FINAL DRAFT
United States er*n n
Environmental Protection CUW-H
Agency Hatch, 1988
SEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR SODIUM DIETHYLDITHIOCARBAMATE
Prepared for
OFFICE OF SOLID WASTE AND
ENERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 1s 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 llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980) 1s provided. These
potency estimates are derived for both oral and Inhalation exposures where
possible. In addition, unit risk estimates for air and drinking water are
presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genldty are derived. The RQ 1s used to determine the quantity of a
hazardous substance for which notification 1s required 1n the event of a
release as specified under the Comprehensive Environmental Response, Compen-
sation and Liability Act (CERCLA). These two RQs (chronic toxldty and
cardnogenlclty) represent two of six scores developed (the remaining four
reflect 1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian
-specific RQs reflect the lowest of these six primary
methodology for chronic toxldty and cancer based RQs are
deflneddo: tf.S. EPA. 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Dlthlocarb 1s a solid at ambient temperatures; H 1s highly soluble 1n
water and In ethanol (Hawley, 1981; IARC, 1976). The compound 1s stable at
pH >9 but decomposes to carbon dlsulflde and dlethylamlne salts In acidic pH
(Wlndholz, 1983; Van Leeuwen et al., 1985a). Currently, Vanderbllt Co.,
Bethel, CT, Alco Chemical, Chattanoga, TN, and Frank Enterprises, Columbus,
OH, produce this chemical In the United States. The current production
volume for dlthlocarb 1s not available (SRI, 1987; USITC, 1986). Olthlocarb
1s used mainly as an accelerator In rubber processing, as an Intermediate In
fungicide manufacture and as a chelatlng agent (U.S. EPA, 1983; NCI, 1979).
Limited data were located 1n the available literature to assess the fate
and transport of dlthlocarb In environmental media. Based on Its physical
properties, the compound Is not likely to accumulate 1n the air compartment.
In the atmosphere, dlthlocarb may undergo hydrolysis 1n the presence of
moisture. Given Us high water solubility, dlthlocarb may be removed from
the air by wet deposition and may not be transported long distances. In
water of pH <7, hydrolysis 1s expected to be the primary process for the
removal of dlthlocarb. The hydrolysis half-lives at pH 5.7 and 7.0 are 40
minutes and <1 day, respectively (Van Leeuwen et al., 1985a). Above pH 7.0,
hydrolysis will become progressively less Important and the compound may
persist longer. Although dlthlocarb may blodegrade 1n water (King and
Painter,^9B5; Brink, 1976), no rate data are available to assess the
:- --'*9±K-£ -
s.1 gn 1 f-tcjnjpjL-QfLthe process 1n water at pH >7. In acidic soils, hydrolysis
may be the primary process for the removal of dlthlocarb (Tate and
Alexander, 1974). Because of the expected toxldtles of the degradation
products, blodegradatlon may be a slow process 1n soil (Kaufman, 1967).
1v
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It Is likely that the compound will leach substantially In soils with low
Ion-exchange capacities.
In a 1965 survey of pesticide residues In food and feed samples from
Kansas City, MO, Duggan et al. (1967) reported 0.5 mg/kg of dHhlocarbamates
1n one sample of grain and cereal and concentrations of 0.4, 0.7 and 0.8
mg/kg In three samples of leafy vegetables. Hemm1nk1 and Valnlo (1984)
estimated the exposure of the Finnish population to dHhlocarbamates from
food (when the chemical was used as a pesticide) to be 29 tig/day. No
other Information regarding exposure to this compound was located In the
available literature.
The acute toxldty of dlthlocarb has been evaluated In fish and
crustaceans. A 96-hour LC,.. of 6.9 mg/l was determined for gupples (Van
Leeuwen et al., 1985a) and 1-hour exposure to 15 mg/8, produced 67X lethal-
ity 1n foldflsh (Oota, 1971). A 48-hour LC5Q was determined for Daphnla
(Van Leeuwen et al., 1985b). A 24-hour LC5Q of 3 mg/l was determined
for frog embryos, and malformations were observed at concentrations as low
as 0.5 mg/l (Ghate and Nulherkar, 1980). Chronic toxldty data for fish
or other vertebrates were not located, but a 21-day LC5Q of 30 vg/l
was determined for Daphnla (Van Leeuwen et al., 1985b). Studies with
aquatic plants have determined a 96-hour EC5Q of 1.4 mg/l for unicellu-
lar green algae (Van Leeuwen et al., 1985a), and that the yield of reproduc-
tive fronds In duckweed was decreased by exposure to 17.1 mg/l for 3 days
{Oota,. 19.7JJU_.
L1m1tedL pharmacok1 net 1c data are available for oral and parenteral
— =.-=^a=i--
adm1n1strat1on of dlthlocarb; no data are available for Inhalation exposure
to this compound. Although dlthlocarb Is thought to decompose to carbon
dlsulflde In the addle environment of the stomach (Stromme, 1965; Evans et
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al., 1979), unchanged dithlocarb and dlthlocarb-S-glucuronlde are detectlble
1n the plasma within 15 minutes of oral administration of dithlocarb to rats
(Craven et al., 1976). The concentration of dithlocarb In plasma slowly
Increased to a maximum by 3 hours after gavage administration to rats, which
1s consistent with the expected low rate of absorption of an Ionized sodium
salt (Baselt and Hanson, 1982) and Indicates that significant quantities of
the compound are absorbed without decomposition. A large percentage of the
orally administered dose, -28-8054, however, 1s excreted by humans and rats
as carbon dlsulflde In the expired air (Herlevede and Casler, 1961; Craven
et al., 1976). The remainder, at least 1n rats, Is excreted as metabolites
(primarily d1th1o-S-glucuron1de and Inorganic sulfate) 1n the urine with
only minor amounts In the feces (Craven et al., 1976). The excretion data
Indicate virtually complete absorption of dithlocarb and metabolites or
decomposition products from the gastrointestinal tract. Following 1ntra-
perltoneal administration to rats, 10X of the dose was expired as carbon
dlsulflde within 4 hours (Stromme, 1965), Indicating that some of the carbon
dlsulflde In the oral experiments may have originated from metabolism after
absorption of dithlocarb from the stomach.
Tissue distribution data were not available, other than the observation
that the concentration of dithlocarb and metabolites 1n the soluble fraction
of liver following IntraperHoneal Injection of 35S-d1th1ocarb Into rats
Is higher than In plasma and that some of the dithlocarb or metabolites In
plasma an
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Subchronlc and chronic oral administration of dlthlocarb to rats, mice,
dogs and rabbits has shown that depression of body weight or body weight
gain Is one of the more sensitive Indicators of toxlclty of this compound
(NCI, 1979; Sunderman et al., 1967; Rasul and Howell, 1973a,b) occurring 1n
subchronlc studies In rats at 100 mg/kg/day (subchronlc LOAEL) (Sunderman et
al., 1967). These studies also Indicate that rats may be slightly more
sensitive to the toxlclty of dlthlocarb than are mice or dogs, but that
species differences In sensitivity are small. (The data for rabbits are
Insufficient to judge their relative sensitivity). Additional effects 1n
subchronlc oral studies Include renal toxlclty 1n rats and hematologlcal
effects (decreases 1n red cell counts, hematocrUs and hemoglobin levels) In
rats and dogs at 300 mg/kg/day (Sunderman et al., 1967) and nervous system
lesions In rabbits at 330 mg/kg/day (5 days/week) (Rasul and Howell, 1973a).
The NOEL for subchronlc oral exposure Is 30 mg/kg/day In rats (Sunderman et
al., 1967).
In chronic studies, rats had cataracts and body weight depression at the
lowest level tested, 1250 ppm of dlthlocarb In the diet (62.5 mg/kg/day,
chronic LOAEL) (NCI, 1979). Mice had body weight depression at the lowest
chronic level tested, 500 ppm of dlthlocarb In the diet (65 mg/kg/day) (NCI,
1979). Higher exposure levels 1n rats and mice 1n this study produced a
more pronounced depression of body weight 1n both species and cataracts
(Incidence not dose-related) In rats. Renal effects were not reported 1n
the chronic portion of the NCI (1979) study, although mild renal effects
were seen^ip: rats In the subchronlc portion of this study, apparently at a
dletary level of 10.000 ppm dlthlocarb. The NCI (1979) study did not
perform hematologlcal tests, but a slight Increase 1n splenic hematopolesls
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was noted 1n rats, apparently at 10,000 ppm In the diet, 1n the subchronlc
portion of the study. The data do not define a NOAEL or NOEL for chronic
oral exposure (NCI, 1979).
Acute toxlclty data Include oral LO-Q values of 1500 mg/kg In both
rats and mice, 1ntraper1toneal LD5Q values of 1250 mg/kg 1n rats and 1302
mg/kg In mice, and a subcutaneous LD_ of 500 mg/kg In rabbits (NIOSH,
1987).
Dlthlocarb 1s a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sunderman, 1979).
Because of Us metal chelatlng properties, dlthlocarb has been used
therapeutkally In human cases of metal poisoning, most commonly nickel
carbonyl poisoning (Sunderman, 1979, 1981). Evidence from numerous studies,
however. Indicates that chelatlon therapy with dlthlocarb may. In animals
treated with various metal compounds, facilitate the entry of metals Into
the brain and Into the fetus, perhaps because the dlthlocarb-metal chelate
Is, llpophlllc. A single study reported a worsening of CMS signs following
Intravenous treatment of thallium-Intoxicated humans with dlthlocarb
(Kamerbeek et al., 1971).
Repeated 1ntraper1toneal administration of dlthlocarb to rabbits and
lambs produced lesions of the nervous system In both species (Edlngton and
Howell, 1966; Howell et al., 1970). Oral administration of dlthlocarb to
chickens produced signs and lesions Indicative of delayed neurotoxlclty
(Rasul and-Howell. 19730, 1974a,b; Fisher and Metcalf, 1983).
~ w__ -.*&_. _
D1 ttLTQcaj" br^1 nh 1 bits the conversion of dopamlne to noradrenalln by
">
dopam1ne-B-hydroxylase, resulting 1n Increased tissue levels of dopamlne and
decreased tissue levels of noradrenalln (Thuranszky et al., 1982; Collins
and West, 1968; Carlsson et al., 1966). Dlthlocarb Inhibits mlcrosomal
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cytochrome P-450 associated oxldatlve metabolism of xenoblotlcs (Siegers et
al.. 1982; ZemaHls and Greene, 1979; Wattenberg et al., 1977) and stimu-
lates DT-d1aphorase and glutathlone transferase (Benson et al., 1986; Benson
and Baretto, 1985).
The protective effect of dlthlocarb against the carcinogenic effects of
l,2-d1methylhydraz1ne was attributed to Inhibition of the oxldatlve metabo-
lism (activation) of !,2-d1methylhydraz1ne (Hattenberg et al., 1977). The
protective effect of dlthlocarb against the carcinogenic effects of Intra-
muscularly Implanted nickel subsulflde was thought to be connected with
dlthlocarb's enhancement of hepatic levels of meta!1oth1one1n (Sunderman et
al., 1984).
Dlthlocarb has been reported to enhance the function of the Immune
system, primarily through effects on the T cells, both 1n animals (Renoux
and Renoux, 1979; Bruley-Rosset et al., 1986) and 1n humans (Renoux et al.,
1983; Lang et al., 1985).
Data regarding the carclnogenldty of dlthlocarb are available for the
oral route of administration, but not for Inhalation. Administration of
dlthlocarb at 215 mg/kg/day by gavage on days 7-28 of age and then at 612
ppm In the diet until week 78 of age to male and female B6C3F1 and B6AKF1
mice resulted 1n a statistically significantly Increased Incidence of tumors
only 1n the case of hepatomas In the B6C3F1 males (BRL, 1968a). Dietary
administration of dlthlocarb at 1250 and 2500 ppm to male and female F344
rats and at 500 and 4000 ppm to B6C3F1 mice for -2 years did not produce any
significant- Increases 1n tumor Incidences (NCI, 1979).
Mutagenlclty testing of dlthlocarb has been effectively limited to bacteria
and negative results have been reported (DeFlora et al., 1984; Hortelmans et
al., 1986; Rosenkranz and Lelfer, 1980).
1x
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There Is IHtle evidence that dlthlocarb 1s genotoxlc. Studies of
reverse mutation 1n Salmonella typhlmurlum (De Flora, 1981; De Flora et al.,
1984; Mortelmans et al., 1986), DNA damage 1n EsheMchla coll (Rosenkranz
and Lelfer, 1980; De Flora et al., 1984) and chromosomal damage In regener-
ating liver (mouse) (Harman et al., 1970) have given negative results for
dHhlocarb. Positive results were obtained for dlthlocarb 1n a chromosomal
damage assay 1n Vlcla faba root tips (Klhlman, 1957).
DHhlocarb has not been tested adequately for teratogenlcHy. The only
study available used subcutaneous Injection rather than a natural route of
administration. In this study (BRL, 1968b), equivocal evidence of feto-
toxlclty was seen following subcutaneous Injection of 215 mg/kg/day of
dHhlocarb Into pregnant mice.
The data base for the reproductive effects of dlthlocarb 1s also
Inadequate. The feeding of dHhlocarb at 5000 ppm In a chicken mash/lard
diet to pregnant mice from day 3 of gestation through delivery had no
adverse effects on number of dams delivering young or number of young/Utter
(Carlton, 1966). Subcutaneous Injection of dHhlocarb at 25 mg/kg, twice
weekly, Into female mice before or before and after mating produced no
adverse effects on reproductive Indices and stimulated Immune T-cell produc-
tion and responsiveness In their offspring (Renoux et al., 1985). Intra-
venous administration of dHhlocarb to pregnant rabbits resulted In loss of
the Utters (Howell, 1964). DHhlocarb Is spermlddal in vitro (Holzaepfel
et al..,_1959:t and suppresses ejaculation 1n dogs following acute IntrapeM-
toneal Injection (Sakal et al., 1979; Klmura et al., 1980a,b).
DHhlocarb 1s classified as an EPA C chemical based on a statistically
significant Increased (p=0.004) Incidence of male B6C3F1 mice hepatoma 1n a
78-week screening study and the lack of pertinent human data. A q,* of
2.69x10-1 (mg/kg/day)'1 for oral exposure was derived from the
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dose-response data for hepatomas 1n male mice In the oral study by BRL
(1968a). The concentrations In water associated with an Increased lifetime
risk of cancer at risk levels of 10~5, 10~6 and 10~7 are 1.3xlO~3,
1.3xlO~4 and 1.3xlO~5 mg/a, respectively. Inhalation cardnogenlclty
data were not available for dltMocarb. Because the oral cardnogenldty
data are limited, estimation of a q * for Inhalation exposure from the
oral data 1s not recommended.
A subchronlc oral RfD of 0.3 mg/kg/day was estimated for dlthlocarb
based on the subchronlc oral NOEL of 30 mg/kg/day from the 90-day oral study
In rats (Sunderman et al., 1967), and using an uncertainty factor of 100. A
decrease In body weight gain occurred In rats at the next higher subchronlc
dosage, 100 mg/kg/day (LOAEL) (Sunderman et al., 1967).
Chronic oral studies of dlthlocarb toxldty do not provide a NOEL or
NOAEL, but do provide a LOAEL of 62.5 mg/kg/day for reduced body weight and
cataracts In female rats (NCI, 1979). Therefore, the U.S. EPA (1983, 1985a)
used the subchronlc NOEL of 30 mg/kg/day determined for rats In the study by
Sunderman et al. (1967), and an uncertainty factor of 1000, as the basis for
the chronic RfD of 0.03 mg/kg/day for dlthlocarb. There are no new data
that would require a reevaluatlon of this verified RfD. No data were
available to support the calculation of Inhalation RfD values.
An RQ of 1000 based on systemic toxldty was derived for dlthlocarb from
the data on cataract formation 1n female rats at the low dose In the NCI
(1976) study;- An F factor of 1.29 (mg/kg/day)"1, which places dlthlocarb
1n Poten&y^Grdup 2, was calculated from the dose-response data on hepatomas
In male mice In the BRL (1968a) study. Dlthlocarb, an EPA Group C chemical
In Potency Group 2, accordingly has a LOU hazard ranking under CERCLA and an
RQ of 100 pounds based on cardnogenlclty.
x1
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TABLE OF CONTENTS
1. INTRODUCTION ........................... 1
1.1. STRUCTURE AND CAS NUMBER ................. 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES ............. 1
1.3. PRODUCTION DATA ............ .......... 2
1.4. USE DATA ......................... 2
1.5. SUMMARY .......................... 2
2. ENVIRONMENTAL FATE AND TRANSPORT ................. 4
2.1. AIR ............. ............... 4
2.2. WATER ........................... 4
2.3. SOIL ........................... 5
2.4. SUMMARY .......................... 6
3. EXPOSURE ............................. 8
4. AQUATIC TOXICITY ......................... 9
4.1. ACUTE TOXICITY ...................... 9
4.2. CHRONIC EFFECTS ...................... 10
4.3. PLANT EFFECTS .................. ..... 10
4.4. OTHER RELEVANT INFORMATION ................ 10
4.5. SUMMARY .......................... 11
5. PHARMACOKINETCS ......................... 12
5.1. ABSORPTION ........................ 12
5.2. DISTRIBUTION ....................... 12
5.3. METABOLISM ........................ 13
5.4. EXCRETION ......................... 15
5.5. SUMMARY AND CONCLUSIONS .................. 15
6. EFFECTS ............................. 17
6.1. SYSTEMIC TOXICITY ..................... 17
6.1.1. Inhalation Exposures ............... 17
6.1.2. Oral Exposures .................. 17
6.1.3. Other Relevant Information ............ 21
ARCINOGENICITY ...................... 25
Inhalation 25
6.2.2. Oral 25
6.2.3. Other Relevant Information 27
6.3. MUTAGENICITY 27
6.4. TERATOGENICITY 29
6.5. OTHER REPRODUCTIVE EFFECTS 30
6.6. SUMMARY AND CONCLUSIONS 31
xll
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TABLE OF CONTENTS (cont.)
Page
7. EXISTING GUIDELINES AND STANDARDS . 36
7.1. HUMAN 36
7.2. AQUATIC 36
8. RISK ASSESSMENT 37
8.1. CARCINOGENICITY 37
8.1.1. Inhalation 37
8.1.2. Oral 37
8.1.3. Other Routes 37
8.1.4. Weight of Evidence 37
8.1.5. Quantitative Risk Estimates 38
8.2. SYSTEMIC TOXICITY 39
8.2.1. Inhalation Exposure 39
8.2.2. Oral Exposure 39
9. REPORTABLE QUANTITIES 42
9.1. BASED ON SYSTEMIC TOXICITY 42
9.2. BASED ON CARCINOGENICITY 46
10. REFERENCES 50
APPENDIX A: LITERATURE SEARCHED 66
APPENDIX B: CANCER DATA SHEET FOR DERIVATION OF q^ FOR ORAL
EXPOSURE 69
APPENDIX C: SUMMARY TABLE FOR OITHIOCARB 70
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LIST OF TABLES
No. Title Page
6-1 Incidence of Hepatomas In B6C3F1 Mice Following Oral
Administration of DHhlocarb 26
6-2 Mutagenldty Testing of DHhlocarb 28
9-1 Oral Toxlclty Summary for D1oth1ocarb 43
9-2 Oral Composite Scores for OHhlocarb 45
9-3 DHhlocarb: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 47
9-4 Derivation of Potency Factor (F) for DHhlocarb 49
xlv
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LIST OF ABBREVIATIONS
CAS
CNS
CS
DMSO
DNA
"50
HPLC
Kow
LC50
LD50
LOAEL
MED
MIC
MTD
NOAEL
NOEL
ppm
RfO
RQ
RVd
RVe
TWA
UV
Chemical Abstract Service
Central nervous system
Composite score
Dimethyl sulfoxlde
Deoxyr1bonucle1c add
Concentration effective In SOX of recipients
High pressure liquid chromatography
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
Minimum Inhibiting concentration
Maximum tolerated dose
No-observed-adverse-effect level
No-observed effect level
Parts per million
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Time-weighted average
Ultraviolet
xv
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Sodium dlethyldlthlocarbamate 1s also called dlthlocarb; dlethylcarbamo-
d1th1on1c add, sodium salt (Chem. Abstr. name); DEDC; N,N-d1ethyld1th1o-
carbamlc add, sodium salt; dlethyl sodium dlthlocarbamate; and sodium DEDT
(IARC, 1976). Sodium dlethyldlthlocarbamate will be referred to as dlthlo-
carb throughout this document. The structure, empirical formula, molecular
weight and CAS Registry number of dlthlocarb are shown below:
C2H5 S
\ II
N-C-S-Na
C2H5
Empirical formula: C.H^NS-Na
Molecular weight: 171.3
CAS Registry number: 148-18-5
1.2. PHYSICAL AND CHEMICAL PROPERTIES
The trlhydrate of dlthlocarb 1s a yellow-white solid (NCI. 1979).
Dlthlocarb 1s also a solid at ambient temperatures and 1s soluble In water
and ethanol (Hawley, 1981; IARC, 1976). Some of the physical properties of
dlthlocarb are given below:
Melting point: 94-96'C (IARC, 1976)
Boiling point: data unavailable
Density: 1.1 g/cma at 20/20°C (Sax, 1984)
120,000 mg/i at 25°C (estimated)
(Jaber et al., 1984)
Vapor pressure: data unavailable
Log Kow: 0.04 (estimated) (Jaber et al., 1984)
UV absorption data: wavelength of absorption max. at 257 and
290 nm (IARC, 1976)
0079d -1- 01/22/88
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Chemically, dlthlocarb decomposes slowly 1n aqueous solution at pH 7.
The decomposition 1s faster under slightly addle conditions; at pH 5.0-6.7,
1t decomposes to carbon dlsulflde and dlethylamlne salt (Wlndholz, 1983;
U.S. EPA, 1983; Van Leeuwen et al., 1985a). It 1s Inert toward oxidation
(Jaber et al., 1984). When heated to decomposition, It may emit toxic fumes
of N0x, S0x and Na 0 (Sax, 1984).
1.3. PRODUCTION DATA
According to the public section of the TSCA production file (U.S. EPA,
1977), seven companies In the United States produced ~12,000-120,000 pounds
of dlthlocarb In 1977. Currently, Vanderbllt Co., Inc., Bethel, CT (USITC,
1986), Alco Chemical Corp., Chattanoga, TN, and Frank Enterprises, Inc.,
Columbus, OH, produce dlthlocarb In the United States (SRI, 1987). The
current U.S. production volume for this chemical 1s not available. Dlthlo-
carb 1s produced by reacting dlethylamlne with carbon dlsulflde and sodium
hydroxide, followed by precipitation with dlethyl ether (HSD8, 1987).
1.4. USE DATA
The zinc, selenium and tellurium salts of dlethyl dlthlocarbamate that
can be produced from the sodium salt are used as accelerators In rubber
processing (NCI, 1979). Dlthlocarb 1s also used In fungicide preparation,
as a chelatlng agent for the treatment of human metal poisoning, as an
oxidation Inhibitor and as an analytical reagent (U.S. EPA, 1983; NCI, 1979).
1.5. SUMMARY
Dlthlocarb Is a solid at ambient temperatures and 1s highly soluble In
water ah9 but decomposes to carbon dlsulflde and dlethylamlne salts 1n addle pH
(Wlndholz, 1983; Van Leeuwen et al., 1985a). Currently, Vanderbllt Co..
Bethel, CT, Alco Chemical, Chattanoga, TN, and Frank Enterprises, Columbus,
0079d -2- 01/22/88
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OH, produce this chemical In the United States. The current production
volume for dHhlocarb Is not available (SRI, 1987; USITC, 1986). It Is used
mainly as an accelerator 1n rubber processing, as an Intermediate 1n fungi-
cide manufacture and as a chelatlng agent (U.S. EPA, 1983; NCI, 1979).
0079d -3- 12/28/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Pertinent data regarding the fate and transport of dHhlocarb 1n the
atmosphere were not located In the available literature. Since dlthlocarb
Is an Ionic compound, 1t Is not expected to be present In the atmosphere In
the vapor state. Small amounts of the chemical may be present 1n the atmo-
sphere In the particle or partlcle-sorbed state. According to Jaber et al.
(1984), photolysis of dHhlocarb In aqueous solutions may not be environ-
mentally Important. It Is likely that atmospheric dlthlocarb will not
undergo significant photolysis, as well. Whether atmospheric dlthlocarb
will undergo oxidation with photochemlcally produced HO* Is not known;
however, dlthlocarb Is known to hydrolyze particularly 1n acid solutions
with the evolution of carbon dlsulflde (Wlndholz, 1983; Van Leeuwen et al.,
1985a). Therefore, H 1s possible that atmospheric dHhlocarb will
hydrolyze 1n moist air. Given Its high water solubility, dHhlocarb Is
likely to be removed from the atmosphere by wet deposition and may not be
transported long distances In the atmosphere.
2.2. WATER
According to Jaber et al. (1984), neither photolysis nor oxidation of
dlthlocarb by common oxldants In water (R0_* and SO*) 1s likely to be
an Important process. DHhlocarb 1s susceptible to hydrolysis under acidic
conditions (U.S. EPA, 1983) and the hydrolysis rate Is slower In aqueous
solutloftilSFpH—7- (Hlndholz, 1983) (see Chapter 1). Van Leeuwen et al.
(1985a)i!gstFtfreV the hydrolysis of dHhlocarb at different pHs and at
unspecified temperatures and estimated half-lives of 0.02, 0.67, 20.0, 200.0
and 1117 hours at pHs of 3.8, 5.7, 7.0, 8.0 and 9.0, respectively. These
data Indicate that hydrolysis of dHhlocarb at neutral and acidic pHs In
0079d -4- 12/28/87
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natural water may be the most significant process. Hydrolysis above pH 8.0
may not be significant. Although the blodegradabllHy of dlthlocarb 1n
natural water has not been studied, Us b1odegradab1!1ty under water treat-
ment conditions has been studied. With activated sludge acclimated to
domestic sewage, King and Painter (1985) observed 8 and 99X degradation of
dlthlocarb at an Initial concentration of 10 mg/i In 7 and 14 days,
respectively. In bench-scale aerobic blodegradatlon units, >90% of dimethyl
dlthlocarbamate at an Initial concentration of 10 mg/i was found to
blodegrade at unspecified residence times (Brink, 1976). These studies
Indicate that dlthlocarb at low concentrations 1n natural waters may be
susceptible to mlcroblal degradation, although the degradation rate of
dlthlocarb Is expected to be slower than the corresponding dimethyl compound
(Kaufman, 1967).
Pertinent data regarding the transport of dlthlocarb 1n aqueous media
were not located 1n the available literature. Based on the limited Informa-
tion available on the physical properties, 1t Is predicted that In natural
waters of pH >8.0, the compound will be stable toward hydrolysis and will be
transported In the dissolved state. In the presence of sediments that have
high Ion exchange capacities, dlthlocarb may adhere to the sediments and may
be transported.
2.3. SOIL
Limited data were available In the literature to assess the fate and
transport of dlthlocarb In soil. Tate and Alexander (1974) observed that
dlethylaralne was formed as a result of Incubation of dlthlocarb In a silt
loam soil of pH 6.4; however, 1n a study with sterile soil, the authors
concluded that the secondary amlne (dlethylamlne) was not formed as a result
of mlcroblal action but was a result of hydrolysis at the acidic pH of the
0079d -5- 12/28/87
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soil. Based on results of a study of degradation of several carbamate
pesticides 1n soil, Kaufman (1967) concluded that m1crob1al degradation of
N,N-d1subst1tuted dUMocarbamlc salts may occur very slowly because of
mlcroblal Inhibitory action of dlthlocarbamlc acid and carbon dlsulflde
formed as a result of mlcroblal action. An alternative pathway for the
mlcroblal degradation of dlthlocarb may be the formation of y-d1ethylth1o-
carbamoylth1o-a-ketobutyr1c acid that may finally form y-d1ethylth1o-
carbamoylth1o-a-am1nobutyr1c acid (Kaufman, 1967).
Pertinent data regarding the transport of dlthlocarb In soil were not
located 1n the available literature. Based on Us high water solubility and
Ionic characteristics, It Is likely that the unhydrolyzed compound will
leach substantially 1n soils with low Ion-exchange capacity. This leaching
action, however, will be greatly reduced In soils with high Ion-exchange
capacity because of fixing of the compound 1n soil.
2.4. SUMMARY
Limited data were located In the available literature to assess the fate
and transport of dlthlocarb In environmental media. Based on Us physical
properties, the compound Is not likely to accumulate 1n the air compartment.
In the atmosphere, dlthlocarb may undergo hydrolysis In the presence of
moisture. Given Us high water solubility, dlthlocarb may be removed from
the air by wet deposition and may not be transported long distances. In
water of pH <7, hydrolysis Is expected to be the primary process for the
removal of,dlthlocarb. The hydrolysis half-lives at pH 5.7 and 7.0 are 40
ro1nutes±3fl
-------
significance of the process In water at pH >7. In acidic soils, hydrolysis
may be the primary process for the removal of dHhlocarb (Tate and
Alexander, 1974). Because of the expected tox1c1t1es of the degradation
products, blodegradatlon may be a slow process 1n soil (Kaufman, 1967). It
1s likely that the compound will leach substantially 1n soils with low
Ion-exchange capacities.
0079d -7- 12/28/87
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3. EXPOSURE
In a 1965 survey of pesticide residues In food and feed samples from
Kansas City, MO, Duggan et al. (1967) reported 0.5 mg/kg of dUhlocarbamates
In one sample of grain and cereal and concentrations of 0.4, 0.7 and 0.8
mg/kg 1n three samples of leafy vegetables. Hemmlnkl and Va1n1o (1984)
estimated the exposure of the Finnish population to dUhlocarbamates from
food (when the chemical was used as a pesticide) to be 29 tig/day. No
other Information regarding exposure to this compound was located 1n the
available literature.
0079d -8- 01/22/88
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The acute toxldty of dlthlocarb was reported for the goldfish, Caras-
slui auratus (Danscher and FJerdlngstad, 1975). Exposure to 1.25, 2.25 or
3.125 mg d1th1ocarb/t for 1 hour resulted 1n no deaths or toxic effects.
Exposure to 7.5 mg/l for 1 hour was lethal within 24 hours postexposure to
-12.6X (17/135) of the tested animals. Exposure to 15, 25 and 100 mg/l
dHhlocarb for 1 hour resulted In 67X (8/12), 43X (13/30) and 100X (6/6)
mortality, respectively. At a dose of 7.5 mg d1th1ocarb/a, most fish were
less active and had "characteristic folding together of fins." Toxic
symptoms occurred within 3 hours of exposure, and those fish surviving after
24 hours appeared to recuperate.
LC5Q concentrations of dHhlocarb were determined to be 6.9 mg/l 1n
a 96-hour assay with gupples, Poedlla retlculata. and 0.91 mg/i In a
48-hour assay with water fleas, Daphnla magna (Van Leeuwen et al., 1985a).
These assays were conducted according to OECO guidelines and test solutions
were renewed dally.
The acute toxldty of two dHhlocarb formulations (each contained SOX
dHhlocarbamate) was studied 1n the crustacean, Gammarus pulex (Bluzat et
al., 1982a). The 24, 48, 72 and 96-hour LC,- values for Product A
(aqueous suspension) were 13.99, 1.21, 0.41 and 0.195 mg/i, respectively.
The 24, 48, 72 and 96-hour LC5Q values for Product B (which contained
adjuvants) were 4.77. 0.48, 0.2 and 0.13 mg/l, respectively. The 48 and
values for Product A were 15 and 10 mg/l, respectively, for
the mo lluslc. Lymnaea staqnalls (Bluzat et al., 1982b). Product B was more
toxic with 48 and 96-hour LC™ values of 4 and 3 mg dHhlocarb/i,
respectively.
0079d -9- 01/22/88
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4.2. CHRONIC EFFECTS
A 21-day life-table and growth experiment was conducted In which water
fleas, Daphnla magna. were exposed to dlthlocarb that was renewed 3 times/
week (Van Leeuwen et al., 1985b). The LC5Q, which reflects reduced
survival and fecundity, was determined to be 30 pg/l. The lowest
concentrations at which mean survival and carapace length were significantly
reduced were 24 and 14 yg/l, respectively.
4.3. PLANT EFFECTS
A 96-hour EC~Q of 1.4 mg d1th1ocarb/i was determined for unicellular
green algae, Chlorella pyrenoldosa (Van Leeuwen et al., 1985a). This
concentration reduced average specific growth rate by 50%.
Dlthlocarb at 17.1 mg/i for periods of 3, 5 or 6 days had little
effect on the growth and flower production of the duckweed, Lemna qlbba
(Oota, 1971). During 3- and 5-day exposure experiments, the yield of
reproductive fronds was decreased compared with controls. This effect was
due to dlthlocarb chelatlon and removal of ferrous Ions (which take part In
the photophlly rhythms) from the plant.
4.4. OTHER RELEVANT INFORMATION
A 15-mlnute EC™ of 1.22 mg d1th1ocarb/l was determined for
bacteria, Photobacterlum phosphoreum (Van Leeuwen et al., 1985a). This
concentration reduced the luminescence of the bacteria by SOX.
The MIC for nitrification In a 3-hour assay with nitrifying bacteria,
Nltrosoroonas-and NVtrobacter. was determined to be 43 mg d1th1ocarb/i (Van
Leeuwethaifcrariv. 1985a).
The embryotoxlc effects and teratogenldty of dlthlocarb have been
studied 1n embryos of the frog, Hlcrohyla ornata (Ghate and Mulherkar,
1980). Based on mortality during the 72 hours subsequent to exposure, a
24-hour LCcn value of 3.0 mg/i was reported. At concentrations between
0079d -10- 12/28/87
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1 and 3 mg dHhlocarb/l, embryos were severely malformed. Abnormalities
Included delayed growth, Inhibition of pigment development and abnormal
notochord development with curvature of the body axis. At 0.5 mg/l,
dHMocarb Induced the development of abnormal, wavy notochords In exposed
embryos.
Dlthlocarb, acting as a chelatlng agent, has been found to remove the
metals nickel, chromium and mercury from the gills, liver, kidney and brain
of the fish, Notopterus notopterus (Verma et al., 1981). Initially, the
fish were exposed to metal salt solutions for 30 days, during which time the
tissues accumulated metals. Subsequently, fish were exposed to 30.2 mg
d1th1ocarb/i for 7 days and examined for tissue-metal concentrations.
DHhlocarb was most effective In removing nickel from the liver and gills
(56.57 and 48.19X removed, respectively), with 14.78 and 17.91X chromium and
14.54 and 24.86X mercury removed from the liver and gills, respectively.
4.5. SUMMARY
The acute toxlclty of dlthlocarb has been evaluated In fish and
crustaceans. A 96-hour LC5Q of 6.9 mg/l was determined for gupples (Van
Leeuwen et al., 1985a), and 1-hour exposure to 15 mg/l produced 67%
lethality In goldfish (Oota, 1971). A 48-hour LC5Q was determined for
Daphnla (Van Leeuwen et al., 1985b). A 24-hour LC5Q of 3 mg/l was
determined for frog embryos, and malformations were observed at concentra-
tions as low as 0.5 mg/l (Ghate and Mulherkar, 1980). Chronic toxlclty
data fors-tUh-or-other vertebrates were not located, but a 21-day LC,. of
~~ -T". " Jw
30 vg/i^Srasi-determined for Daphnla (Van Leeuwen et al., 1985b). Studies
with aquatic plants have determined a 96-hour EC™ of 1.4 mg/l for
unicellular green algae (Van Leeuwen et al., 1985a), and that the yield of
reproductive fronds In duckweed was decreased by exposure to 17.1 mg/l for
3 days (Oota, 1971).
0079d -11- 12/28/87
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5. PHARMACOKINETICS
5.1. ABSORPTION
Craven et al. (1976) studied the fate of "S-d1th1ocarb In male Wlstar
rats (250 g). The compound was dissolved 1n 2 H phosphate buffer and admin-
istered as a single dose of 25 mg/kg. The half-life for disappearance of
radioactivity from the lumen of the small Intestine, after direct Injection
Into the small Intestine, was 2.6 minutes. The half-life for disappearance
of radioactivity from the stomach following gavage was 39 minutes. The
methods by which these half-lives were determined were not described. By 15
minutes after gavage administration, radioactivity was detected In the
plasma at a level equivalent to 11.3 yg/l (expressed as dithlocarb), and
was Identified as approximately equal amounts of unchanged dithlocarb and
d1th1ocarb-S-glucuron1de, plus a small amount of Inorganic sulfate.
Excretion data (60% of the dose of 35S excreted within 3 hours and 96%
within 72 hours, primarily In urine and expired air) Indicate virtually
complete absorption of the compound (or Its metabolites and decomposition
products) from the gastrointestinal tract.
Baselt and Hanson (1982) studied plasma concentrations of dithlocarb In
female Fischer rats (180 g) given a single dose of 500 mg/kg of dithlocarb
1n water by gavage. During the 6 hours following dosing, plasma dithlocarb
levels gradually rose to a maximum of 2 mg/i at 3 hours, and then grad-
ually decreased. The authors pointed out that this observation was consis-
tent w1 thr-the-expected low rate of absorption of an Ionized sodium salt.
5.2 DISTRIBUTION
Fifteen minutes after Intraperltoneal Injection of 25 mg "S-d1th1o-
carb/rat of (222 ymol S/rat) Into 240-300 g male Wlstar rats, 70-90% of
the radioactivity In liver was In the soluble fraction (Stromme, 1965).
0079d -12- 01/22/88
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Most of the radioactivity found 1n plasma (1606 ymol S/mi) and 1n the
liver soluble fraction (3263 umol S/g) was present 1n the form of free
parent compound and metabolites. A small but significant amount, ~2X, was
reverslbly bound to protein, apparently by formation of dlsulflde bonds.
5.3. METABOLISM
Merlevede and Casler (1961) reported that following oral administration
of 50, 100, 250 or 500 mg of dHhlocarb to human subjects, 28, 34, 62 or
82X, respectively, of the dose (on a mole basis) was expired as carbon
dlsulflde within 7 hours, at which time expiration of carbon dlsulflde was
complete. The fate of the remainder of the dose was not determined.
Assuming 70 kg body weights, 50-500 mg corresponds to 0.7-7.1 mg/kg.
Whether the observed dose-dependent expiration of carbon dlsulflde reflects
dose-dependent metabolism/decomposition of dHhlocarb or dose-dependent
disposition of carbon dlsulflde cannot be determined from the data 1n this
study.
After gavage administration of 35S-d1th1ocarbamate to male 250 g
Wlstar rats at 25 mg/kg, Craven et al. (1976) found that plasma radio-
activity at 15 minutes was In the form of unchanged compound and dlthlocarb-
S-glucuronlde In roughly equal amounts, plus a small quantity of Inorganic
sulfate. Slightly more than 50% of the radioactivity appeared as carbon
dlsulflde In the expired air by 72 hours.
Following IntraperHoneal Injection of 39S-d1th1ocarb Into male
240-300 gHlstar rats at 25 mg/rat, 96% of the radlolabel excreted 1n the
urine at^fehour was present as d1th1ocarb-S-glucuron1de and 4X was present
as Inorganic-sulfate (Stromme, 1965). At 4 hours, 76 and 24X of the radio-
label excreted In the urine was present as d1th1ocarb-S-glucuron1de and
Inorganic sulfate, respectively. Less than IX of the urinary radioactivity
0079d -13- 12/28/87
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was detected as unchanged dHhlocarb. Total urinary radioactivity accounted
for 21X of the dose at 1 hour and 43X of the dose at 4 hours. About 7X of
the administered radioactivity was recovered as carbon dlsulflde 1n the
expired air at 1 hour, Increasing to 10X at 4 hours. No significant amounts
of metal chelates of dHhlocarb were detected 1n plasma, liver or urine.
Stromme (1965) suggested that the differences In the percentage of
dlthlocarb excreted as carbon dlsulflde 1n the expired air In oral studies
compared with Intraperltoneal studies may be due to the decomposition of
dlthlocarb to carbon dlsulflde [and dlethyl amlne (Sunderman, 1979)] In the
acidic environment of the stomach. Evans et al. (1979) demonstrated that
dlthlocarb 1s unstable In aqueous solution at low pH, and developed an
enteric coated capsule for oral administration. Renoux et al. (1983) used a
"gastro-protected" pill for oral administration of dlthlocarb to cancer
patients (Section 6.1.3.). Nevertheless, significant levels of unchanged
dlthlocarb were detected In the plasma of rats following oral administration
of dlthlocarb (Craven et al., 1976; Baselt and Hanson, 1982), as noted above.
An additional metabolite, methyl dlethyldlthlocarbamate, was Identified
by Cobby et al. (1978) during Intravenous Infusion of dlthlocarb 1n average
doses of 27.5 mg dlthlocarb an1on/kg Into anesthetized 20-31 kg male dogs.
The experimental procedure Involved Infusion at rates of 2.75 or 5.50 mg/mln
to steady-state, followed by monitoring of venous blood during steady-state
and after cessation of Infusion. Approximately 27X of the dose was
form methyl dlethyldlthlocarbamate, with a first-order rate
constantzErcfe^O.0569- mln-* (t./2=12.2 m1n). The remainder of the dose was
eliminated by other routes having a rate constant of 0.148 mln"1
(t,/2=4.68 m1n), and the methyl dlethyldlthlocarbamate formed from dlthlo-
carb had an elimination rate constant of 0.0141 mln'1 (t, .-=49.2 m1n).
0079d -14- 12/28/87
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5.4. EXCRETION
As described 1n Section 5.3., the excretion of carbon dlsulflde 1n
expired air following oral administration of dlthlocarb to human subjects
was dose-dependent, with 28, 34, 62 or 82% of the administered dose expired
as carbon dlsulflde following single doses of 50, 100, 250 or 500 mg dlthlo-
carb, respectively (Herlevede and Casler, 1961). Expiration of carbon
dlsulflde began rapidly, reached a maximum within 30 minutes and was
complete within 7 hours of administration.
After gavage administration of 25 mg/kg of 35S-d1th1ocarb to male
250 g Mlstar rats, 60% of the dose was excreted 1n 3 hours and 96X of the
dose was excreted by 72 hours after dosing (Craven et al., 1976). Slightly
>50X of the administered radioactivity was excreted In the expired air In
the form of carbon dlsulflde. Host of the remaining radioactivity was
excreted In the urine, with only a small amount detected In the feces.
Following Intraperltoneal Injection of 25 mg of 35S-d1th1ocarb Into
male 240-300 g Ulstar rats, 7% of the radioactivity was expired as carbon
dlsulflde within 1 hour and 10X within 4 hours (Stromme, 1965). Urinary
excretion of radlolabel amounted to 21X of the dose In 1 hour and 43X 1n 4
hours. Longer time periods were not studied.
5.5. SUMMARY AND CONCLUSIONS
Limited pharmacoklnetlc data are available for oral and parenteral
administration of dlthlocarb; no data are available for Inhalation exposure
to this compound. Although dlthlocarb Is thought to decompose to carbon
d1suf1de^tn| the addle environment of the stomach (Stromme, 1965; Evans et
al., 1979)7 unchanged dlthlocarb and d1th1ocarb-S-glucuron1de are detectlble
1n the plasma within 15 minutes of oral administration of dlthlocarb to rats
(Craven et al., 1976). The concentration of dlthlocarb In plasma slowly
0079d -15- 12/28/87
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Increased to a maximum by 3 hours after gavage administration to rats,
consistent with the expected low rate of absorption of an Ionized sodium
salt (Baselt and Hanson, 1982), which Indicated that significant quantities
of the compound are absorbed without decomposition. A large percentage of
the orally administered dose, -28-80X, however, Is excreted by humans and
rats as carbon dlsulflde 1n the expired air (Merlevede and Casler, 1961;
Craven et al., 1976). The remainder, at least In rats, Is excreted as
metabolites (primarily dlthlo-S-glucuronlde and Inorganic sulfate) In the
urine with only minor amounts 1n the feces (Craven et al., 1976). The
excretion data Indicate virtually complete absorption of dHhlocarb and
metabolites or decomposition products from the gastrointestinal tract.
Following IntraperHoneal administration to rats, 10% of the dose was
expired as carbon dlsulflde within 4 hours (Stromme, 1965), Indicating that
some of the carbon dlsulflde In the oral experiments may have originated
from metabolism after absorption of dHhlocarb from the stomach.
Tissue distribution data were not available, other than the observation
that the concentration of dHhlocarb and metabolites In the soluble fraction
of liver following IntraperHoneal Injection of 35S-d1th1ocarb Into rats
1s higher than In plasma and that some of the dHhlocarb or metabolites 1n
plasma and In the liver soluble fraction are reverslbly bound to protein
sulfhydryl groups (Stromme, 1965).
0079d -16- 01/22/88
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. Pertinent data regarding the systemic
toxldty of subchronlc or chronic Inhalation exposure to dlthlocarb were not
located 1n the available literature cited In Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — The subchronlc range-finding portion of the
NCI (1979) study provides some Information on the systemic toxldty of sub-
chronic oral exposure. Groups of five male and five female F344 rats were
fed 0. 1250, 2500. 5000, 10,000, 20,000 or 40,000 ppm dlthlocarb 1n the diet
for 7 weeks, followed by 1 week of observation. Dose-related depression of
mean body weights occurred In the treated groups compared with controls; the
magnitude of this depression reached 10X at 2500 ppm In the females and 5000
ppm In the males. Death, for both sexes, occurred only at the highest
exposure. The NCI (1979) stated that the lowest exposure at which hlsto-
pathologlcal changes occurred was 1000 ppm 1n both male and female rats.
Because 1000 ppm 1s below the lowest level tested In rats, 1250 ppm, 1t
seems likely that the NCI meant 10,000 ppm. A slight Increase 1n splenic
hematopolesis and slight vacuolatlon of renal tubular epithelium were seen
at this exposure level. The occurrence or severity of hlstopathologlcal
effects at higher exposure levels was not discussed.
Also In the subchronlc portion of the NCI (1979) study, groups of five
male mtceiiwere fed~ 2500. 5000, 6000, 8000 or 10,000 ppm of dlthlocarb 1n the
dlet-toi^CjHeeks and groups of five female mice were fed 0, 250, 500, 1000,
2500, 5000 or 10,000 ppm of dlthlocarb In the diet for 12 weeks, followed by
1 week of observation for both sexes. Body weights were not clearly related
0079d -17- 12/28/87
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to dose In the males and were slightly depressed 1n the females; the depres-
sion amounted to >10X only at the highest exposure level In the females. No
treatment-related hlstopathologlcal lesions were seen at 10,000 ppm in the
mice. Survival did not appear to be affected by treatment.
Additional Information on the systemic toxlclty of subchronlc oral
exposure 1s available from the study of Sunderman et al. (1967). Sunderman
et al. (1967) treated groups of 25 male and 25 female albino rats and two
male and two female beagle dogs orally with 0, 30, 100 or 300 mg/kg/day for
90 days. The method of treatment was not stated.
Rats had dose-related decreases 1n body weight gain that were statisti-
cally significant at >100 mg/kg. Food consumption was not reported. No
overt signs of toxlclty were seen. At 300 mg/kg, both sexes of rats had
significantly decreased mean red blood cell counts and females had deceased
mean hemoglobin levels and hematocrlt values. In addition, hlstopathologl-
cal changes and decreased weights were observed 1n the kidneys of the 300
mg/kg rats of both sexes. The hlstopathologlcal changes consisted of an
Increase In the granularity of the cytoplasm, Irregular dilatation and
swelling or, occasionally, shrinkage of the epithelium of the renal tubules.
Congestion of the glomerull was also observed. No changes were seen at any
exposure level on the eyes, liver, gonads, skeleton, endocrine glands or
gastrointestinal tract of treated rats as compared with controls (Sunderman
et al., 1967).
In dogs-,-, serum copper levels were Increased 1n a dose-related manner,
posslbly^as—a-reflectIon of the chelatlng activity of dUhlocarb. Other
effects were seen only at the highest dosage, 300 mg/kg. Slight losses of
body weight occurred In the dogs at this dose level and one female died at
day 70. Values for hematocrlt, hemoglobin level and red blood cell counts
showed a downward trend In the 300 mg/kg group during the 90-day period.
0079d -18- 12/28/87
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Erythrold hyperplasla was seen In the bone marrow of the one female that
died. The three dogs that survived the 300 mg/kg treatment for 90 days then
received 500 mg/kg for 3 days, 600 mg/kg for the next 3 days, 1000 mg/kg for
another 3 days and finally 2000 mg/kg until dead or moribund (1-7 days). As
the dose Increased, the physical condition of the dogs deteriorated with the
development of tremors, general weakness, anorexia, 1ncoord1nat1on, ataxla
and coma (Sunderman et al., 1967).
Carlton (1966) fed dlthlocarb to groups of 10 male weanling Charles
River mice 1n the diet at 0, 0.1 or 0.5X (0, 1000 or 5000 ppm) for 7 weeks.
The diet was chicken mash supplemented with lard. No effects were observed
on growth, clinical signs of toxldty or hlstopathologlcal findings.
Rasul and Howell (1973a) studied the effects of dlthlocarb on the
central and peripheral nervous system of rabbits. Ten Dutch male rabbits
were administered 330 mg/kg/day of dlthlocarb 1n phosphate buffer by gavage
on 5 days/week for 4, 6 or 9 weeks, after which time they were killed and
examined. An additional 10 rabbits served as vehicle controls. After 9
weeks, average body weights had Increased by 150 g 1n controls and had
decreased by 50 g 1n treated rabbits. No overt signs of neurotoxldty were
seen. Hlstologlcal examination, however, revealed lesions of UalleMan
degeneration and eos1nopH1c bodies In the medulla and spinal cord becoming
progressively worse with longer exposures. In rabbits given dlthlocarb for
9 weeks, significantly fewer large-diameter nerve fibers were seen when
compared^wfth control animals (p<0.001). Additional studies on neurotoxlc-
• • .-. •"_«§•??***-" _
1ty havi6gjge7eitrconducted by parenteral routes; these studies are discussed 1n
Section 6.1.3.
6.1.2.2. CHRONIC — The oral cardnogenlclty study by the NCI (1979)
provides limited Information on systemic toxldty. In this study, groups of
0079d -19- 12/28/87
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50 male and 50 female F344 rats were fed 1250 or 2500 ppm of dlthlocarb In
the diet for 104 weeks. Assuming that rats consume the equivalent of 5X of
their body weight/day as food (U.S. EPA, 1980), the dosages would be 62.5 or
125 mg/kg/day (chronic LOAEL). The controls consisted of 16 male and 20
female rats. Survival 1n treated groups did not differ from that 1n
controls. Mean body weights of the high-dose male rats and of both low- and
high-dose female rats were slightly lower than those of the corresponding
controls throughout the study. This effect was dose-related In the females.
Information on food consumption was not provided 1n the report. No clinical
signs of systemic toxldty were observed. The only notable gross or hlsto-
pathologlcal finding was cataracts of the eye 1n treated female rats. The
Incidence of cataracts was 0/20 control, 14/50 low dose and 6/50 high dose
females. Cataracts were not observed 1n male rats. Because only eyes that
were grossly abnormal were examined microscopically, the NCI (1979) was
uncertain of the significance of this finding.
Few effects were seen 1n the mice 1n the NCI (1979) carclnogenlcHy
study. Groups of 50 male and 50 female B6C3F1 mice were administered 500 or
4000 ppm dlthlocarb In the diet for 108 or 109 weeks. Assuming that mice
consume the equivalent of 13% of their body weight/day as food (U.S. EPA,
1980), the dosages would be 65 or 520 mg/kg/day. Controls consisted of 20
male and 20 female mice. Survival was unaffected In males and was signifi-
cantly better 1n high-dose females than 1n controls. Mean body weights of
both sexes-at either dietary level of dlthlocarb were lower than those of
the corresponding controls and were dose-related throughout the study. Food
consumption data were not provided 1n the report. The hlstopathologlc
examinations Included nonneoplastlc lesions, but no such lesions were dis-
cussed under results; hence, It may be Inferred that there were no notable
nonneoplastlc findings.
0079d -20- 01/22/88
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6.1.3. Other Relevant Information. ID™ values for various species and
routes of exposure have been compiled by NIOSH (1987). Oral LD5_ values
for both the rat and mouse are 1500 mg/kg; the Intraperltoneal L0_n value
for the rat 1s 1250 mg/kg and for the mouse Is 1302 mg/kg; the subcutaneous
L05Q for the rabbit 1s 500 mg/kg (NIOSH, 1987).
OUhlocarb Is a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sunderman, 1979).
Dlthlocarb, a metal chelatlng agent, has been used therapeutlcally In
cases of nickel carbonyl poisoning (Sunderman, 1979, 1981) nickel dermatitis
(Sunderman, 1981) and thallium poisoning (Sunderman, 1967; Kamerbeek et a!.,
1971). Oral dlthlocarb treatment was reported to result In Increased
urinary excretion of the metal and alleviation of toxic effects. Dlthlocarb
has also been shown to be an effective antidote, on oral or parenteral
administration, for nickel, thallium, copper and cadmium poisoning In
experimental animals treated with compounds of these metals (Sunderman,
1967, 1979; Gale et al., 1981). Kamerbeek et al. (1971), however, found
that Intravenous treatment of patients with dlthlocarb resulted 1n an
exacerbation of the CNS effects of thallium poisoning. Experiments In
laboratory animals have shown that parenteral or oral administration of
dlthlocarb to animals treated with nickel, thallium, copper, cadmium or lead
compounds Increased the distribution of these metals to the brain and, 1n
pregnant animals, to the fetus (Aaseth et al., 1979; Gale et al.. 1982;
Iwata-ej^afEv, 1970; Jaslm and Tjaelve, 1984a,b, 1986; Jaslm et al., 1985;
KamerbeeEgJtgal.. 1971; Klaassen et al., 1984; Oskarsson, 1984; Szerdahelyl
and Kasa, 1987). Entry of the metal Into the brain and fetus Is thought by
these Investigators to be facilitated by the formation of Upophlllc
metal-d1th1ocarb chelates.
0079d -21- 12/28/87
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Several studies have Investigated the neurotoxlc effects of parenteral
administration of dHhlocarb. Dally 1ntraper1toneal administration of
dithlocarb (dose not specified) to seven rabbits for up to 7.5 months
produced signs of incoordlnatlon, swollen axons and ballooning of myelln
sheaths (characteristic of early WalleMan degeneration) 1n the white matter
of the spinal cord and In the sciatic nerve, and some early degenerative
changes In the gray matter of the spinal cord (Edlngton and Howell, 1966).
These lesions did not occur 1n saline-treated controls. Copper levels of
the liver and spinal cord of treated rabbits were markedly Increased over
those of controls. In a similar study, 5 two-day-old and 11 one-month-old
lambs were given Intraperltoneal Injections of dithlocarb In phosphate
buffer at doses of 165 or 330 mg/kg (5 days/week for up to 16 weeks) and all
but one died (Howell et al., 1970). Four 2-day-old lambs were used as
vehicle controls. At necropsy, treated lambs were found to have local
peritonitis, eoslnophlUc round or avoid lesions of the medulla, Clarke's
column and the spinal cord, and swollen axons 1n the posterior thoracic and
anterior lumbar segments of the spinal cord. Repeated oral administration
of dithlocarb to chickens produced signs and hlstologlcal evidence of
delayed neurotoxldty (ataxla, nerve fiber degeneration In the medulla and
spinal cord) (Rasul and Howell, 1973b, 1974a,b; Fisher and Metcalf, 1983).
Rats treated orally with dithlocarb at doses of 240 mg/kg had decreases
In orientation hypermotmty and subcortlcal EEG activity. Increases In
dopamlne anfr decreases In noradrenalln and adrenalin formation; the same
effects—w€£e-lseen with oral administration of an equlmolar dose of carbon
dlsulflde (Thuranszky et al., 1982). The authors concluded that formation
of carbon dlsulflde from dithlocarb may mediate these effects. Direct
Injection of dithlocarb Into the brains of rats (Klelnrok et al., 1970) and
0079d -22- 01/22/88
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mice (Ooggett and Spencer, 1973} or Intraperltoneal Injection Into rats and
mice (Naj and Vetulanl, 1970) elevated brain dopamlne levels and decreased
brain noradrenallne levels and locomotor activity.
Subcutaneous Injection of dlthlocarb at 400 mg/kg reduced the noradren-
a!1n and Increased the dopamlne content of the 11 euro of rats and rabbits
(Collins and West, 1968). The above results and other J[n vitro and Jji vivo
data Indicate that dlthlocarb Inhibits the conversion of dopamlne to
noradrenalln by dopam1ne-B-hydroxylase (Collins and West, 1968; Carlsson et
al., 1966).
Oral administration of dlthlocarb at 200 mg/kg to rats decreased the
hepatic mlcrosomal cytochrome P-450 content and aniline hydroxylase and
amlnopyrlne demethylase activities (Siegers et al., 1982). Similarly, oral
administration of 1 g/kg of dlthlocarb to rats decreased hepatic mlcrosomal
P-450 levels and the activities of aniline hydroxylase, carboxylesterase and
ethylmorphlne N-demethylase (ZemaHls and Greene, 1979). Dietary adminis-
tration of dlthlocarb at 5000 ppm for 14 days Increased the activities of
DT-dlaphorase (a detoxifying enzyme for qulnones and qulnonelmlnes) and
glutathlone transferase In several tissues (Benson et al., 1986; Benson and
Barretto, 1985).
Inhibition of the oxldatlve metabolism of !,2-d1methylhydraz1ne and
carcinogenic effects of 1 ,2-dlmethylhydrazlne on the colon were reported In
mice treated orally with dlthlocarb; because carbon dlsulflde also Inhibited
the oxldative- metabol 1 sm of l,2-d1methylhydraz1ne, H was suggested that
mediates this antlcarclnogenlc effect of dlthlocarb
(Wattenberg et al., 1977). Sunderman et al. (1984) found that weekly Intra-
perltoneal treatment with dlthlocarb at 20 mg/rat for 6 weeks protected
0079d -23- 12/28/87
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against the carcinogenic effects of Intramuscularly Implanted nickel sub-
sulflde. They proposed that the protective effect might be connected with
the Increased hepatic levels of metallothloneln resulting from dHhlocarb
treatment.
IntraperHoneal Injection of rats every 2 days for 9 weeks with 66.5
mg/kg of dlthlocarb decreased body weight gain and produced reductions In
mean systolic blood pressure at 7 weeks of treatment (Crossley et al., 1969).
Numerous reports of Immune system stimulation or modulation by dlthlo-
carb have been published, Including the following representative studies:
Renoux and Renoux (1979), Renoux et al. (1986) and Bruley-Rosset et al.
(1986). In these studies, 1ntraper1toneal or subcutaneous Injection of
dlthlocarb Into mice enhanced the activity of T cells, activated macrophage
digestive enzyme activity, and had anti-Inflammatory activity against early
changes 1n Immune parameters Induced by nonantlgenlc acute Inflammation.
Neveu et al. (1980, 1982), Neveu (1978) and Neveu and Perdoux (1986)
reported that dlthlocarb enhanced m1togen-1nduced lymphoprollferatlon and
modulated delayed hypersens1t1v1ty reactions 1n guinea pigs in vivo; how-
ever, because of cytotoxkHy, Inhibited mltogen-lnduced lymphoprollferatlon
(measured as thymldlne Incorporation Into DNA) 1n human or guinea pig
lymphocytes in vitro.
In preliminary clinical trials, administration of 2.5, 5 or 10 mg/kg of
dlthlocarb orally (as gastroprotected pills) once a week for 4 weeks to
children- In- remission from leukemia and other cancers restored delayed
hypersens-tttv-lty^reactions In a dose-related manner 1n comparison with
placebo-treated children (Renoux et al., 1983). Lung cancer patients admin-
istered 5 mg/kg of dlthlocarb Intravenously had restoration of T cell
activity and Increases 1n T3 and T4 cells accompanied by decreases 1n the
0079d -24- 01/22/88
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percentage of T8 (suppressor) cells compared with placebo-treated patients
(Renoux et al., 1983). Six patients with AlOS-related complex, treated with
8-10 mg/kg of dlthlocarb orally once every week for 3-6 months had Improve-
ment 1n delayed hypersens1t1v1ty and Increases 1n the proportion and number
of T4 cells compared with pretreatment values (Lang et al., 1985).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled dlthlocarb were not located In the available literature dted In
Appendix A.
6.2.2. Oral. The cardnogenldty of dlthlocarb has been studied In
chronic feeding studies In mice (BRL, 1968a; NCI, 1979) and 1n rats (NCI,
1979).
BRL (1968a) evaluated the cardnogenldty of dlthlocarb during a
large-scale screening study of 130 pesticides 1n two hybrid strains of mice,
B6C3F1 and B6AKF1. Groups of 18 male and 18 female mice of each strain were
given 215 mg d1th1ocarb/kg/day [the MTD, which was calculated using the
average body weight of mice at the start of the study and not corrected for
weight gain] 1n water by gavage from days 7-28 of age, after which dlthlo-
carb was administered 1n the diet at a level of 692 ppm until the mice were
killed and necropsled at 78 weeks of age. Negative controls consisted of
untreated and vehicle-treated mice of both sexes and strains. The only
tumor that occurred at statistically significantly Increased Incidences 1n
dUhlocarfetreated groups was hepatoma In the B6C3F1 males (Table 6-1). The
Inddencf^of^pulmonary adenoma was Increased 1n B6AKF1 males, but the
Increase was of borderline statistical significance from controls (p=0.056,
Fisher Exact Test). Although the hepatomas 1n dithlocarb-treated mice were
not specifically described, the BRL (1968a) report stated that all
0079d -25- 03/04/88
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TABLE 6-1
Incidence of Hepatomas In B6C3F1 Mice
Following Oral Administration of D1th1ocarba
Sex
H
F
Dose
(ppm)
0
692b
0
692b
Hepatoma Incidence
(p value)
8/79
7/17 (0.00447)c
0/87
0/18 (NS)C
QUALITY OF EVIDENCE
Strengths: Compound was administered by a relevant route of exposure to
both sexes of two strains of mice (see text) starting at a very
young age.
Weaknesses: Small sizes of treated groups, Iess-than-l1fet1me exposure,
unknown purity of test material, only one dosage level which
may have been less than the HTD.
aSource: BRL, 1968a
bD1th1ocarb (purity not specified) was administered to the mice at 215
mg/kg/day In distilled water by gavage on days 7-28 of age, and then at 692
ppm In the diet until 78 weeks of age, at which time the mice were killed
and examined.
cNot significant by Fisher Exact Test.
NS = NotrStgnVfleant
0079d
-26-
12/28/87
-------
hepatic tumors In this screening study were termed hepatomas except those In
mice with unmistakable pulmonary metastases, In which case the hepatic
tumors were classified as hepatic carcinomas. In general, the hepatic
tumors 1n the study were locally Invasive, often with massive Involvement of
the liver. In a preliminary report of the data from the BRL (1968a) study,
Innes et al. (1969) categorized the results with dlthlocarb as Indicative of
a need for further study.
The cardnogen1c1ty of dlthlocarb has been tested further by the NCI
(1979) In F344 rats and B6C3F1 mice of both sexes. Dlthlocarb (95X purity
by HPLC) was administered to groups of 50 male and 50 female rats at 1250 or
2500 ppm In the diet for 104 weeks and to groups of 50 male and 50 female
mice at 500 or 4000 ppm In the diet for 108 or 109 weeks. Controls
consisted of 16 male rats, 20 female rats, and 20 male and 20 female mice.
No statistically significant Increases 1n tumor Incidences of any type.
Including hepatic tumors, were seen In treated mice or rats compared with
controls. Data regarding other endpolnts from this study were discussed 1n
Section 6.1. This NCI study does not confirm the BRL (1968a) results over
the same dose range. This may Indicate the possible relationship between
early exposure and tumorlgenlc potential.
6.2.3. Other Relevant Information. The BRL (1968a) study Included sub-
cutaneous as well as oral administration of dlthlocarb. In the subcutaeous
testing phase, B6C3F1 and B6AKF1 mice (18/sex/straln) were given a single
subcutaneous Injection of 464 mg d1th1ocarb/kg 1n water on the 28th day of
age and_w*te_knied 18 months later. No statistically Increased Incidences
of any tumor type were observed 1n treated mice In comparison with controls.
6.3. MUTAGENICITY
Studies of the mutagenlclty of dlthlocarb are presented 1n Table 6-2.
Results of studies of reverse mutation for dlthlocarb In various strains of
0079d -27- 03/04/88
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TABLE 6-2
Nutagentclty Testing of Otthtocarb
00
1
Assay Indicator/
Organ Is*
Reverse Salmonella
•utatlon tvDhlmurlum
TA98. TA100.
TA1S35. 1A1531
TA1538
>! i ;
; Compound
' and/or Application
Purity
MR plate
Incorporation
».
Reverse S. t»ohl*urlu* 99X» prelncubatlon.
•utatlon TA98. TA100. then plate
TA153S. TA1537 Incorporation
DMA damage ischerlchla coll MR spot test
pol A-. pol A»
UNA damage E. coll HP? reagent liquid
(repair pro- grade •Icromethod
flctent); UP67.
CN871 (repair
deficient)
Chromosomal Muse, male LAfl. MR dlthtocarb In
aberrations 21 Months old: diet
regenerating liver
o
o
00
00
Chromosome Vlcla faba
breaks and root ttps
chroMtld
exchange
MR - Mot reported, NC . no «
MR liquid medium
•Bent. NA « not applicable
Concentration Activating Response Coments
Syste*
<9.4xlO» »S-9 - NC
nmol/plate
(-1600 pg/plate)
33-10.000 iS-9 - Negative with
vg/plate • both rat liver
S-9 and hamster
liver S-9.
Aroclor Induced
MR none - NC
NR »S-9 . NC
IX NA - Note: control
Incidence 73X
2.5 or 6x10** N NA » Positive for both
endpolnts at both
concentrations
Reference
DeFlora. 1981;
DeHora
et al.. 1984
Norteloans
et al.. 1986
Rosenkranz and
Lelfer. 1980
DeFlora
et al.. 1984
Harman et al..
1970
Klhlman. 1957
-------
Salmonella typhlmurlum In the presence or absence of a metabolic activating
system have been negative (De Flora, 1981; De Flora et al., 1984; Mortelmans
et al., 1986). Dlthlocarb also gave negative results In an assay for DNA
damage 1n Escher1ch1a coll (Rosenkranz and Lelfer, 1980; De Flora et al.,
1984). Harman et al. (1970) reported that IX dlthlocarb In the diet of LAF1
male mice did not Increase the Incidence of chromosome aberrations 1n
CC14-1nduced regenerating liver. However, since the "control" Incidence was
reported to be 72.8%, this cannot be considered an acceptable study.
Dlthlocarb gave positive results 1n an assay for the production of chromo-
some breaks and chromatld exchanges In V1c1a faba root tips (Klhlman, 1957).
6.4. TERATOGENICITY
The only available study of dlthlocarb teratogenlcUy (BRL, 1968b) was
conducted by parenteral administration rather than by a natural route of
exposure. In this study, pregnant BL6 mice were administered 215 mg/kg/day
of dlthlocarb subcutaneously on days 6-14 of gestation and killed on day 18
of gestation. The solvent was DMSO (six Utters) or saline (two groups: six
Utters and eight litters). Fetal mortality and the percent of abnormal
fetuses were statistically significantly elevated In the d1th1ocarb-DMSO
group and 1n one, but not the other, d1th1ocarb-sa!1ne group, compared with
concurrent solvent control groups. Fetal weight and crown-rump length were
decreased In the d1th1ocarb-DMSO group relative to the appropriate controls.
Testing of C3H mice In the same manner with 464 mg/kg/day of dlthlocarb 1n
DMSO resulted: In 95% mortality In the two Utters studied. AKR mice, which
have_a sll^gfttly longer gestat1on period, were given 215 mg/kg/day of dlthlo-
carb In saline subcutaneously on days 6-15 of gestation and killed on day 19
of gestation; no notable effects were seen.
0079d -29- 03/04/88
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6.5. OTHER REPRODUCTIVE EFFECTS
Carlton (1966) fed dlthlocarb at 0.5% (5000 ppm) In the diet to six
pregnant Charles River mice starting on day 3 of gestation through sponta-
neous delivery. (The diet consisted of chicken mash supplemented with
lard). Controls consisted of eight pregnant mice fed the same diet. In
dlthlocarb-treated mice, there were no effects on relative number of mice
delivering young but there were a slightly greater number of young/Utter
and of live young/Utter than controls.
In a study on reproductive effects and transplacental Immune system
effects, female C3H/HeJ mice were treated with subcutaneous Injections of 0
or 25 mg/kg of purified dlthlocarb In saline buffer twice a week for 3 weeks
before mating (with hlstocompatlble or h1sto1ncompat1ble males) or thoughout
gestation until delivery (Renoux et al., 1985). With the exception of an
Increase 1n the number of offspring/Utter 1n dams treated with dlthlocarb
before or before and after histolncompatlble mating, there were no treat-
ment-related effects on reproductive Indices such as length of gestation,
number of offspring/Utter, number of stlllborns/lHter, weight of offspring
at birth or male/female sex ratios at weaning. The offspring of all groups
of dlthlocarb-treated dams had Increased numbers of spleen T-cells that
demonstrated Increased responsiveness In assays for mltogen-lnduced
proliferation.
Pregnant rabbits given Intravenous Injections of 0.5 or 1.0 g of dUhlo-
carb 1n_^zrpjr_ 10 ml. of water, respectively, on 5 days/week from days 1-20
of gestation-failed to deliver litters; In most cases evidence of abortion
was found (Howell, 1964). Control rabbits, treated similarly with saline
equal In molarlty to the dlthlocarb solution, all delivered Utters.
0079d -30- 03/04/88
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Pretreatment of pregnant rabbits with copper sulfate prevented the decrease
1n blood copper levels caused by dlthlocarb but failed to prevent the
adverse effect of dlthlocarb on gestation.
Several reports from the same laboratory (Sakal et al., 1979; Klmura et
al., 1980a,b) Indicated that ejaculation, but not erection, was suppressed
1n male dogs within 1 hour of an Intraperltoneal Injection of 50:, 75 or 100
mg/kg of dlthlocarb. Partial recovery occurred after 3 hours, with complete
recovery by 24 hours. This suppression was associated with decreased levels
of noradrenalln In the caudate nucleus, ep1d1dym1s, prostate and posterior
urethra, and was reversed by administration of noradrenalln.
Holzaepfel et al. (1959), 1n a survey of the spermlcldal effectiveness
of 581 organic compounds, found that dlthlocarb and two related compounds
had the highest spermlcldal activity of all the compounds tested. R1ce
(1964) reported gross morphological alterations of the tails of human
spermatozoa upon treatment with dlthlocarb in vitro. The alterations
consisted of the formation of bead-like crystals after a small amount of
dlthlocarb was dissolved In a drop of semen on a microscope slide.
Brotherton (1977) found that mixing of dlthlocarb at a concentration of 97.4
pmol/cell with human semen resulted 1n swelling of the spermatozoa (a 9.7X
Increase 1n volume of spermatozoa).
6.6. SUMMARY AND CONCLUSIONS
Pertinent data regarding the effects of Inhaled dlthlocarb were not
locatedSimithe:: available literature cited In Appendix A. A number of
studtefcOf£:system1c toxlclty and carclnogenldty have been conducted by the
oral route.
Subchronlc and chronic oral administration of dlthlocarb to rats, mice,
dogs and rabbits has shown that depression of body weight or body weight
gain 1s one of the more sensitive Indicators of toxldty of this compound
0079d -31- 03/04/88
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(NCI, 1979; Sunderman et al., 1967; Rasul and Howell, 1973a,b), occurring In
subchronk studies In rats at 100 mg/kg/day (subchronk LOAEL) (Sunderman et
al., 1967). These studies also Indicate that rats may be slightly more
sensitive to the toxklty of dlthlocarb than are mice or dogs, but that
species differences 1n sensitivity are small. (The data for rabbits are
Insufficient to Judge their relative sensitivity). Additional effects In
subchronk oral studies Include renal toxklty 1n rats and hematologkal
effects (decreases 1n red cell counts, hematocHts and hemoglobin levels) In
rats and dogs at 300 mg/kg/day (Sunderman et al., 1967) and nervous system
lesions In rabbits at 330 mg/kg/day (5 days/week) (Rasul and Howell, 1973a).
The NOEL for subchronk oral exposure Is 30 mg/kg/day In rats (Sunderman et
al.. 1967).
In chronk studies, rats had cataracts and body weight depression at the
lowest level tested, 1250 ppm of dlthlocarb 1n the diet (62.5 mg/kg/day,
chronk LOAEL) (NCI, 1979). Hke had body weight depression at the lowest
chronk level tested, 500 ppm of dlthlocarb In the diet (65 mg/kg/day) (NCI,
1979). Higher exposure levels In rats and mice 1n this study produced a
more pronounced depression of body weight In both species and cataracts
(Incidence not dose-related) In rats. Renal effects were not reported 1n
the chronk portion of the NCI (1979) study, although mild renal effects
were seen 1n rats In the subchronk portion of this study, apparently at a
dietary level of 10,000 ppm dHhk-carb. The NCI (1979) study did not
performEiheqiaLtologkal tests, but a slight Increase In splenic hematopo1es1s
was naUJPS-lrats, apparently at 10,000 ppm In the diet, In the subchronk
portion of the study. The data do not define a NOAEL or NOEL for chronk
oral exposure (NCI, 1979).
0079d -32- 03/04/88
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Acute toxldty data Include oral L05Q values of 1500 mg/kg In both
rats and mice, IntraperHoneal L05Q values of 1250 mg/kg In rats and 1302
mg/kg In mice, and a subcutaneous LD5Q of 500 mg/kg 1n rabbits (NIOSH,
1987).
Dlthlocarb Is a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sunderman, 1979).
Because of Us metal chelatlng properties, dlthlocarb has been used
therapeutlcally 1n human cases of metal poisoning, most commonly nickel
carbonyl poisoning {Sunderman, 1979, 1981). Evidence from numerous studies,
however, Indicates that chelatlon therapy with dlthlocarb may. In animals
treated with various metal compounds, facilitate the entry of metals Into
the brain and Into the fetus, perhaps because the dithlocarb-metal chelate
Is UpophlUc. A single study reported a worsening of CNS signs following
Intravenous treatment of thallium-Intoxicated humans with dlthlocarb
(Kamerbeek et al.t 1971).
Repeated IntraperHoneal administration of dlthlocarb to rabbits and
lambs produced lesions of the nervous system In both species (Edlngton and
Howell, 1966; Howell et al., 1970). Oral administration of dlthlocarb to
chickens produced signs and lesions Indicative of delayed neurotoxlclty
(Rasul and Howell, 1973b, 1974a,b; Fisher and Metcalf, 1983).
Dlthlocarb Inhibits the conversion of dopamlne to noradrenalln by
dopam1ne-8-hydroxylase, resulting 1n Increased tissue levels of dopamlne and
deer eased-tissue levels of noradrenalln (Thuranszky et al., 1982; Collins
and Wei.|££19.68L Carlsson et al., 1966). Dlthlocarb Inhibits mlcrosomal
cytochrome P-450 associated oxldatlve metabolism of xenoblotlcs (Siegers et
al., 1982; ZemaHls and Greene, 1979; Wattenberg et al., 1977) and stimu-
lates DT-d1aphorase and glutathlone transferase (Benson et al., 1986; Benson
and Baretto, 1985).
0079d -33- 03/04/88
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The protective effect of dlthlocarb against the carcinogenic effects of
1.2-dlmethylhydrazlne was attributed to Inhibition of the oxldatlve metabo-
lism (activation) of l,2-d1methylhydraz1ne (Wattenberg et al., 1977). The
protective effect of dlthlocarb against the carcinogenic effects of Intra-
muscularly Implanted nickel subsulflde was thought to be connected with
dlthlocarb's enhancement of hepatic levels of metalloth1one1n (Sunderman et
al., 1984).
Dlthlocarb has been reported to enhance the function of the Immune
system, primarily through effects on the T cells, both 1n animals (Renoux
and Renoux, 1979; Bruley-Rosset et al., 1986) and 1n humans (Renoux et al.,
1983; Lang et al., 1985).
Data regarding the carclnogenlclty of dlthlocarb are available for the
oral route of administration, but not for Inhalation. Administration of
dlthlocarb at 215 mg/kg/day by gavage on days 7-28 of age and then at 612
ppm 1n the diet until week 78 of age to male and female B6C3F1 and B6AKF1
mice resulted In a statistically significantly Increased Incidence of tumors
only 1n the case of hepatomas In the B6C3F1 males (BRL, 1968a). Dietary
administration of dlthlocarb at 1250 and 2500 ppm to male and female F344
rats and at 500 and 4000 ppm to B6C3F1 mice for ~2 years did not produce any
statistically significant Increases 1n tumor Incidences (NCI, 1979).
Hutagenldty testing of dlthlocarb has been effectively limited to bacteria
and negative results have been reported (DeFlora et al., 1984; Nortelmans et
al., 198&;=Rosenkranz and Lelfer, 1980).
evidence that dlthlocarb Is genotoxlc. Studies of
reverse mutation In Salmonella tvphlmuMuro (De Flora, 1981; De Flora et al.,
1984; Mortelmans et al., 1986), DNA damage 1n Esherlchla coll (Rosenkranz
and Lelfer, 1980; De Flora et al., 1984) and chromosomal damage In regener-
ating liver (mouse) (Harman et al., 1970) have given negative results for
0079d -34- 03/04/88
-------
dlthlocarb. Positive results were obtained for dHhlocarb In a chromosomal
damage assay 1n Vlcla faba root tips (Klhlman, 1957).
Dlthlocarb has not been tested adequately for teratogenlclty. The only
study available used subcutaneous Injection rather than a natural route of
administration. In this study (BRL, 1968b), equivocal evidence of feto-
toxlclty was seen following subcutaneous Injection of 215 mg/kg/day of
dlthlocarb Into pregnant mice.
The data base for the reproductive effects of dlthlocarb Is also
Inadequate. The feeding of dlthlocarb at 5000 ppm 1n a chicken mash/lard
diet to pregnant mice from day 3 of gestation through delivery had no
adverse effects on number of dams delivering young or number of young/Utter
(Carlton, 1966). Subcutaneous Injection of dlthlocarb at 25 mg/kg, twice
weekly. Into female mice before or before and after mating produced no
adverse effects on reproductive Indices and stimulated Immune T-cell produc-
tion and responsiveness In their offspring (Renoux et al., 1985). Intra-
venous administration of dlthlocarb to pregnant rabbits resulted 1n loss of
the litters (Howell, 1964). Dlthlocarb 1s spermlddal in vitro (Holzaepfel
et al., 1959) and suppresses ejaculation In dogs following acute Intraperl-
toneal Injection (Sakal et al., 1979; Klmura et al., 1980a,b).
0079d -35- 03/04/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The U.S. EPA (1985a) has verified an oral RfD of 0.03 mg/kg/day for
dlthlocarb based on the rat subchronlc oral study by Sunderman et al. (1967).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of dlthlocarb were not located 1n the available literature cited
1n Appendix A.
0079d -36- 12/28/87
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenldty of
Inhalation exposure to dlthlocarb were not located In the available litera-
ture cited In Appendix A.
8.1.2. Oral. Administration of dlthlocarb to male and female B6C3F1 and
B6AKF1 mice at 215 mg/kg/day by gavage on days 7-28 of age, and then at 692
ppm In the diet until 78 weeks of age resulted 1n statistically significant
Increased Incidences of tumors only 1n the case of hepatomas In the male
B6C3F1 mice (BRL, 1968a). Dose-response data are summarized 1n Table 6-1.
Administration of dlthlocarb to male and female B6C3F1 mice at 500 or 4000
ppm In the diet for 108 or 109 weeks and to male and female F344 rats at
1250 or 2500 ppm In the diet for 104 weeks produced no statistically
significant Increases 1n tumor Incidences (NCI, 1979).
8.1.3. Other Routes. A single subcutaneous Injection of 464 mg/kg of
dlthlocarb on the 28th day of age did not result In Increased Incidences of
tumors In male and female B6C3F1 or B6AKF1 mice after -18 months (BRL,
1968a).
8.1.4. Weight of Evidence. No data are available for the assessment of
carclnogenldty of dlthlocarb to humans. IARC (1976, 1982) concluded that
the available animal data were not sufficient to assess the carclnogenldty
of dlthlocarb. The data regarding carclnogenldty to animals are limited,
I.e., an Increased Incidence of hepatomas In one sex of one strain of mice
In a slngje^study, which employed only one dosing level. The appropriate
EPA (U.Sr EPA, 1986b) classification for dlthlocarb Is Group C - possible
human carcinogen.
0079d -37- 01/22/88
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8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION — No pertinent Inhalation data are available.
Because the oral data are limited, estimation of a q,* for Inhalation
exposure from the oral data Is not recommended.
8.1.5.2. ORAL — A q^ can be estimated from the dose-response data
for the Induction of hepatomas In male B6C3F1 mice (BRL, 1968a); these are
the only positive cardnogenldty data. The treated males were given 215
mg/kg/day by gavage on days 7-28 of life (3 weeks) and then 692 ppm In the
diet until week 78 of age (I.e., for 74 weeks). Assuming that mice consume
the equivalent of 13% of their body weight dally as food (U.S. EPA, 1980),
dietary exposure to 692 ppm of dlthlocarb corresponds to a dosage of 90.0
mg/kg/day, and the TWA dosage for the entire experiment Is 94.9 mg/kg/day.
Using this dosage, the hepatoma Incidence 1n the B6C3F1 male mice, and the
computerized multistage model developed by Howe and Crump (1982), the
unadjusted (animal) q * Is calculated to be 8.825xlO~a (mg/kg/day)'1
(Appendix B). The human q,*, calculated by multiplying the unadjusted
q * for the study by the cube root of the ratio of reference human body
weight (70 kg) to the TWA mouse body weight (0.037 kg) and by the cube of
the ratio of reference mouse Hfespan (104 weeks) to experiment duration (77
weeks), 1s 2.69xlO-1 (mg/kg/day)'1. This q^ differs slightly from
the q,* estimated previously (U.S. EPA, 1983) because this estimate used
the average body weight of the mice over the entire treatment period
(0.037 g), whereas the previous estimate used the body weight of the mice
during rthelilast-26 weeks of the experiment (0.043 g). Using the human q,*
of 2.69X10"1 (mg/kg/day)'1 and assuming that a 70 kg human consumes 2
ft/day of water, the concentrations of dlthlocarb In drinking water
associated with Increased lifetime risk of cancer at risk levels of 10~9,
10"6 and 10"7 are 1.3xlO"», 1.3xlO"4 and 1.3xlO~s mg/l, respectively.
0079d -38- 12/28/87
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8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. No Inhalation toxldty data were available
from which to calculate a subchronlc or chronic Inhalation RfD.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- The most
adequate subchronlc study of the toxldty of dUhlocarb 1s the study 1n rats
and dogs by Sunderman et al. (1967). Groups of 25 male and 25 female rats
and 2 male and 2 female dogs were given dHhlocarb at 0, 30, 100 or 300
mg/kg/day for 90 days. In rats, no effects were seen at 30 mg/kg/day
(NOEL), dose-related decreases In body weight gain were seen at >100
mg/kg/day (LOAEL), and hematologkal effects (decreased red cell counts,
hemoglobin levels and hematocrU values) and mild hlstopathologlcal effects
In the kidneys were observed at 300 mg/kg/day. In dogs, no effects other
than a slight elevation of serum copper levels occurred at <100 mg/kg/day,
and slight body weight loss, hematologlcal effects similar to those In rats
and the death of one dog occurred at 300 mg/kg/day.
A number of short-term (7- to 9-week) studies have assessed various
aspects of the systemic toxldty of dUhlocarb, but are not adequate to
serve as the basis of a subchronlc RfD because of Inadequacies In the
reporting of the data (NCI, 1979) (see Section 6.1.2.1.), narrowness of
focus (Rasul and Howell, 1973a; neurotoxldty only) or uncertainty regarding
the appropriateness of standard dose-calculation methods for rats when the
chem1calE±tS5Fadm1n1stered 1n a nonstandard diet (Carlton, 1966; chicken-mash
and—lajujfedjet).- These studies provide some support for the NOEL of 30
mg/kg/day and the LOAEL of 100 mg/kg/day determined from the rat data of
Sunderman et al. (1967). Significant body weight depression was seen In the
NCI (1979) 7-week study 1n rats at >2500 ppm In the diet (250 mg/kg/day,
0079d -39- 12/28/87
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assuming a young rat consumes the equivalent of 10X of Its body weight dally
as food) and slight renal toxic effects and slight Increase In splenic
hematopolesls were apparently observed at 10,000 ppm (1000 mg/kg/day). The
no-effect level seems to have been 1250 ppm (125 mg/kg/day) [see Section
6.1.2.1. for explanation of uncertainties regarding data reported by NCI
(1979)]. Mice were less sensitive to dlthlocarb, with no effects other than
body weight depression occurring at the highest level tested, 10,000 ppm In
the diet for 7 or 12 weeks (NCI, 1979). Carlton (1966) found no effects on
mice fed 1000 or 5000 ppm dlthlocarb In a chicken mash/lard diet. Rasul and
Howell (1973a) reported central and peripheral nervous system lesions In
rabbits gavaged with 330 mg/kg/day of dlthlocarb 5 days/week (equivalent to
235.7 mg/kg/day, 7 days/week).
Dividing the NOEL of 30 mg/kg/day [from the rat data of Sunderman et al.
(1967)] by an uncertainty factor of 100 (10 for Interspedes extrapolation
and 10 to protect the most sensitive Individuals) yields a subchronlc oral
RfD for dlthlocarb of 0.3 mg/kg/day or 21 mg/day for a 70 kg human. Confi-
dence In the RfD 1s high because the study was well-conducted and supporting
data are available.
8.2.2.2. CHRONIC EXPOSURES — The only chronic study available 1s the
~2-year feeding study 1n rats and mice by the NCI (1979). In this study,
groups of 50 male and 50 female rats were fed dlthlocarb at 1250 ppm (62.5
mg/kg/day) or 2500 ppm (125 mg/kg/day) 1n the diet for 104 weeks and groups
of 50 male and 50 female mice were fed 500 ppm (65 mg/kg/day) or 4000 ppm
(520 roq/]Tq/dayl for 108 or 109 weeks. Dosages were calculated from dietary
levels by assuming that rats and mice consume the equivalent of 5 and 13%,
respectively, of their body weight dally as food (U.S. EPA, 1980). Control
0079d -40- 01/22/88
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groups consisted of 16 or 20 anlmals/sex/specles. Female rats had depres-
sion of body weight gain (dose-related) and cataracts at both dose levels;
male rats had depression of body weight gain at the higher dose level. Mice
had dose-related depression of body weight at both dose levels. No other
gross or hlstopathologlcal effects were seen In either species. Hence,
these data do not provide a NOEL or NOAEL for chronic exposure, but do
define a chronic LOAEL of 62.5 mg/kg/day for reduced body weight and
cataracts In female rats.
Using this LOAEL and the subchronlc NOEL of 30 mg/kg/day determined for
rats In the study by Sunderman et al. (1967), the U.S. EPA (1983, 1985a) has
calculated and verified a chronic oral RfD for dlthlocarb. The NOEL 1s
divided by an uncertainty factor of 1000 (10 for 1nterspec1es extrapolation,
10 to protect the most sensitive Individuals and 10 to extrapolate from
subchronlc to chronic exposure), resulting 1n a chronic oral RfD of 0.03
mg/kg/day or 2 mg/day for a 70 kg human. Confidence 1n this RfO 1s medium
because, although confidence In the Sunderman et al. (1967) study 1s high.
confidence In the data base Is medium [support for the chronic effects 1s
lacking and hematologlcal endpolnts were not examined 1n the NCI (1979)
study] (U.S. EPA, 1985a). There are no new data that would require a
revaluation of this RfD.
0079d -41- 12/28/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of dlthlocarb was discussed 1n Chapter 6. Pertinent dose-
effect data are summarized 1n Table 9-1. The toxlcologlcal significance of
the body weight depression seen 1n several of the studies Is uncertain
because food consumption data were not reported.
Data from subchronlc studies [NCI (1979) 7- to 12-week range-finding
study; Sunderman et al. (1967) 90-day study; Rasul and Howell (1973a) 9-week
study) are Included In Table 9-1 for comparison and completeness. When
expressed as transformed animal dose or equivalent human dose, doses that
produced effects 1n the subchronlc studies were higher than those associated
with effects In the chronic studies (NCI, 1979). For this reason, and
because the chronic studies are adequate to serve as a basis for the RQ, the
subchronlc studies will not be considered further In the RQ derivation.
The derivation of CSs and RQs 1s summarized In Table 9-2. The most
severe effect seen 1n the chronic NCI (1979) studies was the formation of
cataracts In female rats administered 1250 ppm of dHhlocarb In the diet
(62.5 mg/kg/day). The equivalent human dose of 9.2 mg/kg/day Is multiplied
by 70 kg to yield an MED of 644 mg/day, which corresponds to an RVd of
1.3. Cataracts represent a change that results In a marked sensory deficit
and are accordingly ranked with an RV of 8. The product of the RV. and
RV Is a CS of 10.4, which corresponds to an RQ of 1000.
The-orvly other effect seen 1n the chronic studies was a slight decrease
In body wtght In both rats and mice (NCI, 1979). Because food consumption
data were not provided. It Is not possible to determine whether the decrease
In body weight was due to toxldty of the chemical or to reduced food
Intake. In considering the systemic toxlclty data base as a whole, however,
0079d -42- 12/28/87
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TABLE 9-1
Oral Toxlctty Sundry for Dlthlocarb
vO
°- Average
Species/ No. at {loi
Strain Sex Start 11 if
M»
: '
i , |
Rat/F344 F 5 0.
1
ly. Vehicle/
(MM Physical Purity Exposure
at1 ,.| State
T!-':i
'' t '1 '
M7b i diet 95X 2500 ppm In diet
' i i for 7 weeks
N.F 5/sex 0.29
-------
TABLE 9-1 (cont.)
o
o
-J
\o
a.
Species/
Strain Sex
Rabbits/ N
Dutch
Av
No. at B
Start Hi
j
"i
if
10 :
i
erage
pdy
ght
!fA.
•Ti
r
Vehicle/
Physical
State
ii
v '
i phosphate
: buffer
,
Purity Exposure
NR 330 mg/kg/day
on 5 days /week
for 9 weeks by
gavage
Transformed
Animal Dose
(mg/kg/day)
235.7
Equivalent
Human Dose3
(i»g/kg/day)
89. 2
Response
Slight weight loss, central
and peripheral nervous system
lesions but no overt signs of
neurotoxlclty
Reference
Rasul and
Howell. 1973a
'Calculated by multiplying the animal transformed dose by the cube root of the ratio of the animal body weight to the reference human body weight (70 kg)
^Calculated as 10X depression of reference rat body weight (0.35 kg) (see Response)
cAssumlng that a young rat consumes dally an amount of food equal to 10X of Its body weight
^Calculated as a 17X depression of reference rat body weight (0.3S kg) (see Reference)
'Calculated as 66X depression of reference rat body weight (see Response)
'Narked depression of body weight suggests food refusal. Transformed animal dose calculated assuming dally consumption of an amount of food equal to 5X of
the animals body weight, but this may be an overestimate.
VNot calculated because of uncertainties regarding transformed animal dose
"Estimated from growth curves In the study
'Assuming that a mouse consumes dally an amount of food equal to 13* of Its body weight (U.S. EPA. 19BO)
JAssumlng that a rat consumes dally an amount of food equal to 5* of Its body weight (U.S. EPA. 1980)
^Calculated as 10* depression of reference mouse body weight (0.03 kg) (U.S. EPA. 1980) (see Response)
'Reference dog body weight (U.S. EPA. 1986b)
^Reference rabbit body weight (U.S. EPA. lS86b)
f\>
•»*.
CD
00
-------
TABLE 9-2
Oral Composite Scores for DHhlocarb*
Chronic
Species Animal Dose Human MED RVd
(mg/kg/day) (mg/day)
Effect
RV,
CS
RQ
Rat
House
62.5
65
644
364
1.3
1.7
Cataracts
Decrease 1n
body weight
relative to
controls
8 10.4 1000
4 6.8 1000
*Source: NCI, 1979
0079d
-45-
12/28/87
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body weight depression appears to be a sensitive Indicator of dHhlocarb
toxldty. The RVg for body wleght depression 1s 4. In rats, since the
body weight depression occurred at the same dose level as did cataracts, a
more severe effect, there Is no need to calculate a CS for the less severe
effect In this species. In mice, the decrease 1n body weight occurred at
500 ppm In the diet (65 mg/kg/day). The equivalent human dose of 5.2
mg/kg/day 1s multiplied by 70 kg to yield an MED of 364 mg/day, which
corresponds to an RVrf of 1.7. The product of the RV. and RV 1s a CS
of 6.8, corresponding to an RQ of 1000.
The higher CS of 10.4. based on cataract formation 1n the rat (NCI.
1979) Is recommended as the basis for the RQ of 1000 pounds (Table 9-3).
This 1s the same approach and RQ value as recommended 1n U.S. EPA (1985b).
The CS differs slightly from that derived previously because reference rat
body weights were used In the previous derivation, whereas measured rat body
weights are used In the present derivation. In addition, cataract formation
was ranked with an RV of 7 In the previous assessment, but was judged to
represent a more serious sensory deficit, ranked as an RV of 8, In the
present assessment.
9.2. BASED ON CARCINOGENICITY
DHhlocarb produced a statistically significant Increased Incidence of
hepatomas In male B6C3F1 mice gavaged with 215 mg/kg/day on days 7-28 of age
(3 weeks) and then fed 692 ppm In the diet until 78 weeks of age (I.e., for
74 weeks) (BRL. 1968a). Female B6C3F1 mice and male and female B6AKF1 mice
given th» same-treatment did not have Increased Incidences of any type of
tumor. Negative results for cardnogenlcHy were also reported by the NCI
(1979) In male and female B6C3F1 mice fed 500 or 4000 ppm of dHhlocarb In
the diet for 108 or 109 weeks and 1n F344 rats of both sexes fed 1250 or
0079d -46- 12/28/87
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TABLE 9-3
DUhlocarb
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
CS:
RQ:
oral
644 mg/day
cataracts
NCI, 1979
1.3
8
10.4
1000
*Equ1valent human dose
0079d -47- 12/28/87
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2500 ppm of dlthlocarb In the diet for 104 weeks. A single IntraperHoneal
Injection of 474 mg/kg Into male and female B6C3F1 and B6AKF1 mice produced
no evidence of cardnogenlclty after 18 months (BRL, 1968a). Details of
these studies are presented 1n Section 6.2.2. and In Table 6-1.
Evidence for the cardnogenlclty of dlthlocarb to animals Is limited and
no data are available for humans. Dlthlocarb 1s therefore classified In EPA
Group C (see Section 8.1.4.).
Derivation of the F factor from the dose-response data for hepatoma 1n
B6C3F1 male mice {BRL, 1968a) 1s summarized In Table 9-4. These are the
only positive cardnogenlclty data available. Assuming that mice consume
the equivalent of 13% of their body weight dally 1n food (U.S. EPA, 1980),
the dietary exposure of 692 ppm corresponds to a dosage of 90.0 mg/kg/day,
and the TWA dosage for the entire experiment Is 94.9 mg/kg/day. Using this
dosage, the hepatoma Incidence data, and the computerized multistage model
developed by Howe and Crump (1982), the unadjusted 1/E010 1s calculated to
be 4.239xlO"2 (mg/kg/day)"1. Hultlplylng the unadjusted 1/E01(J by the
cube root of the ratio of the reference human body weight (70 kg) to actual
mouse body weight (0.037 kg) and by the cube of the ratio of assumed mouse
Hfespan (104 weeks) to experiment duration (77 weeks) results In an
adjusted l/ED.g (F Factor) of 1.29 (mg/kg/day)"1. This F factor places
dlthlocarb 1n Potency Group 2. An EPA Group C chemical that Is In Potency
Group 2 ranks LOW In the Hazard Ranking Scheme under CERCLA and 1s accord-
Ingly assigned an RQ of 100.
0079d -48- 01/22/88
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TABLE 9-4
Derivation of Potency Factor (F) for DHhlocarb
Reference:
Exposure route:
Species:
Strain:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed doses (mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED-jg:
Adjusted 1/ED10:
(F factor^.
BRL 1968a
oral; gavage, then diet
mouse
B6C3F1
water (gavage), then diet
0.037 kg
77 weeks
77 weeks
104 weeks
liver
hepatoma
0
215 mg/kg/day for 3 weeks, then
692 ppm In diet for 74 weeks
0 94.9
8/79 7/17
4.28916xlO~2 (mg/kg/day)'1
1.2918 (mg/kg/day T1
0079d
-49-
12/28/87
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0079d -57- 12/28/87
-------
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0079d -58- 12/28/87
-------
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0079d -59- 12/28/87
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0079d -61- 12/28/87
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0079d -62- 12/28/87
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0079d -64- 01/22/88
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0079d -65- 01/22/88
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HS08
These searches were conducted 1n October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton,- G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
.HyEtgfflgani
-------
Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing. C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
1983. The Merck Index. 10th ed. Merck and Co.,
0079d -67- 12/28/87
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0079d -68- 12/28/87
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APPENDIX B
Cancer Data Sheet for Derivation of q^* for Oral Exposure
Compound: DUhlocarb
Reference: BRL,' 1968a
Specles/strain/sex: m1ce/B6C3fl/males
Route/vehicle: oral, by gavage In distilled water for 3 weeks then In diet
for 74 weeks
Length of exposure (1e) = 77 weeks
Length of experiment (Le) = 77 weeks
Llfespan of animal (L) = 104 weeks (assumed)
Body weight = 0.037 kg (measured)
Tumor site and type: liver, hepatoma
215 mg
Exposure Transformed Dose
(mg/kg/day)
0 0
/kg/day for 3 weeks, 94.9+
Incidence
No. Responding/No.
8/79
7/17
Tested
then 692 ppm In diet for
74 weeks
Unadjusted qi* = 8.8250xlO~» (mg/kg/day)'1
Human q^ . 2.6893x10"* (mg/kg/day)"1
^Assuming that mice consume the equivalent of 13X of their body weight
dally as food, dietary exposure to 692 ppm of dlthlocarb corresponds to 90.0
the-TWA dosage for the entire experiment Is 94.9 mg/kg/day.
0079d -69- 12/28/87
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APPENDIX C
Suamary Table for OUhlocarb
• LL
Inhalation Exposure !
Sabchrontc IB
Chronic IB
Carctnogenlctty ID
Oral Exposure
Subchrontc rat
Chronic rat
Carctnogenlctty aou;
MPOHTAUE QUANTITIES
Based on Chronic Toxic Ity:
Bated on Cancer:
its Exposure Effect
IB ID
IB ID
ID ID
30 ag/kg/day Decreased body weight gain at 100
ag/kg/day; renal and heaatologtcal
effects at 300 ag/kg/day
30 ag/kg/day Cataracts and reduced body weight
In feaales at 62.5 ag/kg/day
(NCI. 1979)
te 21S ag/kg/day. gavage. Increased Incidence of hepatoaa
3 weeks; then 692 ppa.
diet. 74 weeks
1000
100
RfD or qj*
ID
ID
ID
0.3 ag/kg/day
or 21 ag/day for
a 70 kg huaan
0.03 ag/kg/day or
0.2 ag/day for a
70 kg huaan
2.69x10"'
(ag/kg/day)-'
Reference
10
ID
ID
Sunderaan
et al.. 1967
Sunderaan
et al.. 1967
BRL. 1966a
NCI. 1979
BRL. 1968a
IB - Insufficient data
r\J
OB
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