-------
DISCLAIMER
This report Is 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.
11
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EXECUTIVE SUMMARY
DHhlocarb 1s a solid at ambient temperatures; It Is highly soluble 1n
water and 1n ethanol (Hawley, 1981; IARC, 1976). The compound Is stable at
pH >9 but decomposes to carbon dlsulflde and d1ethylam1ne salts In acidic pH
(VMndholz, 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). DHhlocarb
1s used mainly as an accelerator In rubber processing, as an Intermediate 1n
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 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
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 In water (King and
Painter, 1985; Brink, 1976), no rate data are available to assess the
significance of the 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 toxlcltles of the degradation
products, blodegradatlon may be a slow process In 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, HO, Duggan et al. (1967) reported 0.5 mg/kg of dlthlocarbamates
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 dlthlocarbamates from
food (when the chemical was used as a pesticide) to be 29 pg/day. No
other Information regarding exposure to this compound was located 1n the
available literature.
The acute toxlclty 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/a produced 67% lethal-
ity In foldflsh (Oota, 1971). A 48-hour LC5Q was determined for Daphnla
(Van Leeuwen et al., 19856). A 24-hour LC™ of 3 mg/a, was determined
for frog embryos, and malformations were observed at concentrations as low
as 0.5: mg/i (Ghate and Mulherkar, 1980).. Chronic toxldty data for fish
or other vertebrates were not located, but a 21-day LC5Q of 30 yg/a
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 1n duckweed was decreased by exposure to 17.1 mg/l for 3 days
(Oota, 1971).
Limited pharmacok1net1c 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
c!1sulf1de 1n the acidic environment of the stomach (Stromme, 1965; Evans et
-------
al., 1979), unchanged dlthlocarb and d1th1ocarb-S-glucuron1de are detectable
In the plasma within 15 minutes of oral administration of dlthlocarb to rats
(Craven et al., 1976). The concentration of dlthlocarb In plasma slowly
Increased to a maximum by 3 hours after gavage administration to rats, which
Is 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, -28-80%, however, 1s excreted by humans and rats
as carbon dlsulflde In the expired air (Merlevede and easier, 1961; Craven
et al., 1976). The remainder, at least In rats, 1s 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 dlthlocarb and metabolites or
decomposition products from the gastrointestinal tract. Following Intra-
perltoneal administration to rats, 10% of the dose was expired as carbon
dlsulflde within 4 hours (Stromme, 1965), Indicating that some of the carbon
dlsulflde 1n the oral experiments may have originated from metabolism after
absorption of dlthlocarb from the stomach.
Tissue distribution data were not available, other than the observation
that the concentration of dlthlocarb 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 dlthlocarb or metabolites In
plasma and 1n the liver soluble fraction are reverslbly bound to protein
sulfhydryl groups (Stromme, 1965).
Pertinent data regarding the effects of Inhaled dlthlocarb were not
located 1n the available literature cited 1n Appendix A. A number of
studies of systemic toxldty and cardnogenldty have been conducted by the
oral route.
v1
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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 1s one of the more sensitive Indicators of toxlclty of this compound
(NCI, 1979; Sunderman et al., 1967; Rasul and Howell, 1973a,b) occurring In
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 1n 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 In red cell counts, hematocrlts and hemoglobin levels) 1n
rats and dogs at 300 mg/kg/day (Sunderman et al., 1967) and nervous system
lesions 1n rabbits at 330 mg/kg/day (5 days/week) (Rasul and Howell, 1973a).
The NOEL for subchronlc oral exposure Is 30 mg/kg/day 1n 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) 1n rats. Renal effects were not reported In
the chronic portion of the NCI (1979) study, although mild renal effects
were seen 1n rats 1n the subchronlc portion of this study, apparently at a
dietary level of 10,000 ppm dlthlocarb. The NCI (1979) study did not
perform hematologlcal tests, but a slight Increase 1n splenic hematopolesls
-------
was noted 1n rats, apparently at 10,000 ppm 1n the diet, In the subchronlc
portion of the study. The data do not define a NOAEL or NOEL for chronic
oral exposure (NCI, 1979).
Acute toxldty data Include oral LD5Q values of 1500 mg/kg In both
rats and mice, 1ntraper1toneal ID™ 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).
DUhlocarb Is a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sunderman, 1979).
Because of Its metal chelatlng properties, dUhlocarb 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, 1n animals
treated with various metal compounds, facilitate the entry of metals Into
the brain and Into the fetus, perhaps because the d1th1ocarb-meta! chelate
1s UpophlUc. A single study reported a worsening of CNS signs following
Intravenous treatment of thallium-Intoxicated humans with dlthlocarb
(Kamerbeek et al., 1971).
Repeated IntraperUoneal administration of dUhlocarb to rabbits and
lambs produced lesions of the nervous system In both species (Edlngton and
Ho well, 1966; Howell et al., 1970). Oral administration of dUhlocarb to
chickens produced signs and lesions Indicative of delayed neurotoxldty
(Rasul and Howell, 19730, 1974a,b; Fisher and Metcalf, 1983).
DUhlocarb Inhibits the conversion of dopamlne to noradrenalln by
dopamlne-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). DUhlocarb Inhibits mlcrosomal
-------
cytochrome P-450 associated oxldatlve metabolism of xenoblotlcs (Siegers et
al., 1982; Zemaltls and Greene, 1979; Hattenberg et al., 1977) and stimu-
lates OT-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 1,2-dlmethylhydrazlne (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 metallothlonein (Sunderman et
al.. 1984).
Dlthlocarb has been reported to enhance the function of the Immune
system, primarily through effects on the T cells, both In animals (Renoux
and Renoux, 1979; Bruley-Rosset et al., 1986) and In humans (Renoux et al.,
1983; Lang et al., 1985).
Data regarding the cardnogenldty 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 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
statistically significant Increases 1n tumor Incidences (NCI, 1979).
Mutagenldty testing of dlthlocarb has been effectively limited to bacteria
and negative results have been reported (DeFlora et al., 1984; Mortelmans et
al., 1986; Rosenkranz and Lelfer, 1980).
1x
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There Is IHtle evidence that dlthlocarb Is genotoxlc. Studies of
reverse mutation 1n Salmonella typhlmurlum (De Flora, 1981; Oe Flora et al.,
1984; Mortelmans et al., 1986), DNA damage 1n Esher1ch1a coll (Rosenkranz
and Lelfer, 1980; Oe Flora et al., 1984) and chromosomal damage In regener-
ating liver (mouse) (Harman et al., 1970) have given negative results for
dlthlocarb. Positive results were obtained for dlthlocarb 1n a chromosomal
damage assay In Vlcla faba root tips (Klhlman, 1957).
Dlthlocarb has not been tested adequately for teratogenldty. The only
study available used subcutaneous Injection rather than a natural route of
administration. In this study (BRL, 1968b), equivocal evidence of feto-
toxUHy was seen following subcutaneous Injection of 215 mg/kg/day of
dlthlocarb Into pregnant mice.
The data base for the reproductive effects of dlthlocarb 1s 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 1n their offspring (Renoux et al., 1985). Intra-
venous administration of dlthlocarb to pregnant rabbits resulted In loss of
the Utters (Howell, 1964). Dlthlocarb Is spermlddal In vitro (Holzaepfel
et al., 1959) and suppresses ejaculation 1n dogs following acute Intraperl-
toneal Injection (Sakal et al., 1979; Klmura et al., 1980a,b).
Dlthlocarb 1s classified as an EPA C chemical based on a. statistically
significant Increased (p=0.004) Incidence of male B6C3F1 mice hepatoma In 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 In 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~« and 10~7 are 1.3xlO~3,
1.3xlO~* and 1.3xlO~5 mg/i, respectively. Inhalation carclnogenlcHy
data were not available for dlthlocarb. Because the oral cardnogenldty
data are limited, estimation of a q * for Inhalation exposure from the
oral data Is 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 1n 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 aT. (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 1n the NCI
(1976) study. An F factor of 1.29 (mg/kg/day)"1, which places dlthlocarb
In Potency Group 2, was calculated from the dose-response data on hepatomas
In male mice 1n the BRL (1968a) study. Dlthlocarb, an EPA Group C chemical
In Potency Group 2, accordingly has a LOW hazard ranking under CERCLA and an
IRQ of 100 pounds based on carclnogenlclty.
xl
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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. HATER 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
6.2. CARCINOGENICITY 25
6.2.1. 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
xVI
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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 DITHIOCARB 70
X111
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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 DHhlocarb 45
9-3 DHhlocarb: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 47
9-4 Derivation of Potency Factor (F) for DHhlocarb 49
x1v
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LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
DMSO Dimethyl sulfoxlde
DNA Deoxyr1bonucle1c add
EC5Q Concentration effective 1n 50% of recipients
HPLC High pressure liquid chromatography
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
MIC Minimum Inhibiting concentration
MTD Maximum tolerated dose
NOAEL No-pbserved-adverse-effect level
NOEL No-observed effect level
ppm Parts per million
RfD Reference dose
RQ Repor table quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Sodium d1ethyld1th1ocarbamate 1s also called dHhlocarb; dlethylcarbamo-
d1th1on1c add, sodium salt (Chem. Abstr. name); DEOC; N,N-d1ethyld1th1o-
carbamlc add, sodium salt; dlethyl sodium dUhlocarbamate; and sodium DEDT
(IARC, 1976). Sodium dlethyldlthlocarbamate will be referred to as dHhlo-
carb throughout this document. The structure, empirical formula, molecular
weight and CAS Registry number of dHhlocarb are shown below:
C2H5 S
\ II
N-C-S-Na
Empirical formula: C5H,QNS2Na
Molecular weight: 171.3
CAS Registry number: 148-18-5
1.2. PHYSICAL AND CHEMICAL PROPERTIES
The trlhydrate of dHhlocarb 1s a yellow-white solid (NCI, 1979).
DHhlocarb Is also a solid at ambient temperatures and Is soluble 1n water
and ethanol (Hawley, 1981; IARC, 1976). Some of the physical properties of
dHhlocarb 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)
Water solubility: 120,000 mg/l 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 Is faster under slightly acidic conditions; at pH 5.0-6.7,
It decomposes to carbon dlsulflde and dlethylamlne salt (Mlndholz, 1983;
U.S. EPA. 1983; Van Leeuwen et a!., 1985a). It 1s Inert toward oxidation
(Jaber et al., 1984). When heated to decomposition, 1t may emit toxic fumes
of NO , SO and Na 0 (Sax, 1984).
A A ff
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 Is produced by reacting dlethylamlne with carbon dlsulflde and sodium
hydroxide, followed by precipitation with dlethyl ether (HSDB, 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 1n rubber
processing (NCI, 1979). Dlthlocarb 1s also used 1n 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 and In ethanol (Hawley, 1981; IARC, 1976). The compound 1s stable at
pH >9 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 1n the United States. The current production
volume for dlthlocarb 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 dlthlocarb 1n the
atmosphere were not located In the available literature. Since dlthlocarb
Is an 1on1c compound, 1t Is not expected to be present 1n 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 dlthlocarb 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 H0> 1s not known;
however, dlthlocarb Is known to hydrolyze particularly 1n add solutions
with the evolution of carbon dlsulflde {Wlndholz, 1983; Van Leeuwen et al.,
1985a). Therefore, 1t 1s possible that atmospheric dlthlocarb will
hydrolyze In moist air. Given Us high water solubility, dlthlocarb 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
dUhlocarb by common oxldants In water (R0.« and SO*) 1s likely to be
an Important process. DUhlocarb Is susceptible to hydrolysis under acidic
conditions (U.S. EPA, 1983) and the hydrolysis rate Is slower In aqueous
solution at pH 7 (Wlndholz, 1983) (see Chapter 1). Van Leeuwen et al.
(1985a) studied the hydrolysis of dlthlocarb 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 dUhlocarb at neutral and acidic pHs 1n
0079d -4- 12/28/87
-------
natural water may be the most significant process. Hydrolysis above pH 8.0
may not be significant. Although the blodegradabllUy of dlthlocarb In
natural water has not been studied, Us blodegradabllUy under water treat-
ment conditions has been studied. With activated sludge acclimated to
domestic sewage, King and Painter (1985) observed 8 and 99% degradation of
dlthlocarb at an Initial concentration of 10 mg/i 1n 7 and 14 days,
respectively. In bench-scale aerobic blodegradatlon units, >90X of dimethyl
dUhlocarbamate at an Initial concentration of 10 mg/8, 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 m1crob1al degradation, although the degradation rate of
dlthlocarb 1s expected to be slower than the corresponding dimethyl compound
(Kaufman, 1967).
Pertinent data regarding the transport of dlthlocarb In aqueous media
were not located 1n the available literature. Based on the limited Informa-
tion available on the physical properties, U Is predicted that In natural
waters, of pH >8.0, the compound will be stab.le toward hydrolysis and will be
transported In the dissolved state. In the presence of sediments that have
high 1on exchange capacities, dlthlocarb may adhere to the sediments and may
be transported.
2.3. SOIL
Limited data were available 1n the literature to assess the fate and
transport of dlthlocarb 1n soil. Tate and Alexander (1974) observed that
dlethylamlne 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 addle pH of the
0079d -5- 12/28/87
-------
soil. Based on results of a study of degradation of several carbamate
pesticides In soil, Kaufman (1967) concluded that mlcroblal degradation of
N,N-d1subst1tuted d1th1ocarbam1c salts may occur very slowly because of
mlcroblal Inhibitory action of d1th1ocarbam1c add and carbon dlsulflde
formed as a result of mlcroblal action. An alternative pathway for the
mlcroblal degradation of dHhlocarb may be the formation of y-d1ethylth1o-
carbamoylth1o-a-ketobutyr1c add that may finally form y-d1ethylth1o-
carbamoylth1o-a-am1nobutyr1c add (Kaufman, 1967).
Pertinent data regarding the transport of dHhlocarb 1n soil were not
located 1n the available literature. Based on Us high water solubility and
Ionic characteristics, 1t Is likely that the unhydrolyzed compound will
leach substantially In 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 dHhlocarb 1n 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
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 In water (King and
Painter, 1985; Brink, 1976), no rate data are available to assess the
0079d -6- 12/28/87
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significance of the process In water at pH >7. In acidic soils, hydrolysis
may be the primary process for the removal of dithlocarb (Tate and
Alexander, 1974). Because of the expected toxlcltles of the degradation
products, blodegradatlon may be a slow process In soil (Kaufman, 1967). It
Is likely that the compound will leach substantially In soils with low
Ion-exchange capacities.
0079d -7- 12/28/87
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3. EXPOSURE
In a 1965 survey of pesticide residues 1n food and feed samples from
Kansas City, MO, Duggan et al. (1967) reported 0.5 mg/kg of dlthlocarbamates
1n 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 Valnlo (1984)
estimated the exposure of the Finnish population to dlthlocarbamates from
food (when the chemical was used as a pesticide) to be 29 yg/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-
slus auratus (Danscher and Fjerdlngstad, 1975). Exposure to 1.25, 2.25 or
3.125 mg d1th1ocarb/l for 1 hour resulted In 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
dlthlocarb 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/i, 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 dlthlocarb were determined to be 6.9 mg/l 1n
a 96-hour assay with gupples, PoeclHa retlculata. and 0.91 mg/l 1n a
48-hour assay with water fleas, Daphnla maqna (Van Leeuwen et al., 1985a).
These assays were conducted according to OECD guidelines and test solutions
were renewed dally.
The acute toxlclty of two dlthlocarb formulations (each contained 80%
dlthlocarbamate) was studied In the crustacean, Gammarus pulex (Bluzat et
al., 1982a). The 24, 48, 72 and 96-hour LC5Q values for Product A
(aqueous suspension) were 13.99, 1.21, 0.41 and 0.195 mg/l, respectively.
The 24, 48, 72 and 96-hour LCrQ values for Product B (which contained
adjuvants) were 4.77, 0.48, 0.2 and 0.13 mg/l, respectively. The 48 and
96-hour LC,- values for Product A were 15 and 10 mg/l, respectively, for
the mollusk, Lymnaea stagnalls (Bluzat et al., 1982b). Product B was more
toxic with 48 and 96-hour LC5Q values of 4 and 3 mg dUhlocarb/l,
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 LCcn, which reflects reduced
bU
survival and fecundity, was determined to be 30 yg/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™ of 1.4 mg d1th1ocarb/l was determined for unicellular
green algae, Chlorella pyrenoldosa (Van Leeuwen et al., 1985a). This
concentration reduced average specific growth rate by 50%.
DHhlocarb at 17.1 mg/l for periods of 3, 5 or 6 days had little
effect on. the growth and flower production of the duckweed, Lemna glbba
(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 photophily rhythms): from the plant.
4.4. OTHER RELEVANT INFORMATION
A !5-m1nute EC5Q of 1.22 mg d1th1ocarb/8. was determined for
bacteria, Photobacterlum phosphoreum (Van Leeuwen et al., 1985a). This
concentration reduced the luminescence of the bacteria by 50%.
The MIC for nitrification 1n a 3-hour assay with nitrifying bacteria,
Nltrosomonas and NUrobacter. was determined to be 43 mg dUhlocarb/t (Van
Leeuwen et al., 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 LCSQ value of 3.0 mg/l was reported. At concentrations between
0079d -10- 12/28/87
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1 and 3 mg dlthlocarb/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/i,
dlthlocarb Induced the development of abnormal, wavy notochords 1n 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
dHhlocarb/j. for 7 days and examined for tissue-metal concentrations.
Dlthlocarb was most effective In removing nickel from the liver and gills
(56.57 and 48.19% removed, respectively), with 14.78 and 17.91% chromium and
14.54 and 24.86% mercury removed from the liver and gills, respectively.
4.5. SUMMARY
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/l produced 67%
lethality 1n goldfish (Oota, 1971). A 48-hour LC5Q was determined for
Daphnla (Van Leeuwen et al., 1985b). A 24-hour LC™ of 3 mg/a, was
determined for frog embryos, and malformations were observed at concentra-
tions as low as 0.5 mg/l (Ghate and Mulherkar, 1980). Chronic toxldty
data for fish or other vertebrates were not located, but a 21-day LC_Q of
30 yg/l was 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 Hlstar
rats (250 g). The compound was dissolved 1n 2 M 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 1n the
plasma at a level equivalent to 11.3 yg/1 (expressed as dlthlocarb), and
was Identified as approximately equal amounts of unchanged dlthlocarb and
d1th1ocarb-S-g!ucuron1det plus a small amount of Inorganic sulfate.
Excretion data (60X 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 dlthlocarb 1n
female Fischer rats (180 g) given a single dose of 500 mg/kg of dlthlocarb
1n water by gavage. During the 6 hours following dosing, plasma dlthlocarb
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 with the expected low rate of absorption of an Ionized sodium salt.
5.2. DISTRIBUTION
Fifteen minutes after Intraperltoneal Injection of 25 mg 35S-d1th1o-
carb/rat of (222 ymol S/rat) Into 240-300 g .male Wlstar rats, 70-90X 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 vmol S/g) was present In 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 easier (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 dithlocarb or dose-dependent
disposition of carbon dlsulflde cannot be determined from the data 1n this
study.
After gavage administration of 3SS-d1th1ocarbamate to male 250 g
.HI star 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 dHhlocarb-
S-glucuron1de 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 Intraperltoneal Injection of 3SS-d1th1ocarb Into male
240-300 g Ulstar rats at 25 mg/rat, 96X of the radlolabel excreted In the
urine at 1 hour 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 dlthlocarb. Total urinary radioactivity accounted
for 21% of the dose at 1 hour and 43% of the dose at 4 hours. About 7% of
the administered radioactivity was recovered as carbon dlsulflde 1n the
expired air at 1 hour, Increasing to 10% at 4 hours. No significant amounts
of metal chelates of dlthlocarb were detected 1n plasma, liver or urine.
Stromme (1965) suggested that the differences 1n 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 1n the plasma of rats following oral administration
of dlthlocarb (Craven et al., 1976; Baselt and Hanson, 1982), as noted above.
An additional metabolite, methyl d1ethyld1th1ocarbamate, was Identified
by Cobby et al. (1978) during Intravenous Infusion of dlthlocarb In 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/m1n
to steady-state, followed by monitoring of venous blood during steady-state
and after cessation of Infusion. Approximately 27% of the dose was
S-methylated to form methyl dlethyldUhlocarbamate, with a first-order rate
constant of 0.0569 mln'1 (t, .-=12.2 mln). 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 d1ethyld1th1ocarbamate 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 In Section 5.3., the excretion of carbon dlsulflde In
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 (Merlevede 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 3SS-d1th1ocarb to male
250 g Wlstar rats, 60% of the dose was excreted In 3 hours and 96% of the
dose was excreted by 72 hours after dosing (Craven et al., 1976). Slightly
>50% of the administered radioactivity was excreted In the expired air In
the form of carbon dlsulflde. Most of the remaining radioactivity was
excreted In the urine, with only a small amount detected In the feces.
Following 1ntraper1toneal Injection of 25 mg of 35S-d1th1ocarb Into
male 240-300 g Wlstar rats, 7% of the radioactivity was expired as carbon
dlsulflde w1.th.in 1 hour and 10% within 4 hours (Stromme, 1965). Urinary
excretion of radiolabel amounted to 21% of the dose In 1 hour and 43% 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 1s thought to decompose to carbon
dlsuflde In the acidic environment of the stomach (Stromme, 1965; Evans et
al., 1979), 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, -28-80%, however, 1s excreted by humans and
rats as carbon dlsulflde In the expired air (Herlevede and easier, 1961;
Craven et al., 1976). The remainder, at least In rats, Is excreted as
metabolites (primarily d1th1o-S-glucuron1de and Inorganic sulfate) 1n the
urine with only minor amounts 1n 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 1ntraper1toneal administration to rats, 10% of the dose was
expired as carbon dlsulflde within 4 hours (Stromme, 1965), Indicating that
some of the carbon dlsulflde 1n 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 In the soluble fraction
of liver following Intraperltoneal Injection of "S-d1th1ocarb Into rats
1s higher than In plasma and that some of the dithlocarb 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 In the available literature dted 1n 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 1n the treated groups compared with controls; the
magnitude of this depression reached 10% 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 In both male and female rats.
Because 1000 ppm Is below the lowest level tested 1n rats, 1250 ppm, 1t
seems likely that the NCI meant 10,000 ppm. A slight Increase 1n splenic
hematopolesls 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 mice were fed 2500, 5000, 6000, 8000 or 10,000 ppm of dlthlocarb 1n the
diet for 7 weeks 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 Is 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 In body weight gain that were statisti-
cally significant at >100 mg/kg. Food consumption was not reported. No
overt signs of toxldty 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,
possibly as a reflection of the chelatlng activity of dlthlocarb. 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 1n 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, Incoordlnatlon, ataxla
and coma (Sunderman et al., 1967).
Car Iton (1966) fed dlthlocarb to groups of 10 male weanling Charles
River mice 1n the diet at 0, 0.1 or 0.5% (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 toxlclty 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
cm 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 Hallerlan
degeneration and eos1nop1l1c bodies 1n 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 with control animals (p<0.001). Additional studies on neurotoxlc-
Ity have been conducted by parenteral routes; these studies are discussed In
Section 6.1.3.
6.1.2.2. CHRONIC — The oral cardnogenlcHy study by the NCI (1979)
provides limited Information on systemic toxlclty. 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 5% of
their body weight/day as food (U.S. EPA, I960), 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 In the report. No clinical
signs of systemic toxlclty 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 In the mice 1n the NCI (1979) cardnogenldty
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 In 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, 1t 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. L050 values for various species and
routes of exposure have been compiled by NIOSH (1987). Oral LD,n values
for both the rat and mouse are 1500 mg/kg; the 1ntraper1toneal LD~. value
for the rat Is 1250 mg/kg and for the mouse 1s 1302 mg/kg; the subcutaneous
L05Q for the rabbit 1s 500 mg/kg (NIOSH, 1987).
DUhlocarb 1s a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sunderman, 1979).
DHhlocarb, a metal chelatlng agent, has been used therapeutlcally 1n
cases of nickel carbonyl poisoning (Sunderman, 1979, 1981) nickel dermatitis
(Sunderman, 1981) and thallium poisoning (Sunderman, 1967; Kamerbeek et al.,
1971). Oral dlthlocarb treatment was reported to result In Increased
urinary excretion of the metal and alleviation of toxic effects. DHhlocarb
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 In an
exacerbation of the CMS 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, In
pregnant animals, to the fetus (Aaseth et al., 1979; Gale et al., 1982;
Iwata et al., 1970; Jaslm and Tjaelve, 1984a.b, 1986; 3as1m et al., 1985;
Kamerbeek et al., 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-dlthlocarb chelates.
0079d -21- 12/28/87
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Several studies have Investigated the neurotoxlc effects of parenteral
administration of dlthlocarb. Dally Intraperltoneal administration of
dlthlocarb (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) In the white matter
of the spinal cord and 1n 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 dlthlocarb 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 a!., 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 dlthlocarb to chickens produced signs and hlstologlcal evidence of
delayed neurotoxlclty (ataxla, nerve fiber degeneration 1n the medulla and
spinal cord) (Rasul and Howell, 1973b, 1974a,b; Fisher and Metcalf, 1983).
Rats treated orally with dlthlocarb at doses of 240 mg/kg had decreases
1n orientation hypermotmty and subcortlcal EEG activity. Increases 1n
dopamlne and decreases 1n noradrenalln and adrenalin formation; the same
effects were seen with oral administration of an equlmolar dose of carbon
dlsulflde (Thuranszky et al., 1982). The authors concluded that formation
of carbon dlsulflde from dlthlocarb may mediate these effects. Direct
Injection of dlthlocarb Into the brains of rats (Klelnrok et al., 1970) and
0079d -22- 01/22/88
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mice (Doggett and Spencer, 1973) or Intraperltoneal Injection Into rats and
mice (Maj 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-
aUn and Increased the dopamlne content of the 1leum of rats and rabbits
(Collins and West, 1968). The above results and other h) vitro and _hi 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
amlnopyMne 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 (Zema1t1s 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-d1methy1hydraz1ne and
carcinogenic effects of !,2-d1methylhydraz1ne on the colon were reported 1n
mice treated orally with dlthlocarb; because carbon dlsulflde also Inhibited
the oxldatlve metabolism of 1,2-dlmethylhydrazlne. H was suggested that
carbon dlsulflde mediates this antlcarclnogenlc effect of dlthlocarb
(Wattenberg et al., 1977). Sunderman et al. (1984) found that weekly 1ntra-
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 dlthlocarb
treatment.
Intraperltoneal 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:
Renroux and Renoux (1979), Renoux et al. (1986) and Bruley-Rosset et al.
(1986). In these studies, Intraperltoneal 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 In Immune parameters Induced by nonantlgenlc acute Inflammation.
Neveu et al. (1980, 1982), Neveu (1978) and Neveu and Perdoux (1986)
reported that dlthlocarb enhanced mltogen-lnduced lymphoprollferatlon and
modulated delayed hypersensltlvlty reactions In guinea pigs in vivo; how-
ever, because of cytotoxUHy, 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
hypersensltlvlty reactions 1n a dose-related manner In 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 AIDS-related complex, treated with
8-10 mg/kg of dlthlocarb orally once every week for 3-6 months had Improve-
ment 1n delayed hypersensHlvlty and Increases In 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 carclnogenldty of
Inhaled dlthlocarb were not located In the available literature cited In
Appendix A.
6.2.2. Oral. The carclnogenldty of dlthlocarb has been studied In
chronic feeding studies 1n mice (BRL, 1968a; NCI, 1979) and 1n rats (NCI,
1979).
BRL (1968a) evaluated the carclnogenldty 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 HTD, 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 In
dlthlocarb-treated groups was hepatoma In the B6C3F1 males (Table 6-1). The
Incidence of pulmonary adenoma was Increased In B6AKF1 males, but the
Increase was of borderline statistical significance from controls (p=0.056.
Fisher Exact Test). Although the hepatomas In dlthlocarb-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 1n B6C3F1 Mice
Following Oral Administration of D1th1ocarba
Sex
M
F
Dose
(ppm)
0
692b
0
69 2b
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 MTD.
aSource: BRL, 1968a
bD1th1ocarb (purity not specified) was administered to the mice at 215
mg/kg/day 1n 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 = Not significant
0079d
-26-
12/28/87
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hepatic tumors 1n 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 dHhlocarb as Indicative of
a need for further study.
The cardnogenldty of dlthlocarb has been tested further by the NCI
(1979) In F344 rats and B6C3F1 mice of both sexes. OHhlocarb (95% 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 1n 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 tumorlgenie 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 (!8/sex/stra1n) were given a single
subcutaneous Injection of 464 mg d1th1ocarb/kg In water on the 28th day of
age and were killed 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 mutagenldty of dlthlocarb are presented 1n Table 6-2.
Results of studies of reverse mutation for dlthlocarb 1n various strains of
0079d -27- 03/04/88
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o
o
1ABLE 6-2
Hutagenlctty Testing of Dlthlocarb
00
1
o
C3
00
00
Assay
Reverse
mutation
Reverse
mutation
DMA damage
ONA damage
Chromosomal
aberrations
Chromosome
breaks and
chromatld
exchange
Indicator/
Organism
Salmonella
tvphlmurlum
TA98. TA100.
1A1535. TA1537.
TA1538
S. tvphlmurtum
TA98. TA100.
TA1535. 1A1537
Eschertchla coll
pol A-. pol A*
E . coll UP2
(repair pro-
ficient); HP67.
CN871 (repair
deficient)
mouse, male LAM.
21 months old:
regenerating liver
Vlcla faba
root tips
Compound
and/or
Purity
NR
99X*
NR
reagent
grade
NR
NR
Application
plate
Incorporation
prelncubatlon.
then plate
Incorporation
spot test
liquid
mlcromethod
dlthtocarb In
diet
liquid medium
Concentration Activating Response
System
<9.4xlO» ±S-9
nmol/plate
(-1600 pg/plate)
33-10.000 »S-9
vg/plate
•R none
NR ±S-9
IX NA
2.5 or 5x10" • N NA »
Coonents
NC
Negative with
both rat liver
S-9 and hamster
liver S-9.
Aroclor Induced
NC
NC
Note: control
Incidence 73X
Positive for both
endpotnts at both
concentrations
Reference
DeFlora. 1981;
Oef lora
et al.. 1984
Nortelmans
et al.. 1986
Rosenkranz and
Lelfer. 1980
DeFlora
et al.. 1984
Harman et al..
1970
Kthlman. 1957
NR * Not reported. NC = no coonent, NA = not applicable
-------
Salmonella typhlmuMum In the presence or absence of a metabolic activating
system have been negative (De Flora, 1981; Oe Flora et a!., 1984; Mortelmans
et al., 1986). DUhlocarb 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 dHhlocarb 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.
DUhlocarb gave positive results In an assay for the production of chromo-
some breaks and chromatld exchanges 1n Vlcla faba root tips (Klhlman, 1957).
6.4. TERATOGENICITY
The only available study of dlthlocarb teratogenldty (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 OMSO (six Utters) or saline (two groups: six
Utters and eight litters)./ Fetal mortality and the percent of abnormal
fetuses were statistically significantly elevated 1n the dlthlocarb-DMSO
group and In one, but not the other, dlthlocarb-sallne group, compared with
concurrent solvent control groups. Fetal weight and crown-rump length were
decreased 1n the dlthlocarb-DMSO group relative to the appropriate controls.
Testing of C3H mice In the same manner with 464 mg/kg/day of dlthlocarb In
OMSO resulted 1n 95X mortality 1n the two Utters studied. AKR mice, which
have a slightly longer gestation 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) 1n 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/litter
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 1n 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 In 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/litter, number of stlllborns/lltter, 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 1n assays for m1togen-1nduced
proliferation.
Pregnant rabbits given Intravenous Injections of 0.5 or 1.0 g of dlthlo-
carb In 5 or 10 mi of water, respectively, on 5 days/week from days 1-20
of gestation failed to deliver Utters; In most cases evidence of abortion
was found (Howe11, 1964). Control rabbits, treated similarly with saline
equal In molarlty to the dlthlocarb solution, all delivered litters.
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 1ntraper1toneal 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 1n the caudate nucleus, epidldymis, 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. Rice
(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-Uke crystals after a small amount of
dlthlocarb was dissolved 1n 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 9.7%
Increase 1n volume of spermatozoa).
6.6. SUMMARY AND CONCLUSIONS
Pertinent data regarding the effects of Inhaled dlthlocarb were not
located 1n the available literature cited In Appendix A. A number of
studies of systemic toxlclty and carc1nogen1c1ty 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
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 dithlocarb 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
subchronlc oral studies Include renal toxlclty In rats and hematologlcal
effects (decreases 1n red cell counts, hematocrlts and hemoglobin levels) 1n
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 1n rats (Sunderman et
al., 1967).
In chronic studies, rats had cataracts and body weight depression at the
lowest level tested, 1250 ppm of dithlocarb 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 dithlocarb 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 In both species and cataracts
(Incidence not dose-related) 1n rats. Renal effects were not reported 1n
the chronic portion of the NCI (1979) study, although mild renal effects
were seen 1n rats In the subchronlc portion of this study, apparently at a
dietary level of 10,000 ppm dithlocarb. The NCI (1979) study did not
perform hematologlcal tests, but a slight Increase In splenic hematopolesls
was noted In rats, apparently at 10,000 ppm In the diet. In the subchronlc
portion of the study. The data do not define a NOAEL or NOEL for chronic
oral exposure (NCI, 1979).
0079d -32- 03/04/88
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Acute toxIcHy data Include oral LD5Q values of 1500 mg/kg In both
rats and mice, IntrapeMtoneal LD.- values of 1250 mg/kg In rats and 1302
mg/kg In mice, and a subcutaneous LO,.. of 500 mg/kg 1n rabbits (NIOSH,
1987).
DUhlocarb Is a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sunderman, 1979).
Because of Us metal chelatlng properties, dlthlocarb has been used
therapeutlcally 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, 1n 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 UpophlUc. A single study reported a worsening of CNS signs following
Intravenous treatment of thallium-Intoxicated humans with dlthlocarb
(Kamerbeek et al.. 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 neurotoxldty
(Rasul and Howell, 1973b, 1974a,b; Fisher and Metcalf, 1983).
Dlthlocarb Inhibits 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
cytochrome P-450 associated oxldatlve metabolism of xenoblotlcs (Siegers et
al., 1982; Zemaltls 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 dHhlocarb against the carcinogenic effects of
1,2-d1methy1hydraz1ne was attributed to Inhibition of the oxldatlve metabo-
lism (activation) of !,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 metallothloneln (Sunderman et
al., 1984).
DHhlocarb has been reported to enhance the function of the Immune
system, primarily through effects on the T cells, both In animals (Renoux
and Renoux, 1979; Bruley-Rosset et al., 1986) and In humans (Renoux et al.,
1983; Lang et al., 1985).
Data regarding the cardnogenldty 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 1n a statistically significantly Increased Incidence of tumors
only 1n the case of hepatomas 1n the B6C3FT 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).
Mutagenldty testing of dlthlocarb has been effectively limited to bacteria
and negative results have been reported (DeFlora et al., 1984; Mortelmans et
al., 1986; Rosenkranz and Lelfer, 1980).
There 1s little evidence that dlthlocarb Is genotoxlc. Studies of
reverse mutation In 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
0079d -34- 03/04/88
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dHhlocarb. Positive results were obtained for dlthlocarb In a chromosomal
damage assay 1n V1c1a faba root tips (Klhlman, 1957).
Dlthlocarb 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
dlthlocarb Into pregnant mice.
The data base for the reproductive effects of dHhlocarb 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 dHhlocarb to pregnant rabbits resulted 1n loss of
the Utters (Howell, 1964). Dlthlocarb 1s sperm1c1dal In vitro (Holzaepfel
et al., 1959) and suppresses ejaculation In dogs following acute IntrapeM-
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. HUMAN
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 In the available literature dted
In 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 cardnogenldty of
Inhalation exposure to dlthlocarb were not located In the available litera-
ture cited 1n 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 In statistically significant
Increased Incidences of tumors only 1n the case of hepatomas 1n 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 1n 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 1n Increased Incidences of
tumors In male and female B6C3F1 or B6AKF1 mice after -18 months (BRL,
1968a);
8.1.4. Height 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 1n one sex of one strain of mice
1n a single study, which employed only one dosing level. The appropriate
EPA (U.S. 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 1n male B6C3F1 mice (BRL, 1968a); these are
the only positive cardnogenlclty 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 In the B6C3F1 male mice, and the
computerized multistage model developed by Howe and Crump (1982), the
unadjusted (animal) q,* 1s calculated to be 8.825xlO~3 (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 llfespan (104 weeks) to experiment duration (77
weeks), 1s 2.69X10"1 (mg/kg/day)'1. This q^ differs slightly from
the q.j* 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 the last 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
I/day of water, the concentrations of dlthlocarb In drinking water
associated with Increased lifetime risk of cancer at risk levels of 10"5,
10"* and 10~7 are I.SxlO"3, 1.3x10~« and 1.3xlO~3 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 dlthlocarb 1s the study In 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 dlthlocarb 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 hematologlcal effects (decreased red cell counts,
hemoglobin levels and hematocrlt 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 dlthlocarb, 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
chemical 1s administered In a nonstandard diet (Carlton, 1966; chicken-mash
and lard diet). 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 1n the
NCI (1979) 7-week study In 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 Us 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 1n 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 Interspecles 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 1n the RfD Is 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 mg/kg/day) for 108 or 109 weeks. Dosages were calculated from dietary
levels by assuming that rats and mice consume the equivalent of 5 and 13X,
respectively, of their body weight dally as food (U.S. EPA, 1980). Control
0079d -40- 01/22/88
-------
groups consisted of 16 or 20 anlmals/sex/spedes. 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 h1stopatholog1cal 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 1n 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 Is
divided by an uncertainty factor of 1000 (10 for Interspedes extrapolation,
10 to protect the most sensitive Individuals and 10 to extrapolate from
subchronlc to chronic exposure), resulting 1n a chronic oral RfO of 0.03
mg/kg/day or 2 mg/day for a 70 kg human. Confidence In this RfD 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 Is
lacking and hematologkal 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 RfO.
0079d -41- 12/28/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of dlthlocarb was discussed In Chapter 6. Pertinent dose-
effect data are summarized In Table 9-1. The toxlcologlcal significance of
the body weight depression seen In several of the studies 1s 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 Howe11 (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 In the subchronlc studies were higher than those associated
with effects 1n 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 Is 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 dlthlocarb 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 RV. of
1.3. Cataracts represent a change that results 1n a marked sensory deficit
and are accordingly ranked with an RV of 8. The product of the RV. and
RV 1s a CS of 10.4, which corresponds to an RQ of 1000.
6
The only other effect seen 1n the chronic studies was a slight decrease
In body weight 1n both rats and mice (NCI, 1979). Because food consumption
data were not provided, H Is not possible to determine whether the decrease
1n body weight was due to toxldty of the chemical or to reduced food
Intake. In considering the systemic toxldty data base as a whole, however,
0079d -42- 12/28/87
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TABLE 9-1
Oral Toxiclty Sumary for OHMocarb
«-J
VD
O.
1
OJ
'
00
^s*
00
Species/ No. at
Strain Sex Start
Rat/F344 F 5
H.F 5/sex
H.F 5/sex
Rat/ F 25
albino R 25
F 25
Rat/F344 F 50
Rouse/ F 5
B6C3F1
Rouse/ F 50
B6C3F1 H 50
Dogs/ H.F 2/sex
beagle
Average
Body
Height
(kg)
0.347b
0.29«*
0.119*
0.225"
0.360h
0.215*
0.225"
0.027*
0.036"
0.043"
12. 71
Vehicle/
Physical
State
diet
diet
diet
NR
NR
diet
diet
diet
NR
Purity Exposure
: . ' :
95X 2500 PPM In diet
for 7 weeks
95X 10.000 ppM In
diet for 7 weeks
95X 40.000 ppM In
diet for 7 weeks
NR 100 Mg/kg/day
for 90 days
NR 300 Mg/kg/day
for 90 days
95X 1250 ppM In diet
for 104 weeks
95X 10.000 ppM lit
diet for 12 weeks
9SX 500 ppM In diet
for 108-109 weeks
NR 300 Mg/kg/day for
90 days
Transformed
Animal Dose
(Mg/kg/day)
250C
10.000C
2,000f
100
300
62. 5 J
1.300*
65*
300
Equivalent
Human Dosea
(mg/kg/day)
42.6
160.6
NA9
14.8
17.3
43.6
9.2
94.6
5.2
5.5
169.8
Response
10X depression of body weight
relative to controls
-17X depression of body weight
relative to controls, slight
vacuolatlon of renal tubular
epithelium, slight Increase
In splenic hematopotests
66X depression of body weight
In 3 survivors relative to
controls; 7/10 rats died
Significant decrease In body
weight gain
Significant decrease In body
weight gain, decreased red
cell counts, hemoglobin levels
and hematocrlts; decreased
kidney weight and Mild hlsto-
pathologlcal changes
Decrease In body weight
relative to control, cataracts
10X depression In body weight
relative to controls
Decrease In body weight
relative to controls
Slight weight loss, death of
1 female, decrease In red
cell count, hemoglobin level
and hematocrlt
Reference
NCI. 1979
Sunderman
et al. . 1967
NCI. 1979
NCI. 1979
Sunderman
et al.. 1967
-------
TABLE 9-1 (cont.)
0
o
S> Species/ No. at
°- Strain Sex Start
Rabbits/ N 10
Dutch
Average
Body Vehicle/
Height Physical
(kg) State
3.8" 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 Dosea
(mg/kg/day)
89.2
Response
Slight weight loss.
central
and peripheral nervous system
lesions but no overt
neurotoxlclty
signs of
Reference
Rasul and
Howell. 1973a
'Calculated by Multiplying the anlnal 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)
cAssum1ng 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 (0.35 kg) (see Reference)
'Calculated as 66X depression of reference rat body weight (see Response)
^Marked 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.
9Not 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 13X of Its body weight (U.S. EPA. 1980)
JAssumlng that a rat consumes dally an amount of food equal to 5X of Its body weight (U.S. EPA. 1980)
kCalculated 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. 1986b)
IS)
00
CO
-------
TABLE 9-2
Oral Composite Scores for DHhlocarb*
Species
Rat
Mouse
Animal Dose
(mg/kg/day)
62.5
65
Chronic
Human MED RVd
(mg/day)
644 1.3
364 1.7
Effect RVe
Cataracts 8
Decrease 1n 4
body weight
relative to
controls
CS RQ
10.4 1000
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 dUhlocarb
toxldty. The RV for body wleght depression Is 4. In rats, since the
body weight depression occurred at the same dose level as did cataracts, a
more severe effect, there 1s no need to calculate a CS for the less severe
effect 1n 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 RV. 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 (19855).
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 1n the previous assessment, but was judged to
represent a more serious sensory deficit, ranked as an RV of 8, 1n the
present assessment.
9.2. BASED ON CARCINOGENICITY
DUhlocarb 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 the same treatment did not have Increased Incidences of any type of
tumor. Negative results for cardnogenldty were also reported by the NCI
(1979) In male and female B6C3F1 mice fed 500 or 4000 ppm of dithlocarb In
the diet for 108 or 109 weeks and In F344 rats of both sexes fed 1250 or
0079d -46- 12/28/87
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TABLE 9-3
DHhlocarb
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
^Equivalent human dose
0079d -47- 12/28/87
-------
2500 ppm of dlthlocarb In the diet for 104 weeks. A single IntrapeMtoneal
Injection of 474 mg/kg Into male and female B6C3F1 and B6AKF1 mice produced
no evidence of cardnogenldty after 18 months (BRL, 1968a). Details of
these studies are presented 1n Section 6.2.2. and 1n Table 6-1.
Evidence for the cardnogenldty of dlthlocarb to animals Is limited and
no data are available for humans. Dlthlocarb 1s therefore classified 1n EPA
Group C (see Section 8.1.4.).
Derivation of the F factor from the dose-response data for hepat'oma In
B6C3F1 male mice (BRL, 1968a) 1s summarized In Table 9-4. These are the
only positive cardnogenldty 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/ED,_ 1s calculated to
be 4.239xlO~2 (mg/kg/day)'1. Multiplying the unadjusted 1/ED1Q 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 1/ED1Q (F Factor) of 1.29 (mg/kg/day)'1. This F factor places
dlthlocarb In Potency Group 2. An EPA Group C chemical that Is In Potency
Group 2 ranks LOU In the Hazard Ranking Scheme under CERCLA and Is 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 D1th1ocarb
Reference:
Exposure route:
Species:
Strain:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed doses (mg/kg/day)
Tumor Incidence:
Unadjusted 1/ED10:
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/dayr1
0079d
-49-
12/28/87
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-------
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0079d -58- 12/28/87
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Neveu, P.J. and D. Perdoux. 1986. Evaluation of the mechanisms Involved 1n
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0079d -59- 12/28/87
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0079d -60- 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 -63- 01/22/88
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0079d -64- 01/22/88
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Van Leeuwen, C.J., F. Hoberts and G. Nlebeek. 1985b. Aquatic lexicological
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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)
HSDB
These searches were conducted In 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 In 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
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0079d -66- 12/28/87
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer 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, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, MHO, Lyons, France.
Jaber, H.H., M.R. Habey, 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 1n
Programs. Registration Standards and the Data Call In Programs.
Off tee 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.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0079d -67- 12/28/87
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In addition, approximately 30 compendia of aquatic toxlclty 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 H.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty 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 (le) = 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, 94.9-1*
Incidence
No. Responding/No.
8/79
7/17
Tested
then 692 ppm In diet for
74 weeks
Unadjusted qi* = 8.8250xlO~3 (mg/kg/day)'1
Human q-j* * 2.6893X10"1 (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
mg/kg/day and the TMA dosage for the entire experiment 1s 94.9 mg/kg/day.
0079d -69- 12/28/87
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; APPENDIX C .... ->
SuHury Table for OHMocarb
Species
Inhalation Exposure
Subchrontc ID
Chronic ID
Carclnogenlclty ID
Oral Exposure
Subchrontc rat
i
° Chronic rat
Carclnogenlclty aouse
REPORTABLE QUANTITIES
Based on Chronic Toxlclty:
Based on Cancer:
Exposure
ID
ID
ID
30 ag/kg/day •
30 ag/kg/day
215 ag/kg/day. gavage.
3 weeks; then 692 ppa.
diet. 74 weeks
1000
100
? Effect
. V
ID
ID
ID
Decreased body weight gain at 100
ag/kg/day; renal and heaatologlcal
effects at 300 ag/kg/day
. Cataracts and reduced body weight
In feaales at 62.5 ag/kg/day
(NCI. 1979)
Increased Incidence of hepatoaa
RfO or QI*
10
10
ID
0.3 ag/kg/day
or 21 ag/day for
a 70 kg human
0.03 ag/kg/day or
0.2 ag/day for a
70 kg human
2.69x10"'
(ag/kg/day)-»
Reference
10
ID
10
Sunderaan
et al.. 1967
Sunderaan
et al.. 1967
BRL. 1968a
NCI. 1979
BRL. 1968a
ID - Insufficient data
00
CO
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