessment of hematological, serum
and urinary biomarkers (Tusing, 1963). Assuming a 70 kg body weight, these amounts
correspond to doses of 0.36 or 0.71 mg/kg. There are no short-term studies of TPA or MTP
exposure in humans
4.1.2 Long-term Exposure
There are no studies in humans of long-term exposure to dacthal, TPA, or MTP.
4.1.3 Reproductive and Developmental Effects
No studies were identified regarding reproductive or developmental effects in humans exposed
to dacthal, TPA, or MTP
4.1.4 Carcinogenicity
No data were located regarding the potential carcinogen!city of dacthal, TPA, or MTP in
humans.
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Dacthal and Dacthal Degradates
4.2 Animal Studies
4.2.1 Short-term Exposure
Dacthal
The oral LD50 for dacthal is greater than 12,500 mg/kg in Spartan rats and greater than 10,000
mg/kg in beagle dogs (Wazeter et al., 1974a; 1974b).
Groups of CD Sprague-Dawley rats (5/sex/dose) were administered technical grade dacthal in
the diet for 28 days at calculated doses of 0, 215, 860, or 1720 mg/kg/day for males and 0, 228,
890, or 1760 mg/kg/day for females. Food and water were available ad libitum. No treatment-
related effects were observed on survival, clinical signs, body weight, body-weight gain, food
consumption, urinalyses, hematology or clinical chemistry in either sex at any dose. A dose-
related increase in absolute and relative liver weights was observed along with centrilobular
hepatocyte hypertrophy. These effects were observed at the lowest dose tested, making the
LOAEL 215 mg/kg/day in males and 228 mg/kg/day in females (ISK Biotech Corp., 1990a).
In an earlier 28-day study, Keller and Kundzin (1960) reported a NOAEL of 758 mg/kg/day (the
highest dose evaluated) in weanling male Sprague-Dawley rats. A dose of 800 mg/kg/day given
by capsule to beagle dogs (2/sex) for 28 days resulted in reduced body weight, decreased
appetite, increased liver weight, and centrilobular liver congestion and degeneration (U.S. EPA,
1989a; Keller, 1961).
Monomethyl Tetrachloroterephthalic Acid
Hazleton Laboratories (1961) conducted a 28-day study of 0 or 1% MTP (860 mg/kg/day based
on U.S. EPA (1988) data on food intake and body weight) in the diet of male Sprague Dawley
rats (n= 10/group). Nasal discharge was noted in some control and exposed rats during the study
but did not appear to be treatment related. Clinical signs, body weights, liver and kidney weights
were measured and the tissues subjected to gross and histological examination. No signs of
toxicity were noted at the dose tested.
Tetrachloroterephthalic Acid
A 30-day intubation study with TPA in 0.5% methylcellulose solution at doses of 0, 100, 500 or
2000 mg/kg/day was conducted in groups of 10 male and 10 female Sprague-Dawley rats
(Major, 1985). There were no treatment-related mortalities or changes in organ weights
(adrenals, brain, gonads, heart, liver and kidney). Gross and histological evaluations of the
organs at the high dose and selected tissues at the lower doses did not reveal any abnormalities.
Soft stools (both sexes) as well as occult blood in the urine and increases in hemoglobin and
hematocrit for males at the 2000 mg/kg/day dose, were originally identified as a non-adverse
LOEL (U.S. EPA, 1994, 1998a) and the NOEL was 500 mg/kg/day.
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Dacthal and Dacthal Degradates
The results of a 28-day study of TPA by Hazleton Laboratory (1961), comparable to the MTP
study described above, did not identify any signs of toxicity at the 1% (860 mg/kg/day) dietary
dose tested.
4.2.2 Long-term Exposure
Dacthal
Several subchronic (90-day) feeding studies are available for dacthal. In the study that identified
the lowest response level, groups of 15 Sprague-Dawley rats/sex/dose group were administered
technical dacthal in the diet at levels of 10, 50, 100, 150, or 1000 mg/kg/day for 90 days. No
clinical signs were observed. Body weight was comparable among treatment groups, but body
weight gain was decreased in high-dose males (92% of controls) and females (86% of controls).
There were dose-related effects on the liver (increased weight and centrilobular hypertrophy),
lung (increased accumulation of foamy macrophages), kidney (increased weight, epithelial
hyperplasia, tubular hypertrophy, regenerative epithelium in males) and thyroid (follicular
hypertrophy). Based on hepatocellular hypertrophy and microscopic findings in the liver, the
LOAEL and NOAEL for dacthal in this study were set at 50 and 10 mg/kg/day, respectively
(ISK Biotech Corp., 1991; U.S. EPA, 1994).
The liver was also the target organ in a 13-week study of dacthal in groups of 15 male and 15
female CD-I mice (Fermenta Plant Protection Co., 1988). Calculated doses were 0, 100, 199,
406, and 1235 mg/kg/day for males and 0, 223, 517, 1049, and 2198 mg/kg/day for females. The
LOAELs were 1235 mg/kg/day for male mice and 1049 mg/kg/day for female mice, based on
centrilobular hepatocyte hypertrophy. The NOAELs in male and female mice were 406 and 517
mg/kg/day, respectively (U.S. EPA, 1994).
There are two important studies of chronic exposures to Dacthal in rats that differ in the strain
tested, the purity of the test material, the highest dose evaluated, and the number of animals per
dose group. In the more recent of the two studies (ISK Biotech Corporation, 1993; U.S. EPA,
1994, 1998a), groups of Sprague-Dawley rats (70/sex/dose) were administered technical dacthal
in the diet at doses of 0, 1, 10, 50, 500, or 1000 mg/kg/day for two years. The technical dacthal
contained 0.13% hexachlorobenzene as an impurity (equivalent to doses of 0.0013, 0.013, 0.065,
0.65, or 1.3 mg/kg/day for the respective dacthal doses). [The NOAEL for HCB based on liver
effects is 0.08 mg/kg/day with a LOAEL of 0.29 mg/kg/day in a chronic feeding study in rats
(U.S. EPA, 1989b), indicating that the hexachlorobenzene exposure from dacthal exceeded its
experimental LOAEL as a pure compound.] Survival in high-dose males was reduced, and
animals of both sexes in the two highest dose groups showed clinical signs of poor health,
including decreased body-weight gain. There was a dose-related increase in the incidence and
severity of focal accumulation of foamy-appearing macrophages in the lungs in males and
females. At study termination, a dose-related increase in the incidence of bilateral retinal
atrophy was observed in females.
Increases in both the incidence and severity of centrilobular hepatocytic hypertrophy were
observed at both interim (52-week) and terminal (104-week) sacrifices. Chronic nephropathy
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Dacthal and Dacthal Degradates
was increased in severity in males and in incidence in females. Thyroid-stimulating hormone
(TSH) was elevated at 52 weeks in a dose-related manner. It also was increased at 104 weeks,
but the increase was not dose related. Thyroxin (T4) was decreased throughout the study, and
triiodothyronine (Ts) was decreased at 52 weeks. The LOAEL for systemic toxicity was 10
mg/kg/day on the basis of effects observed in the lungs, kidneys, thyroid, and thyroid hormone
levels in both sexes. The NOAEL was 1 mg/kg/day. Tumors of the thyroid and liver were also
observed. The cancer findings from this study are discussed in Section 4.2.6.
Tumors were not observed in an earlier study of a purer grade of dacthal by Paynter and
Kundzin/Diamond Alkali Co. (1963; U.S. EPA 1994) but one that used a lower dose range and
fewer animals. Albino rats (35/sex/dose; 70/sex for controls) were fed dacthal in the diet for 2
years at 0, 100, 1000 or 10,000 ppm (approximately to 0, 5, 50 or 500 mg/kg/day). Physical
appearance, behavior, hematology, biochemistry, organ weight, body weight, gross pathology
and histopathology of treated and control animals were monitored. After 3 months at 500
mg/kg/day, slight hyperplasia of the thyroid was reported in both sexes. After 1 year, increased
hemosiderosis of the spleen of females occurred at 500 mg/kg/day, and there were slight
alterations in the centrilobular cells of the liver of both sexes. At the end of the study, kidney
weight was increased significantly in males fed 500 mg/kg/day, and adrenal weight was
increased significantly in females fed 500 mg/kg/day. Based on these data, a NOAEL of 50
mg/kg/day and LOAEL of 500 mg/kg/day were identified.
A 2-year study in CD-I mice identified the liver as the critical target organ after exposure to
technical grade dacthal (Fermenta Plant Protection Co., 1988). The doses were 0, 12, 123, 435
or 930 mg/kg/day in males and 0, 15, 150, 510 or 1141 mg/kg/day in females. The NOAEL for
systemic toxicity was 435 mg/kg/day in males; 510 mg/kg/day in females and the LOAEL 930
mg/kg/day for males and 1141 mg/kg/day in females based on hepatocyte enlargement increased
sorbitol dehydrogenase (SDH) and ALT activities, and hepatocyte vacuolization. A dose-related
increase in cholesterol was seen in females in the two highest dose groups but was not
considered as a critical effect (U.S. EPA, 1994). A dose-related trend for liver tumors was also
observed in females; liver tumors in males fell within the range for historic controls (U.S. EPA
1995a).
No effects were identified in beagle dogs (four/sex/dose) fed dacthal in the diet at 0, 100, 1000
or 10,000 ppm (approximately 0, 2.5, 25 or 250 mg/kg/day) for two years. Therefore, the NOEL
was equal to or greater than 250 mg/kg/day (U.S. EPA, 1994, 1998a).
Monomethyl Tetrachloroterephthalic Acid
There were no subchronic or chronic studies of MTP.
Tetrachloroterephthalic Acid
A 90-day feeding study with disodium TPA was performed in Charles River CD rats
(15/sex/dose group), using doses of 0, 50, 500, 1000, or 10,000 ppm (0, 2.5, 25, 50 or 500
mg/kg/day) in the diet (Goldenthal et al., 1977). The animals were evaluated for clinical signs,
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Dacthal and Dacthal Degradates
body weights, tissue histopathology (controls and high dose), and organ weights. Blood and
urine samples were collected for analysis at 1,2, and 3 months. There were no significant
changes in clinical observations, histopathology, and other standard measures of toxicity, such as
hematology and organ weights. Occasional soft stools were seen in the controls and high dose
animals. A non-significant increase in thyroid: body weight ratio was observed at the highest
dose. The NOAEL was set at >500 mg/kg/day, the highest dose tested (U.S. EPA, 1998a).
4.2.4 Reproductive and Developmental Effects
Dacthal
In a two-generation study of dacthal with Sprague-Dawley rats, dacthal was administered in the
diet at concentrations of 0, 1000, 5000 or 20,000 ppm (Male: 0, 45, 233 or 952 mg/kg-day;
Female: 0, 63, 319 or 1273 mg/kg-day). In the FI generation, there was an increase in stillbirths
at the highest dose level (1273 mg/kg/day), which was more pronounced in the second
generation than in the first (ISK Biotech Corp., 1990b). Decreased body weight gain in the
parents established the LOAELs at 319 mg/kg/day for the dams and 952 mg/kg/day for the
males. The NOAELs were 63 and 233 mg/kg/day for the females and males, respectively. Based
on weight decrements, the FI and F2a offspring LOAEL was 319 mg/kg/day, the same as that of
the dams. On day 0 for the F2b litters, the diets for the low and mid-dose groups were changed to
18 and 47 mg/kg/day, respectively. For this generation, the offspring NOEL was set at 18
mg/kg/day and the LOEL was 47 mg/kg/day (U.S. EPA, 1994).
Developmental testing of dacthal with CD (25/group) rats exposed to gavage doses of 0, 500,
100 or 2000 mg/kg-day on gestation days (gd) 6-15 failed to identify a LOAEL; the NOAEL was
2000 mg/kg/day (SDS Biotech Corp., 1986). Similar results were seen in New Zealand White
rabbits exposed by gavage at doses of 0, 125, 250 or 500 mg/kg-day during gd 7-19. The
NOAEL and highest dose tested was 500 mg/kg/day (Fermenta Plant Protection Co., 1989). In a
second study in New Zealand White rabbits by the same company, dacthal was given by gavage
on gestation days 6-19 at doses of 0, 500, 1000 or 1500 mg/kg-day from day (Fermenta Plant
Protection Co., 1989). There were four maternal deaths at the lowest dose of 500 mg/kg/day.
Thirteen maternal deaths occurred at a dose of 1000 mg/kg/day and 12 maternal deaths occurred
at 1500 mg/kg/day. The animals that died had signs of neurotoxicity, and the mid- and high-
dose groups had higher incidences of gastric ulcerations than controls. No embryo or fetal
toxicity or teratogenicity was observed. When the results of the two studies were considered, the
LOAEL for maternal toxicity was 500 mg/kg/day and the NOAEL was 250 mg/kg/day. The
NOAEL for developmental toxicity was set at 500 mg/kg/day (U.S. EPA, 1994, 1998a).
Monomethyl Tetrachloroterephthalic Acid
There were no reproductive or developmental studies of MTP.
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Dacthal and Dacthal Degradates
Tetrachloroterephthalic Acid
Pregnant COBS CD rats (25 per dose group) were administered 0, 625, 1250, or 2500 mg of
TPA per kg/day via gavage in methyl cellulose on gd 6-15 (Mizen, 1985; U.S. EPA, 1998a).
The dams were observed for clinical signs, body weights, and food intake. After sacrifice, the
ovaries were examined for corpora lutea, and the uterus for implantations, early and late
resorptions, live and dead pups. Because no developmental effects were noted at the highest
dose, the NOAEL for developmental effects was identified as 2500 mg/kg/day. Maternal
toxicity, however, was noted at 2500 mg/kg/day, based on soft or liquid stools, red mucus in the
feces, labored breathing, decreased body weight gain, and decreased food consumption. Excess
salivation was observed at the two highest doses but was considered to be the result of the
acidity of TPA. A LOAEL of 2500 mg/kg/day and a NOAEL of 1250 mg/kg/day were set for the
dams. There were no reproductive studies of TPA.
4.2.5 Genotoxicity
Dacthal
Dacthal had no mutagenic activity, with or without activation, in Salmonella assays (Auletta et
al., 1977), in in vivo cytogenetic tests (Kouri et al., 1977b), in DNA repair tests (Auletta and
Kuzava, 1977), or in dominant lethal tests (Kouri et al., 1977a).
Monomethyl Tetrachloroterephthalic Acid
No genotoxicity studies of MTP were identified.
Tetrachloroterephthalic Acid
TPA did not induce a mutagenic response in either the Ames (Godek, 1984) or hypoxanthine
guanine phosphoribosyl transferase assays with or without metabolic activation (Godek, 1985) .
It did not induce a significant increase in the frequency of sister chromatid exchanges in Chinese
hamster ovary cells with or without metabolic activation (San Sebastian, 1985). TPA does not
appear to induce unscheduled DNA synthesis (Barfknecht, 1984). An in vivo mouse
micronucleus assay (7/sex/group) with TPA was negative in females and equivocal in males (a
weak response at the highest dose) in a study by Siou (1985). The males were given doses of 0,
1000, 5000, or 10000 mg/kg by gavage and the females 0, 500, 2500, or 5000 mg/kg, both in
methylcellulose. High doses were used in most of the genotoxicity assays; limitations on
solubility may have influenced the results.
4.2.6 Carcinogenicity
Dacthal
Dacthal (technical grade, purity 97.7%), at doses of 0, 1, 10, 50, 500 or 1000 mg/kg/day induced
thyroid tumors in male and female rats, and liver tumors in female rats (ISK Biotech Corp.,
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Dacthal and Dacthal Degradates
1993). However, there was no significant increase in tumor incidence in the Paynter and
Kundzin/ Diamond Alkali Co. (1963) study in albino rats (35/sex/dose and 70/sex for the
controls) which used fewer animals and a lower dose range (0, 5, 50 or 500 mg/kg/day) of a
purer grade of dacthal.
In the ISK Biotech Corp. (1993) study, 70 Sprague-Dawley rats/sex/dose were administered
technical dacthal in the diet at doses of 0, 1, 10, 50, 500 or 1000 mg/kg/day for two years. The
material used contained 0.13% hexachlorobenzene as an impurity. This is equivalent to doses of
0, 0.0013, 0.013, 0.065, 0.65, or 1.3 mg/kg/day hexachlorobenzene for the respective dacthal
doses. Incidences of thyroid follicular cell adenomas in male rats for the respective dose groups
were 1, 2, 2, 8, 10, and 7; thyroid follicular cell carcinomas were not increased. In females,
incidences of thyroid follicular cell adenomas in the respective dose groups were 1, 1, 2, 4, 1,
and 4, and incidences of thyroid follicular cell carcinomas in the respective dose groups were 0,
0, 1,0, 1, and 4. Hepatocellular adenomas were increased in females (0, 0, 1, 1, 5, 7 in the
respective dose groups) as were hepatocellular carcinomas (0, 0, 1, 0, 3, 3 in the respective dose
groups). Hepatocholangiocarcinomas were increased in females in the high-dose group only (2
vs. none in all other groups) (U.S. EPA 2002).
Male and female CD-I mice (90/sex/dose) both developed carcinomas and adenomas in the
liver after chronic exposure to dacthal in the diet at concentrations of 0, 100, 1000, 3500 or
7500 ppm (Male: 0, 12, 123, 435 or 930 mg/kg-day; Female: 0, 15, 150, 510 or 1141 mg/kg-
day) for 2 years. (Fermenta Plant Protection Company, 1988). Tumors were found in the
controls as well as the exposed animals. The tumors in male mice fell within the range for
historical controls from 9 studies in CD-I mice (U.S.. EPA, 1995a). The incidence of adenomas
in the female mice at the high dose (11%) was slightly greater than that for the historic controls
(2-8%). The same was true for combined adenomas and carcinomas (12%) when compared to
the historic controls. There was also a dose-response trend for the numbers of adenomas with
incidences of 3%, 0%, 3%, 5%, and 11% for the 0, 100, 1000, 3500, and 7500 ppm doses,
respectively (U. S. EPA, 1995a).
Dacthal Degradates
There are no carcinogenicity studies for either TPA or MTP. The short-term studies that have
been conducted for TPA did not identify thyroid or liver effects at the doses tested, reducing
concern that TPA might have tumorigenic properties similar to dacthal. Klopman et al. (1996)
used a Multicase QSAR analytical model to predict the carcinogenicity potential of TPA. Based
on the results from this QSAR model, the authors concluded "that TPA does not present any
substantial carcinogenic risk."
4.3 Proposed Mode of Action
4.3.1 Noncancer Effects
There are no mode-of-action data for any of the noncancer effects of dacthal or TPA except for
TPA's laxative effect. Ten- and 30-day gavage studies of TPA in adult rats were reported to
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Dacthal and Dacthal Degradates
cause soft or liquid stools at doses of 2000 and 2500 mg/kg/day (Major, 1985; Mizen, 1985).
Gavage doses of 500 and 1250 mg/kg/day did not have an effect (Goldenthal et al., 1977; Major,
1985; Mizen, 1985). Neither did dacthal in subchronic and chronic dietary studies at doses of
1760 mg/kg/day or 1000 mg/kg/day, respectively (ISK Biotech Corp., 1990a, 1993).
TPA and dacthal are poorly absorbed in the gastrointestinal tract when high doses are
administered. In the case of TPA, both studies that resulted in soft stools were studies where the
compound was administered by gavage in methylcellulose, a reflection of it poor solubility.
Poorly absorbed substances increase intraluminal osmotic activity, causing the retention of water
within the intestine. The result is excess water in the fecal matter (soft stools) or diarrhea. The
gavage administration and osmolality of TPA in the 30-day and developmental studies provides
a probable mode of action that explains its laxative effect at high doses.
4.3.2 Cancer Effects
There are few data on the mode of action for the tumorigenic effects of dacthal. Thyroid
follicular cell hyperplasia or hypertrophy occurred in the ISK Biotech Corp (1991) 90-day rat
studies of dacthal, as well as in the long-term ISK Biotech Corporation (1993) and Paynter and
Kundzen (1963) studies and may contribute to tumor initiation in the thyroid. Hypertrophy,
eosinophilic foci, and/or centrilobular cellular vacuolization of the liver were observed in the
subchronic and chronic studies of dacthal in mice and rats but none of these studies reported
necrotic lesions and biomarkers of membrane damage, where observed, did not show a dose-
related response.
Dacthal used in the more recent chronic rodent studies (Fermenta Plant Protection Company,
1988; ISK Biotech Corporation, 1993 ) contained 0.13% hexachlorobenzene as an impurity. The
Agency has classified hexachlorobenzene as a 82 (probable human) carcinogen based on
significant increases of tumor incidence in rodents. Hexachlorobenzene induced tumors in the
livers of rats, hamsters and mice. Neoplasms of the thyroid and kidney have also been observed
(U.S. EPA 1989b). EPA (1998a) concluded that the dacthal impurities could contribute to its
tumorigenicity but could not fully explain the observed potency.
Klopman et al. (1996) examined the alkylating properties of dacthal, as reflected in its ability to
react with Y-4-nitrobenzylpyridine (y4-NBP). Dacthal demonstrated some ability to react with
y4-NBP raising the possibility that alkylating potential, alone or in combination with the
carcinogenicity of the product impurities, might explain the weak tumorigenic response.
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Dacthal and Dacthal Degradates
5.0 QUANTIFICATION OF TOXICOLOGICAL EFFECTS
HAs describe nonregulatory concentrations of drinking water contaminants at which adverse
health effects are not anticipated to occur over specific exposure durations. HAs are developed
for both short-term and long-term (Longer-term and Lifetime) exposure periods based on data
describing noncarcinogenic endpoints of toxicity.
Short-term exposures can include One-day and Ten-day exposure periods. One-day and Ten-day
HA's use parameters that reflect exposures and effects for a 10 kg child consuming 1 liter of
water per day.
A Longer-term HA covers an exposure period of approximately 7 years, or 10 percent of an
individual's lifetime. Longer-term HAs can incorporate parameters for either a child (10 kg body
weight consuming 1 liter per day water) or an adult (70 kg body weight consuming 2 liters per
day water) parameters.
A Lifetime HA covers an individual's lifetime, approximately 70 years. A lifetime HA considers
a 70 kg adult consuming 2 Liters of water per day. The lifetime HA is considered protective of
non-carcinogenic adverse health effects over a lifetime exposure. A relative source contribution
from water is also factored into the lifetime HA calculation to account for contaminant exposures
from other sources (air, food, soil, etc). For those substances that are Carcinogenic to Humans,
Likely to Be Carcinogenic to Humans (U.S. EPA, 2005b), known (Group A), or probable
(Groups BI and 82) human carcinogens (U.S. EPA, 1986), the development of a Lifetime Health
Advisory is not usually recommended. A Lifetime HA can be calculated for substances that are
possible carcinogens (U.S. EPA, 1986) or provide "Suggestive Evidence of Carcinogenic
Potential"(U.S. EPA 2005b).
The One-day, Ten-day, or Longer-term HA is derived using the following formula:
TT A NOAEL or LOAEL x BW
HA =
UF x DW
Where:
NOAEL or = No- or Lowest-Observed-Adverse-Effect Level (in mg/kg bw/day)
LOAEL from a study of an appropriate duration
BW = Assumed body weight of a child (10 kg) or an adult (70 kg).
UF = Uncertainty factor in accordance with EPA guidelines
DWI = Assumed human daily water consumption for a child (1 L/day) or
an adult (2 L/day)
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Dacthal and Dacthal Degradates
The Lifetime HA is calculated in a three-step process:
Step 1: Adopt a pre-existing Reference Dose (RfD) or calculate an RfD using the following
equation:
_ - NOAEL, LOAEL or BMDL
RID —
UF
Where:
NOAEL or = No- or Lowest-Observed-Adverse-Effect Level (in mg/kg bw/day).
LOAEL
BMDL = Lower confidence bound on the Bench Mark Dose (BMD). The
BMD and BMDL are obtained through modeling of the dose-
response relationship.
UF = Uncertainty factor established in accordance with EPA guidelines.
Step 2: Calculate a Drinking Water Equivalent Level (DWEL) from the RfD. The DWEL
assumes that 100% of the exposure comes from drinking water.
DWEL =
DWI
Where:
RfD = Reference Dose (in mg/kg bw/day).
BW = Assumed body weight of an adult (70 kg).
DWI = Assumed human daily water consumption for an adult (2 L/day)
Step 3: The Lifetime HA is calculated by factoring in other sources of exposure (such as air,
food, soil) in addition to drinking water using the RSC for the drinking water.
Lifetime HA = DWEL x RSC
Where:
DWEL = Drinking Water Equivalent Level (calculated from step 2)
RSC = Relative source contribution
Note. The procedure for establishing the RSC is described in U.S. EPA (2000a): Methodology
for deriving Ambient Water Quality Criteria for the Protection of Human Health (pages 4-5 to 4-
17). The methodology can be accessed at:
http ://www. epa. .gov/waterscience/criteria/humanhealth/method/complete. pdf
In cases where monitoring data are available for both dacthal and its degradates, and an HA is
only available for dacthal, the combined degradate concentrations can be multiplied by 1.09 to
convert them to dacthal equivalent estimates and added to the dacthal concentration for
comparison with the dacthal HA. The 1.09 conversion factor is the ratio of the dacthal molecular
weight to the formula weight for TPA.
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Dacthal and Dacthal Degradates
5.1 One-day Health Advisory
Dacthal
No suitable information was found for determining the One-day HA for dacthal. The study of
dacthal in humans by Tusing (1963) is not appropriate since no effects were observed when low
doses (0.36 or 0.71 mg/kg) were tested in few individuals. Animal data for an appropriate
exposure duration are not available. Therefore, it is recommended that the Ten-day HA value for
dacthal be used as conservative estimate of the One-day HA.
Dacthal Degradates
There are no appropriate data to support derivation of a One-day health advisory for MTP or
TPA. It is recommended that the Ten-day HA value for TPA be used as conservative estimate of
the One-day HA.
5.2 Ten-day Health Advisory
Dacthal
The 28-day rat study by ISK Biotech Corp. (1990a) was selected to serve as the basis for the
Ten-day HA for dacthal. In this study, a LOAEL for increased liver weight and centrilobular
hepatocyte hypertrophy of 215 mg/kg/day in males and 228 mg/kg/day in females was identified.
There was no NOAEL in this study. This study was selected because it is of appropriate
duration, had sufficient dose groups, and was conducted in the most sensitive of the non-primate
species evaluated.
The Ten-day HA for a 10-kg child is calculated as follows:
Ten Day HA = 215m§/k§/day x 10 Kg = 2l (rounded to 2 mg/L)
1000 x 1 L/day
Where:
215 mg/kg/day = LOAEL for hepatotoxicity in male rats (ISK Biotech Corp.,
1990a).
10 kg = Assumed body weight of a child
1000 = Uncertainty factor chosen for interspecies (10), intraspecies (10)
differences, and a LOAEL to NOAEL (10) adjustment
1 L = Assumed daily water consumption of a child.
Note. A 10-fold adjustment was used for the LOAEL to NOAEL because the 90-day
subchronic study by ISK Biotech Corp. (1991) observed similar effects in the liver at a
NOAEL of 10 mg/kg/day and a LOAEL of 50 mg/kg/day, well below the LOAEL in the
ISK Biotech Corp. (1990a) study.
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Dacthal and Dacthal Degradates
Monomethyl Tetrachloroterephthate
There are no data that are appropriate for the derivation of a longer term HA for MTP. The only
study identified was a 28-day single dose (860 mg/kg/day) dietary study in rats that observed no
adverse effects. Although the duration of the study would support its use for a ten-day HA, the
evaluation of toxicological endpoints was limited.
Tetrachloroterephthalic Acid
Both the 10-day developmental study with pregnant rats (Mizen, 1985) and the 30-day gavage
study with male and female Sprague-Dawley rats (Major, 1985) can be considered as the basis
for the 10-day HA for TPA because both studies showed that TPA has an effect on stool
consistency and possibly causes intestinal irritation. There were no developmental effects in the
Mizen (1985) study, but aNOAEL of 1250 and LOAEL of 2500 mg/kg/day, respectively, were
determined for the dams based on soft stools, red mucus in the feces, and effects on food
consumption and weight gain. In the 30-day study (Major, 1985), soft stools were observed in
both sexes at 2000 mg/kg/day, but not at the next lowest dose of 500 mg/kg/day. The highest
NOAEL of 1250 mg/kg/day in the study of Mizen (1985) was selected as the basis of the ten-day
HA for TPA.
The Ten-day HA for a 10-kg child is calculated as follows:
TenDay HA = 1.250 mg/kg/day x 10 Kg = (rOundedtolOOmg/L)
y 100 x 1 L/day
Where:
1,250 mg/kg/day = NOAEL for soft stools (Mizen, 1985).
10 kg = Assumed body weight of a child
100 = Uncertainty factor chosen for interspecies (10) intraspecies (10)
differences
1 L = Assumed daily water consumption of a child.
Note. A 10-fold interspecies uncertainty factor was applied because the impact of TPA on the
consistency of stools may depend on the total osmolality of the diet. Human diets are far
more varied than those of laboratory animals providing opportunities for additive effects
if TPA were combined with a diet containing high concentrations of other osmotically
active solutes.
5.3 Longer-term Health Advisory
Dacthal
The study by ISK Biotech Corp. (1991) was selected to serve as the basis for the Longer-term
HA for dacthal. The NOAEL was 10 mg/kg/day based on for centrilobular hypertrophy of the
liver in rats at a LOAEL of 50 mg/kg/day in a subchronic (90-day) duration study. This study
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Dacthal and Dacthal Degradates
was selected because it is of appropriate duration and was conducted in the most sensitive of the
non-primate species evaluated.
For a 10 kg child, the Longer-term HA is calculated as follows:
lOmg/kg/day x 10 Kg
Longer - term HA = 2_e—* e = j ^
100 x 1 L/day
Where:
lOmg/kg/day = NOAEL for hepatotoxicity (ISK Biotech Corp., 1991)
10 kg = Assumed body weight of a child
100 = Uncertainty factor, chosen for interspecies (10) and intraspecies
(10) differences
1 L = Assumed daily water consumption of a child.
For an adult, the Longer-term HA is calculated as follows:
Longer - term HA = —mg g ay = 3.5mg/L (rounded to 4 mg/L)
5 100 x 2 L/day
Where:
lOmg/kg/day = NOAEL for hepatotoxicity (ISK Biotech Corp., 1991)
70 kg = Assumed body weight of an adult
100 = Uncertainty factor, chosen for interspecies (10) and intraspecies
(10) differences
2 L = Assumed daily water consumption of an adult.
Monomethyl Tetrachloroterephthalate
There are no data that are appropriate for the derivation of a longer term HA for MTP. The only
study identified (Hazleton Laboratories, 1961) was a 28-day single dose study (860 mg/kg/day)
in rats that does not meet the duration requirements for a longer-term HA.
Tetrachloroterephthalic Acid
The data from the subchronic study (Goldenthal et al., 1977) of TPA were selected as the basis
for a longer term HA. Charles River CD rats (15/sex/dose) received doses of 0, 2.5, 25, 50 or 500
mg/kg/day in their diets for 90 days. The animals were evaluated for clinical signs, body
weights, organ weights and tissue histopathology for the control and high dose animals. Blood
and urine were evaluated at 1, 2, and 3 months. The highest dose tested was identified as a
NOAEL.
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Dacthal and Dacthal Degradates
For a 10 kg child, the Longer-term HA is calculated as follows:
500mg/kg/day x 10 Kg
Longer - term HA = - 2_2 — I - &. = 50 mg/L
100 x 1 L/day
Where:
500mg/kg/day = NOAEL (highest dose tested; Goldenthal et al., 1977)
10 kg = Assumed body weight of a child
100 = Uncertainty factor, chosen for interspecies (10) and intraspecies
(10) differences
1 L = Assumed daily water consumption of a child.
For an adult, the Longer-term HA is calculated as follows:
Longer -term HA = 500 ^g/kg/day x 70 Kg = n5 mg/L (rounded to 200 mg/L)
100 x 2 L/day
Where:
500mg/kg/day = NOAEL (highest dose tested; Goldenthal et al., 1977)
70 kg = Assumed body weight of an adult
100 = Uncertainty factor, chosen for interspecies (10) and intraspecies
(10) differences
2 L = Assumed daily water consumption of an adult.
5.4 Lifetime Health Advisory
Dacthal
An oral RfD of 0.01 mg/kg/day has been established for dacthal (U.S. EPA, 1994, 1998a). The
RfD was derived from a NOAEL of 1 mg/kg/day in a 2-year feeding study with rats (ISK
Biotech Corp., 1993). The LOAEL was 10 mg/kg/day for a decrease in T4j increased thyroid
follicular cell hyperplasia, and hepatic eosinophilic foci and centrilobular hypertrophy.
RfD = = 0.01 mg/kg/day
Where:
1 mg/kg/day = NOAEL for thyroid toxicity and hepatotoxicity (ISK Biotech
Corp., 1993)
100 = Uncertainty factor, chosen for interspecies (10) and intraspecies
(10) differences
A Drinking Water Equivalent Level (DWEL) can be derived from the oral RfD as follows:
DWEL = 0-01 ^/kg/day x 70Kg =
2 L/day
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Dacthal and Dacthal Degradates
Where:
0.01 mg/kg/day = Oral Reference Dose
70 Kg = Assumed body weight of an adult
2 L/day = Assumed daily water consumption of an adult.
The Lifetime HA is calculated as follows:
Lifetime HA = 0.35 mg/L x 0.20 = 0.07 mg/L (70|ig/L)
Where:
0.35 mg/kg/day = Drinking Water Equivalent Level
0.20 = Relative source contribution (default value of 20%)
Note. Because data on the relative contributions of food and air to total exposure are inadequate,
the default value of 20% was used for drinking water (U.S. EPA, 2000a). There are no
Total Diet Study- type data for MTP or TPA in foods that provide the national estimates
needed to determine a value other than a default for the sum of dacthal and its degradates.
However OPP modeled estimates for residues of dacthal and its degradates in foods and
drinking water indicate that total residues are below levels of concern (U.S. EPA, 2004a);
Earlier OPP concerns related to the levels of degradates in ground water were addressed
by restricting use on some commodities (U.S. EPA, 2005a)
Dacthal Degradates
Data are inadequate to establish lifetime HAs for MTP and TPA. Based on the relative toxicities
for dacthal and TPA in subchronic studies, the lifetime HA for dacthal will be protective when
applied to the sum of dacthal and its degradates after molar conversion of the degradate
concentrations to dacthal equivalents.
5.5 Evaluation of Carcinogenic Potential
Dacthal
The HA evaluation of carcinogenic potential includes the U.S. EPA descriptors for the weight of
evidence for the likelihood that the agent is a human carcinogen and the conditions under which
the carcinogenic effects may be expressed, as well as a quantitative estimate of cancer potency
(slope factor), where available. The Cancer Slope Factor (CSF) is the result of the application of
a low-dose extrapolation procedure and is presented as the risk per mg/kg/day of the
contaminant. In cases where a CSF has been derived, HAs include the drinking water
concentrations equivalent to an upper-bound excess lifetime cancer risk of one-in-ten-thousand
(1 x 10"4), one-in-one-hundred-thousand (1 x 10"5), to one-in-one-million (1 x 10"6).
Cancer assessments conducted before 1996 used the five-category, alpha-numeric system for
classifying carcinogens established by the Guidelines for Carcinogen Risk Assessment (U.S.
EPA, 1986). The EPA currently requires that all new cancer risk assessments comply with the
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005b) or, if conducted between 1996
and 2005, comply with the draft versions of the 2005 Cancer guidelines.
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Dacthal and Dacthal Degradates
Dacthal has not been evaluated by the Agency using the 2005 cancer guidelines. The OPP has
classified dacthal as Group C,possible human carcinogen (U.S. EPA, 1998a) based on evidence
of an increased incidence of thyroid tumors in both sexes of rats and liver tumors in female rats
and mice. The OPP used a multi-stage model to calculate a cancer slope factor (Qi*) of 1.49 x
10"3 (mg/kg/day)"1. Concentrations equivalent to an upper-bound excess lifetime cancer risk of
one-in-ten-thousand (1 x 10"4), one-in-one-hundred-thousand (1 x 10"5), and one-in-one-million
(1 x 10"6) are 2300, 230 and 23 |ig/L, respectively.
The evidence for the carcinogen!city of dacthal may reflect, at least in part, the carcinogen!city
of several of the impurities of the test material although OPP concluded that neither
hexachlorobenzene nor dioxin/furans can fully account for the tumorigenic response from the
study of technical dacthal containing these impurities (U.S. EPA, 1998a). Hexachlorobenzene is
a probable human carcinogen and, like dacthal, is associated with liver and thyroid tumors in
laboratory animals.
Dacthal Degradates
There are no cancer data for either MTP or TPA. Accordingly, they can be described as having
inadequate information to assess carcinogenic potential. The mutagenicity data for TPA are
negative (U.S. EPA, 1998a) as are the findings from carcinogenic structure-activity analysis
(Klopman et al. 1996).
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Dacthal and Dacthal Degradates
6.0 OTHER CRITERIA, GUIDANCE, AND STANDARDS
The states of Arizona and Florida both have drinking water guidelines for dacthal of 3500 |ig/L,
and the State of Wisconsin has a drinking water guideline of 4000 |ig/L (HSDB, 2005).
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Dacthal and Dacthal Degradates
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Dacthal and Dacthal Degradates
7.0 ANALYTICAL METHODS
EPA Method 508 is used to detect dacthal in drinking water (U.S. EPA, 1995a) using a gas
chromatographic (GC) method applicable to the determination of some chlorinated pesticides in
water. In this method, approximately 1 liter of sample is extracted with methylene chloride. The
extract is concentrated and the compounds are separated using capillary column GC.
Measurement is made using an electron capture detector (ECD). The estimated detection limit
for dacthal is 0.025 |ig/L.
Four analytical methods are available for detecting MTP and TPA in water. EPA Methods 508,
515.1,515.2, 515.3, and 515.4 involve hydrolyzation, extraction, derivatization, and cleanup
steps before detection by GC/ECD (U.S. EPA 1995b; 1995c; 1995d; 1996b; 2000b). Methods
515.1, 515.2, and 515.4 do not distinguish between the two degradates and give the total
degradate concentration. Method 515.3 gives the total concentration of dacthal plus the two
degradates. The method detection limit (MDL) for the MTP and TPA degradates using Method
515.1 is 0.067 |ig/L, and the average recovery ranges from 74-81% (U.S. EPA 1995b). The
MDL for the MTP and TPA degradates using Method 515.2 is 0.13 |ig/L, and the recovery
ranges from 60-118%. Using Method 515.3, the MDL for total dacthal and degradates ranges
from 0.38 to 0.63 |ig/L, and the recovery ranges from 88-123%. The MDLs for Method 515.4 is
0.113 |ig/L (primary column) and 0.105 |ig/L (secondary column) in reagent water; the average
recovery ranges from 92-100%, depending on the method option used.
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Dacthal and Dacthal Degradates
8.0 TREATMENT TECHNOLOGIES
Potential treatment technologies for removing dacthal and its degradates from water include
membrane processes, activated carbon, and advanced oxidation. High pressure technologies that
use nanofiltration and reverse osmosis are capable of removing dissolved organic contaminants
including dacthal and its degradates.
Granular activated charcoal treatment removes contaminants via the physical and chemical
process of sorption. Contaminants with double bonds and low water solubility such as dacthal
generally have a high affinity for carbon. MTP and TPA which are more water soluble than
dacthal, are expected to be less amenable to activated carbon treatment.
Advanced oxidation processes using a combination of oxidants produce free hydroxyl radicals
that can oxidize organic or inorganic contaminants in water. Compounds with short aerobic
metabolism half-lives are expected to be amenable to treatment using advanced oxidation
processes. U.S. EPA (1998a) reports that the half-life of DCPA is between 18 to 37 days, while
the half-life of MTP is shorter (2.8 days) and that of TPA is longer (virtually no degradation in
300 days). These findings suggest that advanced oxidation processes may be effective for MTP,
less effective for dacthal, and not effective for TPA.
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Dacthal and Dacthal Degradates
9.0 REFERENCES
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