Environmental Protection
Agency March, 1988
>°/EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR SODIUM DIETHYLDITHIOCARBAMATE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by .he U.S. Environmental Protection Agency and should not at this stage be
com trued to represent Agency policy. It Is being circulated for cowments
on Its technical accuracy and policy Implications.
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•Oi ;,' Street, S
, DC
rii r-otoction
•01 PM-211-A
.«.
20460
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
doe; not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Haste and Emergency Response (OSUER). This document series
Is intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer {OSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subcironlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfOs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980) Is provided. These
poteicy estimates are derived for both oral and Inhalation exposures where
possible. In addition, unit risk estimates for air and drinking water are
presented based on Inhalation and oral data, respectively.
^portable quantities (RQs) based on both chronic toxlclty and carcino-
gen! :1ty are derived. The RQ Is used to determine the quantity of a
hazardous substance for which notification Is required In the event of a
release as specified under the Comprehensive Environmental Response, Compen-
sation and Liability Act (CERCLA). These two RQs (chronic toxlclty and
care inogenkHy) represent two of six scores developed (the remaining four
reflect 1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian
tox1i:1ty). Chemical-specific RQs reflect the lowest of these six primary
crltifrlar The methodology for chronic toxlclty and cancer based RQs are
definedJjj U.S. EPA, 1964 and 1986a, respectively.
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EXECUTIVE SUMMARY
Dlthlocarb Is a solid at ambient temperatures; It Is 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 In acidic pH
(Wlrdholz, 1983; Van Leeuwen et al., 1985a). Currently, VanderbUt 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 Is not available (SRI, 1987; USITC, 1986). Dlthlocarb
Is used mainly as an accelerator 1n rubber processing, as an Intermediate In
fungicide manufacture and as a chelatlng agent (U.S. EPA. 1983; NCI, 1979).
.ImUed data were located In the available literature to assess the fate
and transport of dlthlocarb In environmental media. Based on Us physical
properties, the compound 1s not likely to accumulate In the air compartment.
In Ihe atmosphere, dlthlocarb may undergo hydrolysis In the presence of
molsiure. 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
mlnules and <1 day, respectively (Van Leeuwen et al., 1985a). Above pH 7.0,
hydr7. In acidic soils, hydrolysis
may be the primary process for the removal of dlthlocarb (Tate and
Alexander, 1974). Because of the expected tox1cU1es of the degradation
products, blodegradatlon may be a slow process in soil (Kaufman. 1967).
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It s likely that the compound will leach substantially In soils with low
Ion-exchange capacities.
In a 1965 survey of pesticide residues In food and feed samples from
Kansas City, MO, Ouggan et al. (1967) reported 0.5 mg/kg of dlthlocarbamates
In cne sample of grain and cereal and concentrations of 0.4, 0.7 and 0.8
mg/kg In 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
othe • Information regarding exposure to this compound was located In the
aval able literature.
he acute toxlclty of dUhlocarb has been evaluated 1n fish and
crustaceans. A 96-hour 1C™ of 6.9 mg/l was determined for gupples (Van
Leeuvien et al., 1985a) and 1-hour exposure to 15 mg/l produced 67% lethal-
ity in foldflsh (Oota, 1971). A 48-hour LC5Q was determined for Daphnla
(Van Leeuwen et al., 1985b). A 24-hour LC5Q of 3 mg/l was determined
for rrog embryos, and malformations were observed at concentrations as low
as 0.5 mg/l (Ghate and Hulherkar, 1980). Chronic toxlclty data for fish
or other vertebrates were not located, but a 21-day LC50 of 30 fig/l
was jetermlned for Daphnla (Van Leeuwen et al., 1985b). Studies with
aquatic plants have determined a 96-hour EC™ of 1.4 mg/l for unicellu-
lar green algae (Van Leeuwen et al., 1985a), and that the yield of reproduc-
tive fronds In duckweed was decreased by exposure to 17.1 mg/l for 3 days
(Oota, 1971).
Llnltett pharmacoklnetlc data are available for oral and parenteral
administration of dlthlocarb; no data are available for Inhalation exposure
to this compound. Although dlthlocarb Is thought to decompose to carbon
dlsul :1de In the acidic environment of the stomach (Stromme, 1965; Evans et
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al., 1979), unchanged dHhlocarb and d1th1ocarb-S-glucuron1de are detectlble
In the plasma within 15 minutes of oral administration of dlthlocarb to rats
(Craven et al., 1976). The concentration of dHhlocarb 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, -28-80X, however, Is excreted by humans and rats
as carbon dlsulflde 1n the expired air (Merlevede and easier. 1961; Craven
et al., 1976). The remainder, at least In rats, Is excreted as metabolites
(primarily dlthlo-S-glucuronlde and Inorganic sulfate) In the urine with
only minor amounts In the feces (Craven et al., 1976). The excretion data
1nd1
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Subchronlc and chronic oral administration of dHhlocarb to rats, mice,
dog: and rabbits has shown that depression of body weight or body weight
galr 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 dHhlocarb than are mice or dogs, but that
species differences In sensitivity are small. (The data for rabbits are
InsuFfldent to judge their relative sensitivity). Additional effects In
subcironic 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 IIOEL for subchronlc oral exposure Is 30 mg/kg/day In rats (Sunderman et
al., 1967).
In chronic studies, rats had cataracts and body weight depression at the
lowest level tested, 1250 ppm of dHhlocarb 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 dHhlocarb In the diet (65 mg/kg/day) (NCI,
1979). Higher exposure levels 1n rats and mice In this study produced a
more pronounced depression of body weight 1n both species and cataracts
(IncUence not dose-related) In rats. Renal effects were not reported 1n
the chronic portion of the NCI (1979) study, although mild renal effects
were se«ft_ln rats 1n the subchronlc portion of this study, apparently at a
dletaiy level of 10,000 ppm dHhlocarb. The NCI (1979) study did not
perform hematologlcal tests, but a slight Increase 1n splenic hematopolesls
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was noted In rats, apparently at 10,000 ppm In the diet, 1n the subchronlc
por Ion of the study. The data do not define a NOAEL or NOEL for chronic
ora exposure (NCI, 1979).
Acute toxlclty data Include oral L05Q values of 1500 mg/kg In both
rat; and mice, IntraperHoneal LD5Q values of 1250 mg/kg 1n rats and 1302
mg/lg In mice, and a subcutaneous LIL- of 500 mg/kg 1n rabbits (NIOSH,
198').
DUhlocarb Is a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sumerman, 1979).
Because of Us metal chelatlng properties, dlthlocarb has been used
therapeutlcally In human cases of metal poisoning, most commonly nickel
cartonyl poisoning (Sunderman, 1979, 1981). Evidence from numerous studies,
however, Indicates that chelatlon therapy with dlthlocarb may. In animals
tree ted with various metal compounds, facilitate the entry of metals Into
the brain and Into the fetus, perhaps because the dlthlocarb-metal chelate
Is Ipophlllc. A single study reported a worsening of CNS signs following
Intravenous treatment of thallium-Intoxicated humans with dlthlocarb
(Kanerbeek et al., 1971).
Repeated Intraperltoneal administration of dlthlocarb to rabbits and
lambs produced lesions of the nervous system In both species {Edlngton and
Howell, 1966; Howe11 et al., 1970). Oral administration of dlthlocarb to
chickens produced signs and lesions Indicative of delayed neurotoxlclty
(Rasul MiMoiMll. 1973b, 1974a,b; Fisher and Met calf, 1963).
D1tts9K3rl> Inhibits the conversion of dopamlne to noradrenalln by
dopan1ne-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
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cytochrome P-450 associated oxldatlve metabolism of xenoblotlcs (Siegers et
al., 1982; Zemaltls and Greene, 1979; Wattenberg et al.. 1977) and stimu-
lates DT-dlaphorase and glutathlone transferase (Benson et al., 1986; Benson
and Baretto, 1985).
The protective effect of dHhlocarb against the carcinogenic effects of
1,2 -dlmethylhydrazlne was attributed to Inhibition of the oxldatlve metabo-
I1sn (activation) of 1,2-dlmethylhydrazlne (Hattenberg et al., 1977). The
provectlve effect of dlthlocarb against the carcinogenic effects of Intra-
muscularly Implanted nickel subsulflde was thought to be connected with
dHMocarb's enhancement of hepatic levels of metallothloneln (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.,
198;; Lang et al., 1985).
Data regarding the cardnogenlclty of dlthlocarb are available for the
oral route of administration, but not for Inhalation. Administration of
dHMocarb at 215 mg/kg/day by gavage on days 7-28 of age and then at 612
ppm In the diet until week 78 of age to male and female 86C3F1 and B6AKF1
mice resulted In a statistically significantly Increased Incidence of tumors
only In the case of hepatomas In the 86C3F1 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 In 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).
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There 1s IHtle evidence that dlthlocarb 1s genotoxlc. Studies of
reverse mutation In Salmonella typhlmuMuro (De Flora, 1981; Oe Flora et al..
1984; Mortelmans et al., 1986), UNA damage In 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
dlthlocarb. Positive results were obtained for dlthlocarb 1n a chromosomal
darnaje assay In V1c1a fafaa root tips (Klhlman, 1957).
mtilocarb has not been tested adequately for teratogenldty. The only
studf available used subcutaneous Injection rather than a natural route of
administration. In this study (BRL, 1968b), equivocal evidence of feto-
toxldty was seen following subcutaneous Injection of 215 mg/kg/day of
dlth ocarb Into pregnant mice.
"he data base for the reproductive effects of dlthlocarb Is also
Inadequate. The feeding of dlthlocarb at 5000 ppm In a chicken mash/lard
diet to pregnant mice from day 3 of gestation through delivery had no
adverse effects on number of dams delivering young or number of young/Utter
(Carlton, 1966). Subcutaneous Injection of dlthlocarb at 25 mg/kg, twice
weekly. Into female mice before or before and after mating produced no
adverse effects on reproductive Indices and stimulated Immune T-cell produc-
tion and responsiveness In their offspring (Renoux et al., 1985). Intra-
venous administration of dlthlocarb to pregnant rabbits resulted In loss of
the litters (Howe 11. 1964). Dlthlocarb 1s spermlddal In vitro (Holzaepfel
et al., 1959) and suppresses ejaculation 1n dogs following acute Intraperl-
toneal Infection (Sakal et al.. 1979; Klmura et al.. 1980a,b).
D thlocarb Is classified as an EPA C chemical based on a statistically
significant Increased (p-0.004) Incidence of male B6C3H mice hepatoma In a
78-week screening study and the lack of pertinent human data. A q,* of
2.69x"0~1 (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 8RL
(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,
1.3x10'* and 1.3xlO~5 mg/i, respectively. Inhalation carclnogenlclty
data were not available for dHhlocarb. Because the oral carclnogenlclty
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
base
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 2
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 4
2.3. SOIL 5
2.4. SUMMARY 6
3. EXPOSURE 8
4. AQUATIC TOXICITY 9
4.1. ACUTE TOXICITY 9
4.2. CHRONIC EFFECTS 10
4.3. PLANT EFFECTS 10
4.4. OTHER RELEVANT INFORMATION 10
4.5. SUMMARY 11
5. PHARHACOKINETCS 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. CARCIN06ENICITY 25
±t -6.2.1. Inhalation 25
6.2.2. Oral 25
6.2.3. Other Relevant Information 27
6.3. MUTAGINICITY 27
6.4. TERATOGENICITY 29
6.5. OTHER REPRODUCTIVE EFFECTS 30
6.6. SUMMARY AND CONCLUSIONS 31
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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
APPEIIDIX A: LITERATURE SEARCHED 66
APPEIIDIX B: CANCER DATA SHEET FOR DERIVATION OF q]* FOR ORAL
EXPOSURE 69
APPEJIDIX C: SUMMARY TABLE FOR OITHIOCARB 70
Xlll
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No.
6-1
6-2
9-1
9-2
9-3
LIST OF TABLES
Title
Incidence of Hepatomas In 86C3F1 Nice Following Oral
Administration of DUhlocarb ,
Paqe
26
Nutagenldty Testing of DUhlocarb 28
Oral Toxlclty Summary for Dlothlocarb 43
Oral Composite Scores for DUhlocarb 45
OHhlocarb: Minimum Effective Dose (NED) and Reportable
Quantity (RQ) 47
9-4 Derivation of Potency Factor (F) for DUhlocarb 49
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LIST OF ABBREVIATIONS
CAS
CNS
CS
DHSO
DNA
"50
HPLC
"50
LOAEI.
NED
MIC
MTD
NOAE1
NOEL
ppm
RfD
RQ
RVe
TWA
UV
Chemical Abstract Service
Central nervous system
Composite score
Dimethyl sulfoxlde
Deoxyr1bonucle1c add
Concentration effective In 50% of recipients
High pressure liquid chromatography
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
Minimum Inhibiting concentration
Maximum tolerated dose
No-observed-adverse-effect level
No-observed effect level
Parts per million
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Time-weighted average
Ultraviolet
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
:;od1ura d1ethyld1th1oearbamate 1s also called dHhlocarb; dlethylcarbamo-
dlth onlc acid, sodium salt (Chem. Abstr. name); DEDC; N,N-d1ethyld1th1o-
cartomlc add, sodium salt; dlethyl sodium dlthlocarbamate; and sodium DEOT
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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 Jecomposes to carbon dlsulflde and dlethylamlne salt (Hlndholz, 1983;
U.S. EPA, 1983; Van Leeuwen et al., 1985a). It 1s Inert toward oxidation
(Jaber et al., 1984). When heated to decomposition, It may emit toxic fumes
of NDx, S0x and Na20 (Sax, 1984).
1.3. PRODUCTION DATA
kcordlng 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 1n 1977. Currently, Vanderbllt Co., Inc., Bethel, CT (USITC,
1986 , Alco Chemical Corp., Chattanoga, TN, and Frank Enterprises, Inc.,
Colunbus, OH, produce dlthlocarb In the United States (SRI, 1987). The
current U.S. production volume for this chemical 1s not available. DUhlo-
carb Is produced by reacting dlethylamlne with carbon dlsulflde and sodium
hydrtxlde, followed by precipitation with dlethyl ether (HSDB, 1987).
1.4. USE DATA
Ihe zinc, selenium and tellurium salts of dlethyl dlthlocarbamate that
can he produced from the sodium salt are used as accelerators In rubber
processing (NCI, 1979). Dlthlocarb Is also used In fungicide preparation,
as a chelatlng agent for the treatment of human metal poisoning, as an
oxidation Inhibitor and as an analytical reagent (U.S. EPA, 1983; NCI, 1979).
1.5. SUMMARY
Dithlocarb Is a solid at ambient temperatures and Is highly soluble In
water amt In ethanol (Hawley, 1981; IARC, 1976). The compound Is stable at
pH >9 but decomposes to carbon dlsulflde and dlethylamlne salts In acidic pH
(yindliolz, 1983; Van Leeuwen et al.. 1985a). Currently. Vanderbllt Co.,
Bethe , CT, Alco Chemical, Chattanoga, TN, and Frank Enterprises, Columbus,
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OH, produce this chemical In the United States. The current production
volune for dlthlocarb Is not available (SRI. 1987; USITC, 1986). It Is used
mainly as an accelerator In 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 In the
atmosphere were not located In the available literature. Since dlthlocarb
Is an Ionic compound, It Is not expected to be present In the atmosphere In
the vapor state. Small amounts of the chemical may be present In the atmo-
sphe-e 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 photochemically produced H0« Is not known;
howe\er, dlthlocarb Is known to hydrolyze particularly In add solutions
with the evolution of carbon dlsulflde (Ulndholz, 1983; Van Leeuwen et al.,
1985a). Therefore, It Is possible that atmospheric dlthlocarb will
hydralyze 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
Arcordlng to Jaber et al. (1984), neither photolysis nor oxidation of
d1th1>carb by common oxldants In water (R0?» and SO*) Is likely to be
an Important process. Dlthlocarb Is susceptible to hydrolysis under acidic
conditions (U.S. EPA, 1983) and the hydrolysis rate Is slower In aqueous
solut on- at pH 7 (Hlndholz, 1983) (see Chapter 1). Van Leeuwen et al.
(1985;i) atB41ed the hydrolysis of dlthlocarb at different pHs and at
unspe<1f1ed 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 dlthlocarb at neutral and acidic pHs 1n
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12/28/87
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natiral water may be the most significant process. Hydrolysis above pH 8.0
may not be significant. Although the blodegradabllUy of dlthlocarb In
naUral 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/t, In 7 and 14 days,
resp?ct1vely. In bench-scale aerobic blodegradatlon units, >90X of dimethyl
dlthlocarbamate at an Initial concentration of 10 mg/i was found to
blodjgrade at unspecified residence times (Brink. 1976). These studies
Indicate that dlthlocarb at low concentrations In natural waters may be
susceptible to mlcroblal degradation, although the degradation rate of
dlth ocarb 1s expected to be slower than the corresponding dimethyl compound
(Kaulman, 1967).
Fertlnent data regarding the transport of dlthlocarb In aqueous media
were not located In the available literature. Based on the limited Informa-
tion available on the physical properties, It Is predicted that In natural
waters of pH >8.0, the compound will be stable toward hydrolysis and will be
transported In the dissolved state. In the presence of sediments that have
high 1on exchange capacities, dlthlocarb may adhere to the sediments and may
be tr insported.
2.3. SOIL
Limited data were available In the literature to assess the fate and
transport of dlthlocarb In soil. Tate and Alexander (1974) observed that
d1eth*'lairtne 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
conclided that the secondary amlne (d1ethylam1ne) was not formed as a result
of mliroblal action but was a result of hydrolysis at the addle pH of the
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12/28/87
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sol . Based on results of a study of degradation of several carbamate
pesllcldes 1n soil, Kaufman (1967) concluded that mlcroblal degradation of
N,N-d1substltuted dHhlocarbamlc salts may occur very slowly because of
mlcroblal Inhibitory action of dHhlocarbamlc add and carbon dlsulflde
forned as a result of mlcroblal action. An alternative pathway for the
mlcroblal degradation of dlthlocarb may be the formation of Y-d1ethylth1o-
carbamoylth1o-a-ketobutyr1c add that may finally form y-d1ethylth1o-
carbamoylth1o-
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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
Ale>ander, 1974). Because of the expected toxlcltles of the degradation
procucts, blodegradatlon may be a slow process 1n 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 rag/kg of dHhlocarbamates
In cne sample of grain and cereal and concentrations of 0.4, 0.7 and 0.8
mg/kj 1n three samples of leafy vegetables. Hemm1nk1 and Va1n1o (1984)
estimated the exposure of the Finnish population to dHhlocarbamates from
food (when the chemical was used as a pesticide) to be 29 ug/day. No
other Information regarding exposure to this compound was located 1n the
aval able literature.
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4. AQUATIC TOXICITY
4.1 ACUTE TOXICITY
The acute toxlclty of dlthlocarb was reported for the goldfish, Caras-
s1u« auratus (Danscher and Fjerdlngstad, 1975). Exposure to 1.25. 2.25 or
3.1;5 rag dlthlocarb/t for 1 hour resulted In no deaths or toxic effects.
Exposure to 7.5 mg/i 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/i
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
syrup :oms occurred within 3 hours of exposure, and those fish surviving after
24 hours appeared to recuperate.
I C,Q concentrations of dlthlocarb were determined to be 6.9 mg/i In
a 9e-hour assay with gupples, Poecllla retlculata. and 0.91 mg/i In a
48-hcur assay with water fleas, Daphnla magna (Van Leeuwen et al., 1985a).
These assays were conducted according to OECO guidelines and test solutions
were renewed dally.
The acute toxlclty of two dlthlocarb formulations (each contained 80%
dUhlxarbamate) was studied 1n 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/i, respectively.
The 24, 48, 72 and 96-hour LC™ values for Product B (which contained
adjuviints) were 4.77, 0.48, 0.2 and 0.13 mg/t, respectively. The 48 and
96-hOiir L€j. values for Product A were 15 and 10 mg/i, respectively, for
the molltisk, Lymnaea staqnalls (Bluzat et al., 1982b). Product B was more
toxic with 48 and 96-hour LC5Q values of 4 and 3 mg dUhlocarb/i,
respectively.
0079d -9- 01/22/88
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4.2 CHRONIC EFFECTS
A 21-day life-table and growth experiment was conducted In which water
flees, Daphnla magna. were exposed to dlthlocarb that was renewed 3 times/
week (Van Leeuwen et al., 1985b). The LC5Qt which reflects reduced
survival and fecundity, was determined to be 30 jjg/l. The lowest
concentrations at which mean survival and carapace length were significantly
reduced were 24 and 14 jig/i, respectively.
4.3. PLANT EFFECTS
\ 96-hour EC50 of 1.4 mg dlthlocarb/t was determined for unicellular
green algae, Chlorella pyrenoldosa (Van Leeuwen et al., 1985a). This
concentration reduced average specific growth rate by 50%.
['Hhlocarb at 17.1 mg/i for periods of 3, 5 or 6 days had little
effect on the growth and flower production of the duckweed, Lemna qlbba
(Oota, 1971). During 3- and 5-day exposure experiments, the yield of
reproductive fronds was decreased compared with controls. This effect was
due to dHhlocarb chelatlon and removal of ferrous Ions (which take part In
the piotophlly rhythms) from the plant.
4.4. OTHER RELEVANT INFORMATION
1.22 mg d1th1ocarb/t was determined for
bacteria, Photobacterlum phosphoreum (Van Leeuwen et al.. 1985a). This
concentration reduced the luminescence of the bacteria by SOX.
The MIC for nitrification In a 3-hour assay with nitrifying bacteria,
N1tro;o«oaav and NUrobacter. was determined to be 43 mg d1th1ocarb/l (Van
A !5-m1nute EC5Q of
Leeuwcn t$ *!., 1985a).
The enbryotoxlc effects and teratogenlcUy of dlthlocarb have been
studied In embryos of the frog, Mlcrohvla ornata (Ghate and Hulherkar,
1980). Based on mortality during the 72 hours subsequent to exposure, a
24-hoir LCeQ value of 3.0 mg/i was reported. At concentrations between
0079d
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1 7 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 toxlclty of dUhlocarb has been evaluated In fish and
crustaceans. A 96-hour LC5Q of 6.9 mg/i was determined for gupples (Van
Leeuten et al., 1985a), and 1-hour exposure to 15 mg/i produced 67%
lethality 1n goldfish (Oota, 1971). A 48-hour LC5Q was determined for
Daphnla (Van Leeuwen et al., 1985b). A 24-hour LC,Q of 3 mg/l was
deter nlned for frog embryos, and malformations were observed at concentra-
tions as low as 0.5 mg/l (Ghate and Mulherkar, 1980). Chronic toxlclty
data for -fish or other vertebrates were not located, but a 21 -day LC— of
30 yCj/t-Ligs determined for Daphnla (Van Leeuwen et al., 1985b). Studies
with aquatic plants have determined a 96-hour EC5Q of 1.4 mg/i for
unlce lular green algae (Van Leeuwen et al., 1985a), and that the yield of
reprocuctlve fronds In duckweed was decreased by exposure to 17.1 mg/i for
3 day; (Oota, 1971).
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5. PHARHACOKINETICS
5.1. ABSORPTION
:raven et al. (1976) studied the fate of 39S-d1th1ocarb In male HHtar
rats (250 g). The compound was dissolved 1n 2 M phosphate buffer and admln-
1ste-ed as a single dose of 25 mg/kg. The half-life for disappearance of
radioactivity from the lumen of the small Intestine, after direct Injection
Into the small Intestine, was 2.6 minutes. The half-life for disappearance
of radioactivity from the stomach following gavage was 39 minutes. The
methods by which these half-lives were determined were not described. By 15
minutes after gavage administration, radioactivity was detected In the
plasna at a level equivalent to 11.3 wg/i (expressed as dlthlocarb), and
was identified as approximately equal amounts of unchanged dlthlocarb and
dlthlocarb-S-glucuronlde, plus a small amount of Inorganic sulfate.
Excretion data (60X of the dose of «S excreted within 3 hours and 96X
wlthli 72 hours, primarily In urine and expired air) Indicate virtually
complete absorption of the compound (or Us metabolites and decomposition
products) from the gastrointestinal tract.
B.iselt and Hanson (1982) studied plasma concentrations of dlthlocarb In
female Fischer rats (180 g) given a single dose of 500 mg/kg of dlthlocarb
1n wa ;er by gavage. During the 6 hours following dosing, plasma dlthlocarb
level! 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 hlth th* expected low rate of absorption of an Ionized sodium salt.
5.2. DISTRIBUTION
Fifteen minutes after IntrapeMtoneal Injection of 25 mg "S-d1th1o-
carb/nt of (222 timol S/rat) Into 240-300 g male Wlstar rats, 70-90X of
the radioactivity 1n liver was In the soluble fraction (Stromme, 1965).
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Most of the radioactivity found In plasma (1606 nmol S/iwt) and 1n the
liver soluble fraction (3263 ymol S/g) was present 1n the form of free
parent compound and metabolites. A small but significant amount, ~2%t was
rev?rs1bly bound to protein, apparently by formation of dlsulflde bonds.
5.3. METABOLISM
Merlevede and Casler (1961) reported that following oral administration
of 50, 100, 250 or 500 mg of dHhlocarb to human subjects, 28, 34, 62 or
82% respectively, of the dose (on a mole basis) was expired as carbon
dlsilflde within 7 hours, at which time expiration of carbon dlsulflde was
complete. The fate of the remainder of the dose was not determined.
Assimlng 70 kg body weights, 50-500 mg corresponds to 0.7-7.1 mg/kg.
Whether the observed dose-dependent expiration of carbon dlsulflde reflects
dose-dependent metabolism/decomposition of dHhlocarb or dose-dependent
disposition of carbon dlsulflde cannot be determined from the data In this
studf.
After gavage administration of "S-dlthlocarbamate to male 250 g
Ulst.ir rats at 25 mg/kg, Craven et al. (1976) found that plasma radlo-
actli'Hy at 15 minutes was In the form of unchanged compound and dlthlocarb-
S-glicuron1de In roughly equal amounts, plus a small quantity of Inorganic
sulfete. Slightly more than 50% of the radioactivity appeared as carbon
dlsulflde In the expired air by 72 hours.
Following IntraperUoneal Injection of "S-d1th1ocarb Into male
240-300 g Ulstar rats at 25 mg/rat, 96% of the radlolabel excreted 1n the
urine atjt hour was present as dlthlocarb-S-glucuronlde and 4% was present
as Inorganic sulfate (Stromme, 1965). At 4 hours, 76 and 24% of the radio-
label excreted In the urine was present as dlthlocarb-S-glucuronlde and
1norg.m1c sulfate, respectively. Less than 1% of the urinary radioactivity
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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 in the
exp1"ed air at 1 hour, Increasing to 10% at 4 hours. No significant amounts
of mjtal chelates of dlthlocarb were detected In plasma, liver or urine.
itromme (1965) suggested that the differences 1n the percentage of
dlth ocarb excreted as carbon dlsulflde In the expired air In oral studies
compared with Intraperltoneal studies may be due to the decomposition of
dlth'ocarb 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
"gast-o-protected" pill for oral administration of dlthlocarb to cancer
patleits (Section 6.1.3.). Nevertheless, significant levels of unchanged
dlthl jcarb were detected 1n the plasma of rats following oral administration
of dl :h1ocarb (Craven et al., 1976; Baselt and Hanson. 1982), as noted above.
An additional metabolite, methyl dlethyldlthlocarbamate, was Identified
by Cobby et al. (1978) during Intravenous Infusion of dlthlocarb In average
doses of 27.5 mg dlthlocarb an Ion/kg Into anesthetized 20-31 kg male dogs.
The e>per1mental procedure Involved Infusion at rates of 2.75 or 5.50 mg/mln
to steady-state, followed by monitoring of venous blood during steady-state
and after cessation of Infusion. Approximately 27% of the dose was
S-methylated to form methyl dlethyldlthlocarbamate, with a first-order rate
constait-afcfl.0569 mln'1 (t,/2«12.2 mln). The remainder of the dose was
eliminated by other routes having a rate constant of 0.148 mln"1
(t,/2="i.68 mln), and the methyl dlethyldlthlocarbamate formed from dlthlo-
carb h«.d an elimination rate constant of 0.0141 mln*1 (t. ._«49.2 mln).
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S.4. EXCRETION
As described 1n Section 5.3., the excretion of carbon dlsulMde 1n
exp red air following oral administration of dUhlocarb 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-
cart, respectively (Merlevede and easier, 1961). Expiration of carbon
dlsulflde began rapidly, reached a maximum within 30 minutes and was
complete within 7 hours of administration.
\fter gavage administration of 25 mg/kg of "S-dlthlocarb to male
250 ] Mlstar rats, 60X of the dose was excreted 1n 3 hours and 96X of the
dose was excreted by 72 hours after dosing (Craven et al., 1976). Slightly
>50% of the administered radioactivity was excreted 1n 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 Intraperltoneal Injection of 25 mg of "S-dlthlocarb Into
male 240-300 g Wlstar rats, 7% of the radioactivity was expired as carbon
dlsulflde within 1 hour and 10% within 4 hours (Stromme, 1965). Urinary
excretion of radlolabel amounted to 21X of the dose In 1 hour and 43X 1n 4
hours. Longer time periods were not studied.
5.5. SUMMARY AND CONCLUSIONS
L mUed pharmacoklnetlc data are available for oral and parenteral
admin'stratlon of dUhlocarb; no data are available for Inhalation exposure
to this compound. Although dUhlocarb Is thought to decompose to carbon
dlsuMde tir the acidic environment of the stomach (Stromme, 1965; Evans et
al., 1979), unchanged dUhlocarb and dUhlocarb-S-glucuronlde are detectlble
In the plasma within 15 minutes of oral administration of dUhlocarb to rats
(Craven et al., 1976). The concentration of dUhlocarb 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 Ihe compound are absorbed without decomposition. A large percentage of
the orally administered dose, -28-80X, however, Is excreted by humans and
rats as carbon dlsulflde In the expired air (Merlevede and Casler, 1961;
Craven et al.f 1976). The remainder, at least In rats, Is excreted as
metabolites (primarily d1th1o-S-glucuron1de and Inorganic sulfate) In the
urlno with only minor amounts 1n the feces (Craven et al., 1976). The
excretion data Indicate virtually complete absorption of dlthlocarb and
metatolltes or decomposition products from the gastrointestinal tract.
Follcwlng Intraperltoneal administration to rats, 10X 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 netabollsm 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 Intraperltoneal Injection of "S-dlthlocarb Into rats
1s hi jher than In plasma and that some of the dlthlocarb or metabolites In
plasm and 1n the liver soluble fraction are reverslbly bound to protein
sulfhjdryl groups (Stromme, 1965).
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6. EFFECTS
6.1 SYSTEMIC TOXICITY
6.1 1. Inhalation Exposures. Pertinent data regarding the systemic
tox'cHy of subchronlc or chronic Inhalation exposure to dlthlocarb were not
located In the available literature cited 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 toxlclty of sub-
chroilc oral exposure. Groups of five male and five female F344 rats were
fed ), 1250, 2500, 5000, 10,000, 20,000 or 40,000 ppm dlthlocarb 1n the diet
for ? weeks, followed by 1 week of observation. Dose-related depression of
mean body weights occurred In the treated groups compared with controls; the
magnitude of this depression reached 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-
pathcloglcal changes occurred was 1000 ppm In both male and female rats.
Because 1000 ppm 1s below the lowest level tested 1n rats, 1250 ppm, U
seems likely that the NCI meant 10,000 ppm. A slight Increase 1n splenic
hemat>po1es1s and slight vacuolatlon of renal tubular epithelium were seen
at tMs exposure level. The occurrence or severity of hlstopathologlcal
effee ,s at higher exposure levels was not discussed.
A so In the subchronlc portion of the NCI (1979) study, groups of five
male nice wtre fed 2500. 5000, 6000, 8000 or 10,000 ppm of dlthlocarb In the
d1et i;o*^4-ij*i«ks and groups of five female mice were fed 0, 250, 500, 1000,
2500, 5000 or 10,000 ppm of dlthlocarb 1n the diet for 12 weeks, followed by
1 weed of observation for both sexes. Body weights were not clearly related
0079d -17- 12/28/87
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to Jose \n the males and were slightly depressed In the females; the depres-
sloi amounted to >10% only at the highest exposure level In the females. No
treatment-related hlstopathologlcal lesions were seen at 10,000 ppm in the
m1c100 mg/kg. Food consumption was not reported. No
over: signs of toxldty were seen. At 300 mg/kg, both sexes of rats had
sign flcantly decreased mean red blood cell counts and females had deceased
mean hemoglobin levels and hematocrH values. In addition, hlstopathologl-
cal rhanges and decreased weights were observed In the kidneys of the 300
mg/kc 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
exposjre 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 In a dose-related manner,
posslMy.-tS-a reflection of the chelatlng activity of dlthlocarb. Other
effeels were seen only at the highest dosage, 300 mg/kg. Slight losses of
body uelght occurred In the dogs at this dose level and one female died at
day 7d. Values for hematocrU, hemoglobin level and red blood cell counts
showed a downward trend In the 300 mg/kg group during the 90-day period.
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Erylhrold hyperplasla was seen In the bone marrow of the one female that
diet. 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).
Carlton (1966) fed dlthlocarb to groups of 10 male weanling Charles
Rive* mice In 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.
iasul and Howe11 (1973a) studied the effects of dlthlocarb on the
central and peripheral nervous system of rabbits. Ten Dutch male rabbits
were administered 330 mg/kg/day of dlthlocarb 1n phosphate buffer by gavage
on 5 days/week for 4, 6 or 9 weeks, after which time they were killed and
exam'ned. An additional 10 rabbits served as vehicle controls. After 9
week;, average body weights had Increased by 150 g In controls and had
decreased by 50 g 1n treated rabbits. No overt signs of neurotoxlclty were
seen. Hlstologlcal examination, however, revealed lesions of Uallerlan
degeneration and eoslnoplllc bodies 1n the medulla and spinal cord becoming
progressively worse with longer exposures. In rabbits given dlthlocarb for
9 wejks, significantly fewer large-diameter nerve fibers were seen when
compare
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50 nale 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
the r body weight/day as food (U.S. EPA, 1980), the dosages would be 62.5 or
125 mg/kg/day (chronic LOAEL). The controls consisted of 16 male and 20
femele rats. Survival In treated groups did not differ from that In
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
sign; 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
fema'es. 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 In 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 13X 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 .ind 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 ,exes at either dietary level of dlthlocarb were lower than those of
the ctrresponding controls and were dose-related throughout the study. Food
consumption data were not provided 1n the report. The hlstopathologlc
examinations Included nonneoplastlc lesions, but no such lesions were dis-
cussed under results; hence, It may be Inferred that there were no notable
nonneoplastlc findings.
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6.1.3. Other Relevant Information. LD5Q values for various species and
rout?s of exposure have been compiled by NIOSH (1987). Oral LD5Q values
for both the rat and mouse are 1500 mg/kg; the Intraperltoneal LD5Q 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).
lilthlocarb 1s a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sundirman, 1979).
tlthlocarb, a metal chelatlng agent, has been used therapeutlcally In
cases of nickel carbonyl poisoning (Sunderman, 1979, 1981) nickel dermatitis
(Sunderman, 1981} and thallium poisoning (Sunderman, 1967; Kamerbeek et al.,
1971). Oral dlthlocarb treatment was reported to result In Increased
urinary excretion of the metal and alleviation of toxic effects. Dlthlocarb
has clso 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.t 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 1n
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 ai., 1970; Jaslm and Tjaelve, 1984a,b, 1986; Jaslm et al., 1985;
KamerbMl£=»t al., 1971; Klaassen et al.. 1984; Qskarsson. 1984; Szerdahelyl
and Kasa. 1987}. Entry of the metal Into the brain and fetus 1s thought by
these Investigators to be facilitated by the formation of llpophlllc
metal-dlthlocarb chelates.
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Several studies have Investigated the neurotoxlc effects of parenteral
administration of dlthlocarb. Dally Intraperltoneal administration of
dHhlocarb (dose not specified) to seven rabbits for up to 7.5 months
produced signs of Incoordlnatlon, swollen axons and ballooning of myelln
shetths (characteristic of early Mallerlan degeneration) In the white matter
of the spinal cord and In the sciatic nerve, and some early degenerative
charges 1n the gray matter of the spinal cord (Edlngton and Howell, 1966).
These lesions did not occur In 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 IntraperUoneal Injections of dlthlocarb 1n phosphate
buff ;r at doses of 165 or 330 mg/kg (5 days/week for up to 16 weeks) and all
but one died (Howell et al., 1970). Four 2-day-old lambs were used as
vehicle controls. At necropsy, treated lambs were found to have local
perVonltls, eoslnophlUc round or avoid lesions of the medulla, Clarke's
colunn and the spinal cord, and swollen axons In 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 In the medulla and
spinal cord) (Rasul and Howell, 1973b, 1974a,b; Fisher and Netcalf. 1983).
Rats treated orally with dlthlocarb at doses of 240 mg/kg had decreases
In o-lentatlon hypermotmty and subcortlcal EEG activity. Increases In
dopamlne and decreases In noradrenalln and adrenalin formation; the same
effects w«« seen with oral administration of an equlmolar dose of carbon
d1sul:1de (Thuranszky et al.. 1982). The authors concluded that formation
of c
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mice (Doggett and Spencer, 1973) or 1ntraper1toneal Injection Into rats and
mice (MaJ and Vetulanl, 1970) elevated brain dopamlne levels and decreased
brali noradrenallne levels and locomotor activity.
Subcutaneous Injection of dHhlocarb at 400 mg/kg reduced the noradren-
alln and Increased the dopamlne content of the lleum of rats and rabbits
(Col Ins and West, 1968). The above results and other In vitro and \j\ vivo
data Indicate that dHhlocarb Inhibits the conversion of dopamlne to
noracrenalln by dopamlne-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
amlnoyMne 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
ethylriorphlne N-demethylase (Zemaltls and Greene, 1979). Dietary admlnls-
trathn of dlthlocarb at 5000 ppm for 14 days Increased the activities of
DT-dUphorase (a detoxifying enzyme for qulnones and qulnonelmlnes) and
glutathlone transferase In several tissues (Benson et al., 1986; Benson and
Barretto, 1985).
Inhibition of the oxldatlve metabolism of !,2-d1methylhydraz1ne and
cardnigenlc effects of !,2-d1methylhydraz1ne on the colon were reported In
mice treated orally with dlthlocarb; because carbon dlsulflde also Inhibited
the o>1d*ilv* metabolism of 1,2-dlmethylhydrazlne. It was suggested that
carbon ttuHflde mediates this antlcardnogenlc effect of dlthlocarb
(Watterberg et al.. 1977). Sunderman et al. (1984) found that weekly 1ntra-
perltoreal treatment with dlthlocarb at 20 mg/rat for 6 weeks protected
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aga'nst 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
rag/kg of dlthlocarb decreased body weight gain and produced reductions 1n
mean systolic blood pressure at 7 weeks of treatment (Crossley et al.f 1969).
Numerous reports of Immune system stimulation or modulation by dlthlo-
carb have been published, Including the following representative studies:
Renoix and Renoux (1979), Renoux et al. (1986) and Bruley-Rosset et al.
(198ii). In these studies, Intraperltoneal or subcutaneous Injection of
dlth ocarb Into mice enhanced the activity of T cells, activated macrophage
digestive enzyme activity, and had anti-Inflammatory activity against early
chances In Immune parameters Induced by nonantlgenlc acute Inflammation.
heveu et al. (1980, 1982), Neveu (1978) and Neveu and Perdoux (1986)
reported that dlthlocarb enhanced mltogen-lnduced lymphoprollferatlon and
modulated delayed hypersens1t1v1ty reactions In guinea pigs in vivo; how-
ever, because of cytotoxldty. Inhibited mltogen-lnduced lymphoprollferatlon
(measjred as thymldlne Incorporation Into DMA) In human or guinea pig
lymphocytes h^ vitro.
In preliminary clinical trials, administration of 2.5, S or 10 mg/kg of
dlthlocarb orally (as gastroprotected pills) once a week for 4 weeks to
chlldi en In remission from leukemia and other cancers restored delayed
hyper*enslilyUy reactions In a dose-related manner In comparison with
placeto-treated children (Renoux et al., 1983). lung cancer patients admin-
istered S mg/kg of dlthlocarb Intravenously had restoration of T cell
activity and Increases In T3 and T4 cells accompanied by decreases In the
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percentage of T8 (suppressor) cells compared with placebo-treated patients
(Reroux et al.t 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 Tl cells compared with pretreatment values (Lang et a!., 1985).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled dlthlocarb were not located In the available literature cited 1n
Appendix A.
6.2.;. Oral. The carclnogenlclty of dlthlocarb has been studied In
chrorlc feeding studies In mice (BRL, 1968a; NCI, 1979) and 1n rats (NCI.
1979).
BRL (1968a) evaluated the carclnogenlclty of dlthlocarb during a
large-scale screening study of 130 pesticides In 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 MTO, which was calculated using the
average body weight of mice at the start of the study and not corrected for
weigh1, gain] 1n water by gavage from days 7-28 of age, after which dlthlo-
carb was administered In the diet at a level of 692 ppm until the mice were
klllec 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
d 1th1ocarto-treated groups was hepatoma In the B6C3F1 males (Table 6-1). The
Incidence- o* 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 dHhlocarb-treated mice were
not specifically described, the BRL (1968a) report stated that all
0079d -25- 03/04/88
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TABLE 6-1
Incidence of Hepatomas In B6C3F1 Mice
Following Oral Administration of D1th1ocarba
Sex
M
F
Dose
(ppra)
0
69 2b
0
692b
Hepatoma Incidence
(p value)
8/79
7/17 (0. 00447 )c
0/87
0/18 (NS)C
QUALITY OF EVIDENCE
Streigths: 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.
Heakiesses: Small sizes of treated groups, less-than-llfetlme exposure,
unknown purity of test material, only one dosage level which
may have been less than the MTD.
aSouice: BRL, 1968a
bD1tli1ocarb (purity not specified) was administered to the mice at 215
mg/lg/day In distilled water by gavage on days 7-28 of age, and then at 692
ppm In the diet until 78 weeks of age, at which time the mice were killed
and examined.
cNot significant by Fisher Exact Test.
NS » Not significant
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hep.itlc tumors In this screening study were termed hepatomas except those In
m1ci> with unmistakable pulmonary metastases, in which case the hepatic
tumors were classified as hepatic carcinomas. In general, the hepatic
turners In the study were locally Invasive, often with massive Involvement of
the Hver, In a preliminary report of the data from the BRL (1968a) study,
Innes et al. (1969) categorized the results with dlthlocarb as Indicative of
a need for further study.
The cardnogenlclty of dlthlocarb has been tested further by the NCI
(1973) 1n F344 rats and B6C3F1 mice of both sexes. Dlthlocarb (95% purity
by H3LC) 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
cons sted of 16 male rats, 20 female rats, and 20 male and 20 female mice.
No statistically significant Increases In tumor Incidences of any type,
Inclidlng hepatic tumors, were seen 1n treated mice or rats compared with
controls. Data regarding other endpolnts from this study were discussed In
Section 6.1. This MCI study does not confirm the BRL (1968a) results over
the
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0079d
03/04/88
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Salnonella typhlmuriurn 1n the presence or absence of a metabolic activating
system have been negative (De Flora, 1981; De Flora et al., 1984; Mortelmans
et il., 1986). DUhlocarb also gave negative results In an assay for DNA
damage 1n Escherlchla coll (Rosenkranz and Lelfer, 1980; De Flora et al.,
1984). Harman et al. (1970) reported that 1% dHhlocarb In the diet of LAF1
male mice did not Increase the Incidence of chromosome aberrations In
CCl4-1nduced regenerating liver. However, since the "control" Incidence was
reported to be 72.8X, this cannot be considered an acceptable study.
Dlthiocarb gave positive results 1n an assay for the production of chromo-
some breaks and chromatld exchanges In V1c1a faba root tips (Klhlman, 1957).
6.4. TERAT06ENICITY
Ihe only available study of dlthlocarb teratogenlclty (BRL, 1968b) was
condicted by parenteral administration rather than by a natural route of
exposure. In this study, pregnant 8L6 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 DHSO (six Utters) or saline (two groups: six
Utte-s and eight litters). Fetal mortality and the percent of abnormal
fetus<;s were statistically significantly elevated 1n the dHhlocarb-DMSO
group and In one, but not the other, dUhlocarb-sallne group, compared with
concurrent solvent control groups. Fetal weight and crown-rump length were
decreesed 1n the dHhlocarb-OMSO group relative to the appropriate controls.
Testlrg of C3H mice In the same manner with 464 mg/kg/day of dlthlocarb In
DNSO resulted In 95% mortality 1n the two Utters studied. AKR mice, which
have a tligllUy 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 dUhlocarb at 0.5% (5000 ppm) In the diet to six
precnant Charles River mice starting on day 3 of gestation through sponta-
neous delivery. (The diet consisted of chicken mash supplemented with
Tare). Controls consisted of eight pregnant mice fed the same diet. In
dlthlocarb-treated mice, there were no effects on relative number of mice
delivering young but there were a slightly greater number of young/Utter
and af live young/litter than controls.
In a study on reproductive effects and transplacental Immune system
effe:ts, female C3H/HeJ mice were treated with subcutaneous Injections of 0
or 2i mg/kg of purified dHhlocarb In saline buffer twice a week for 3 weeks
bef01e mating (with hlstocompatlble or Msto1ncompat1ble males) or thoughout
gestitlon until delivery (Renoux et al., 1985). With the exception of an
Increase In the number of offspring/Utter In dams treated with dUhlocarb
before or before and after hlstolncompatlble 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 d thlocarb-treated dams had Increased numbers of spleen T-cells that
demonitrated Increased responsiveness In assays for mltogen-lnduced
proliferation.
Pregnant rabbits given Intravenous Injections of 0.5 or 1.0 g of dUhlo-
carb In 5 or 10 mi of water, respectively, on 5 days/week from days 1-20
of ge;tatIon failed to deliver litters; In most cases evidence of abortion
was fnind (Howell, 1964). Control rabbits, treated similarly with saline
equal 1n molarlty to the dUhlocarb solution, all delivered litters.
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Pretreatment of pregnant rabbits with copper sulfate prevented the decrease
In 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
In nale dogs within 1 hour of an Intraperltoneal Injection of 50, 75 or 100
mg/l:g of dlthlocarb. Partial recovery occurred after 3 hours, with complete
recovery by 24 hours. This suppression was associated with decreased levels
of toradrenalln 1n the caudate nucleus, ep1d1dym1s, prostate and posterior
urethra, and was reversed by administration of noradrenalln.
Holzaepfel et al. (1959), 1n a survey of the spermlddal effectiveness
of !81 organic compounds, found that dlthlocarb and two related compounds
had the highest spermlddal activity of all the compounds tested. Rice
(1961) reported gross morphological alterations of the tails of human
spermatozoa upon treatment with dlthlocarb in vitro. The alterations
cons sted of the formation of bead-like crystals after a small amount of
dHh ocarb was dissolved In a drop of semen on a microscope slide.
BroUerton (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, Ut the available literature cited In Appendix A. A number of
studljmt systemic toxlclty and carclnogenlcHy have been conducted by the
oral ioute.
Subchronlc and chronic oral administration of dlthlocarb to rats, mice,
dogs and rabbits has shown that depression of body weight or body weight
gain is one of the more sensitive Indicators of toxlclty of this compound
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(NCI, 1979; Sunderraan et al., 1967; Rasul and Howell, 1973a,b), occurring In
sub(hron1c 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
subcironlc oral studies Include renal toxlclty In rats and hematologlcal
effe:ts (decreases 1n red cell counts, hematocrUs and hemoglobin levels) In
rats and dogs at 300 mg/kg/day (Sunderman et al., 1967) and nervous system
lesions In rabbits at 330 mg/kg/day (5 days/week) (Rasul and Howell, 1973a).
The JOEL for subchronlc oral exposure Is 30 mg/kg/day In rats (Sunderman et
al., 1967).
In chronic studies, rats had cataracts and body weight depression at the
lowest level tested, 1250 ppm of dlthlocarb 1n 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 In rats and mice In this study produced a
more pronounced depression of body weight 1n both species and cataracts
(Incidence not dose-related) In rats. Renal effects were not reported 1n
the chronic portion of the NCI (1979) study, although mild renal effects
were ;een In rats 1n the subchronlc portion of this study, apparently at a
dietary level of 10,000 ppm dlthlocarb. The NCI (1979) study did not
performhtpitologlcal tests, but a slight Increase In splenic hematopolesls
was nut*^ 1t» rats, apparently at 10,000 ppn In the diet, In the subchronlc
• - if -
portion of the study. The data do not define a NOAEL or NOEL for chronic
oral exposure (NCI, 1979).
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Acute toxlclty data Include oral LD5Q values of 1500 mg/kg In both
rat; and mice, Intraperltoneal L05_ values of 1250 mg/kg In rats and 1302
mg/cg \n mice, and a subcutaneous LD5Q of 500 mg/kg 1n rabbits (NIOSH,
198').
Dlthlocarb Is a metabolite of dlsulfuram (Antabuse) (Stromme, 1965;
Sumerman, 1979).
Because of Us metal chelatlng properties, dlthlocarb has been used
therapeutlcally 1n human cases of metal poisoning, most commonly nickel
carbonyl poisoning (Sunderman, 1979, 1981). Evidence from numerous studies,
however, Indicates that chelatlon therapy with dlthlocarb may, 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 llpophlllc. A single study reported a worsening of CNS signs following
Intravenous treatment of thallium-Intoxicated humans with dlthlocarb
(Kami-beek et al.. 1971).
repeated IntraperUoneal administration of dlthlocarb to rabbits and
lambs produced lesions of the nervous system In both species (Edlngton and
Howell, 1966; Howe11 et al., 1970). Oral administration of dlthlocarb to
chickens produced signs and lesions Indicative of delayed neurotoxlclty
(Rasul and Howe11, 1973b, 1974a,b; Fisher and Netcalf, 1983).
Dlthlocarb Inhibits the conversion of dopamlne to noradrenalln by
dopam ne-B-hydroxylase, resulting 1n Increased tissue levels of dopamlne and
decreased tissue levels of noradrenalln (Thuranszky et al., 1982; Collins
and UesWr 1968; Carlsson et al., 1966). Dlthlocarb Inhibits mlcrosomal
cytotfroM P-450 associated oxldatlve metabolism of xenoblotlcs (Siegers et
al., 982; ZemaHls and Greene, 1979; Uattenberg et al.r 1977) and stimu-
lates DT-dlaphorase and glutathlone transferase (Benson et al.. 1986; Benson
and Baretto, 1985).
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The protective effect of dlthlocarb against the carcinogenic effects of
1,2-d1nethy1hydraz1ne was attributed to Inhibition of the ox1dative metabo-
lism (activation) of 1,2-dlmethylhydrazlne (Wallenberg et al., 1977). The
protective effect of dlthlocarb against the carcinogenic effects of Intra-
muscjlarly Implanted nickel subsulflde was thought to be connected with
dlthlocarb's enhancement of hepatic levels of metalloth lone In (Sunderman et
al., 1984).
IHthlocarb has been reported to enhance the function of the Immune
system, primarily through effects on the T cells, both In animals (Renoux
and lienoux, 1979; Bruley-Rosset et al., 1986) and In humans (Renoux et al.,
1983; Lang et al., 1985).
Data regarding the carclnogenldty of dlthlocarb are available for the
oral route of administration, but not for Inhalation. Administration of
dithlacarb at 215 mg/kg/day by gavage on days 7-28 of age and then at 612
ppm In the diet until week 78 of age to male and female 86C3F1 and B6AKF1
mice -esulted In a statistically significantly Increased Incidence of tumors
only In the case of hepatomas In the 86C3F1 males (BRL, 1968a). Dietary
admin strati on of dlthlocarb at 1250 and 2500 ppm to male and female F344
rats < nd at 500 and 4000 ppm to B6C3F1 mice for -2 years did not produce any
statistically significant Increases In tumor Incidences (NCI, 1979).
Hutagenlclty testing of dlthlocarb has been effectively limited to bacteria
and negative results nave been reported (OeFlora et al., 1984; Hortelmans et
al., 1984^ Bosenkranz and Lelfer, 1980).
Thtfs^isr little evidence that dlthlocarb Is genotoxlc. Studies of
revers> nutation In Salmonella typhlmurlum (De Flora, 1981; De Flora et al.,
1984; Hortelmans et al., 1986), DNA damage In 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
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dlthlocarb. Positive results were obtained for dUhlocarb In a chromosomal
damage assay In Vic la faba root tips (Klhlman, 1957).
Dlthlocarb has not been tested adequately for teratogenlclty. The only
stujy available used subcutaneous Injection rather than a natural route of
administration. In this study (BRL, 1968b). equivocal evidence of feto-
toxicUy was seen following subcutaneous Injection of 215 mg/kg/day of
dlthlocarb Into pregnant mice.
The data base for the reproductive effects of dlthlocarb Is also
1nacequate. The feeding of dlthlocarb at 5000 pprn In a chicken mash/lard
diet to pregnant mice from day 3 of gestation through delivery had no
adverse effects on number of dams delivering young or number of young/Utter
(Carlton, 1966). Subcutaneous Injection of 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 dUhlocarb to pregnant rabbits resulted 1n loss of
the litters (Howell. 1964). Dlthlocarb Is spermlcldal In vitro (Holzaepfel
et a I., 1959) and suppresses ejaculation 1n dogs following acute IntrapeM-
toneel Injection (Sakal et al., 1979; Klmura et al., 1980a,b).
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The U.S. EPA (1985a) has verified an oral RfD of 0.03 mg/kg/day for
dlthlocarb based on the rat subchronlc oral study by Sunderman et al. (1967).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of dlthlocarb were not located 1n the available literature cited
In Appendix A.
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.t. Inhalation. Pertinent data regarding the cardnogenldty of
Inhalation exposure to dHhlocarb were not located In the available litera-
ture cited In Appendix A.
8.1.,?. Oral. Administration of dHhlocarb to male and female B6C3F1 and
86AKI 1 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 In Table 6-1.
Administration of dHhlocarb to male and female B6C3F1 mice at 500 or 4000
ppm n the diet for 108 or 109 weeks and to male and female F344 rats at
1250 or 2500 ppm 1n the diet for 104 weeks produced no statistically
significant Increases In tumor Incidences (NCI, 1979).
8.1.3. Other Routes. A single subcutaneous Injection of 464 mg/kg of
d1th1 >carb on the 28th day of age did not result In Increased Incidences of
tumor; In male and female B6C3F1 or B6AKF1 mice after -18 months {BRL,
1968a .
8.1.4 Weight of Evidence. No data are available for the assessment of
cardrogenlclty of dHhlocarb to humans. IARC (1976, 1982) concluded that
the available animal data were not sufficient to assess the carclnogenlclty
of dl :h1ocarb. The data regarding cardnogenldty to animals are limited,
I.e., an Increased Incidence of hepatomas In one sex of one strain of mice
In a »1ftf)* study, which employed only one dosing level. The appropriate
EPA (l.S. EPA, 1986b) classification for dlthlocarb Is Group C - possible
human :ardnogen.
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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 1s not reconmended.
8.1.5.2. ORAL — A q * can be estimated from the dose-response data
for the Induction of hepatomas In male B6C3F1 mice (BRL, 1968a); these are
the only positive carclnogenlclty 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),
dletiry exposure to 692 ppm of dlthlocarb corresponds to a dosage of 90.0
rog/kj/day, and the TWA dosage for the entire experiment Is 94.9 mg/kg/day.
Uslmj this dosage, the hepatoma Incidence 1n the B6C3F1 male mice, and the
computerized multistage model developed by Howe and Crump (1982), the
unad;usted (animal) q^ Is calculated to be 8.825x10'* (mg/kg/day)'1
(Appendix B). The human q^, calculated by multiplying the unadjusted
q.|* :or 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"* (mg/kg/day)~l. This QI* differs slightly from
the (^ estimated previously (U.S. EPA, 1983) because this estimate used
the .iverage body weight of the mice over the entire treatment period
(0.03' g), whereas the previous estimate used the body weight of the mice
during th» last 26 weeks of the experiment (0.043 g). Using the human q.,*
of 2.69XTCT1 (mg/kg/day)'1 and assuming that a 70 kg human consumes 2
l/day of water, the concentrations of dlthlocarb In drinking water
associated with Increased lifetime risk of cancer at risk levels of 10"*,
10~* and 10"' are 1.3xlO~», 1.3x10"* and 1.3xlO~s mg/i, respectively.
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8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. No Inhalation toxlclty data were available
froir which to calculate a subchronlc or chronic Inhalation RfO.
8.2.2. Oral Exposure.
3.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — The most
adeqjate subchronlc study of the toxldty of dlthlocarb Is 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/kij/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/kti/day (LOAEL), and hematologlcal effects (decreased red cell counts,
hemoglobin levels and hematocrlt values) and mild hlstopathologlcal effects
In tlie 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 toxlclty of dlthlocarb, but are not adequate to
serve as the basts of a subchronlc RfD because of Inadequacies In the
repor:1ng 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
cheflilial 1t^administered In a nonstandard diet (CarIton, 1966; chicken-mash
and Urdfr41«t). These studies provide some support for the NOEL of 30
mg/kg/day and the LOAEL of 100 mg/kg/day determined from the rat data of
Sunderman et al. (1967). Significant body weight depression was seen In the
NCI (979) 7-week study 1n rats at >2500 ppm In the diet (250 mg/kg/day,
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assuming a young rat consumes the equivalent of 10% of its body weight dally
as food) and slight renal toxic effects and slight Increase 1n splenic
hematopolesls were apparently observed at 10,000 ppm (1000 mg/kg/day). The
no-»ffect 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
(19'9)]. Mice were less sensitive to dlthlocarb, with no effects other than
bod/ 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
mi a fed 1000 or 5000 ppm dlthlocarb In a chicken mash/lard diet. Rasul and
Howell (1973a) reported central and peripheral nervous system lesions In
rabbits gavaged with 330 mg/kg/day of dlthlocarb 5 days/week (equivalent to
235.7 mg/kg/day, 7 days/week).
Dividing the NOEL of 30 mg/kg/day [from the rat data of Sunderman et al.
(196H] by an uncertainty factor of 100 (10 for Interspecles extrapolation
and 10 to protect the most sensitive Individuals) yields a subchronlc oral
RfO :or dlthlocarb of 0.3 mg/kg/day or 21 mg/day for a 70 kg human. Confi-
dence In the RfD Is high because the study was well-conducted and supporting
data are available.
£.2.2.2. CHRONIC EXPOSURES — The only chronic study available Is the
~2-year feeding study In 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 ng/jtfl/4ay) for 108 or 109 weeks. Dosages were calculated from dietary
level:; by assuming that rats and mice consume the equivalent of 5 and 13X,
respeitlvely, of their body weight dally as food (U.S. EPA, 1980). Control
0079d -40- 01/22/88
-------
-------
groips consisted of 16 or 20 an1mals/sex/spec1es. Female rats had depres-
slor of body weight gain (dose-related) and cataracts at both dose levels;
male rats had depression of body weight gain at the higher dose level. Mice
had dose-related depression of body weight at both dose levels. No other
gross or hlstopathologlcal effects were seen In either species. Hence,
thes? data do not provide a NOEL or NOAEL for chronic exposure, but do
defile a chronic LOAEL of 62.5 mg/kg/day for reduced body weight and
cata-acts In female rats.
Using this LOAEL and the subchronlc NOEL of 30 mg/kg/day determined for
rats In the study by Sunderman et al. (1967), the U.S. EPA (1983, 1985a) has
calcilated and verified a chronic oral RfO for dlthlocarb. The NOEL 1s
dlvUed by an uncertainty factor of 1000 (10 for Interspedes extrapolation,
10 t> protect the most sensitive Individuals and 10 to extrapolate from
subchronlc to chronic exposure), resulting 1n a chronic oral RfD of 0.03
mg/kg/day or 2 mg/day for a 70 kg human. Confidence In this RfD Is medium
because, although confidence 1n the Sunderman et al. (1967) study 1s high,
confluence In the data base 1s medium [support for the chronic effects Is
lacking and hematologlcal endpolnts were not examined In the NCI (1979)
study (U.S. EPA, 1985a). There are no new data that would require a
reeva uatlon of this RfD.
0079d -41- 12/28/87
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-------
9. REPORTABLE QUANTITIES
9.1 BASED ON SYSTEMIC TOXICITY
The toxUHy of dlthlocarb was discussed In Chapter 6. Pertinent dose-
effect data are summarized In Table 9-1. The lexicological significance of
the body weight depression seen In several of the studies Is uncertain
because food consumption data were not reported.
Data from subchronlc studies [NCI (1979) 7- to 12-week range-finding
studf; Sunderman et al. (1967) 90-day study; Rasul and Howe11 (1973a) 9-week
studf) 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
becaise the chronic studies are adequate to serve as a basis for the RQ, the
subchronlc studies will not be considered further In the RQ derivation.
The derivation of CSs and RQs 1s summarized In Table 9-2. The most
severs effect seen In the chronic NCI (1979) studies was the formation of
catancts In female rats administered 1250 ppnt 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 NED of 644 ing/day, which corresponds to an RVd of
1.3. Cataracts represent a change that results 1n a marked sensory deficit
and a-e accordingly ranked with an RV of 8. The product of the RV. and
RV Is a CS of 10.4, which corresponds to an RQ of 1000.
The only other effect seen 1n the chronic studies was a slight decrease
In body titlght In both rats and mice (NCI, 1979). Because food consumption
data were not provided. It Is not possible to determine whether the decrease
In body weight was due to toxldty of the chemical or to reduced food
Intake In considering the systemic toxldty data base as a whole, however,
0079d
-42-
12/28/87
-------
-------
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0079d
44
01/22/88
-------
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TABLE 9-2
Oral Composite Scores for DUhlocarb*
Species
Rat
House
Animal Dose
(mg/kg/day)
62.5
65
Chronic
Human NED RVd
(mg/day)
644 1.3
364 1.7
Effect RVe
Cataracts 8
Decrease In 4
body weight
relative to
controls
CS RQ
10.4 1000
6.6 1000
•Source: NCI, 1979
0079d
-45-
12/28/87
-------
-------
bod] weight depression appears to be a sensitive Indicator of dlthlocarb
toxldty. The RVg for body wleght depression Is 4. In rats, since the
bod) weight depression occurred at the same dose level as did cataracts, a
more severe effect, there Is no need to calculate a CS for the less severe
effect 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
rog/kj/day Is 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
a d e
of 6 8, corresponding to an RQ of 1000.
'he 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 Is the same approach and RQ value as recommended In U.S. EPA (1985b).
The (S differs slightly from that derived previously because reference rat
body weights were used In the previous derivation, whereas measured rat body
weights are used In the present derivation. In addition, cataract formation
was ranked with an RV& of 7 In the previous assessment, but was Judged to
repreient a more serious sensory deficit, ranked as an RV of 8. In the
present assessment.
9.2. BASED ON CARCINOGENICITY
DUhlocarb produced a statistically significant Increased Incidence of
hepatcmas 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). (BRt. 1968a). Female B6C3F1 mice and male and female B6AKF1 mice
given ttuj^, tim treatment did not have Increased Incidences of any type of
tumor. Negative results for carc1nogen1c1ty were also reported by the NCI
(1979) In male and female B6C3F1 mice fed 500 or 4000 ppm of dUMocarb In
the diet for 108 or 109 weeks and 1n F344 rats of both sexes fed 1250 or
0079d -46- 12/28/87
-------
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TABLE 9-3
Dlthlocarb
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Rout;: oral
Dose": 644 mg/day
Effect: cataracts
Reference: NCI, 1979
RVd: 1.3
RVe: 8
CS: 10.4
RQ: 1000
'Equivalent human dose
0079d -47- 12/28/87
-------
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250C ppifl of dHhlocarb 1n the diet for 104 weeks. A single Intraperltoneal
Injection of 474 mg/kg Into male and female B6C3F1 and B6AKF1 ralce produced
no evidence of carclnogenldty after 18 months (BRL, 1968a). Details of
thess studies are presented In Section 6.2.2. and In Table 6-1.
•vldence for the carclnogenldty of dHhlocarb to animals Is limited and
no dita are available for humans. Olthlocarb is therefore classified In EPA
Group C (see Section 8.1.4.).
Derivation of the F factor from the dose-response data for hepat'oma 1n
B6C3I1 male mice {BRL, 1968a) 1s summarized In Table 9-4. These are the
only positive carclnogenldty data available. Assuming that mice consume
the equivalent of 13% of their body weight dally In food (U.S. EPA. 1980),
the
-------
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TABLE 9-4
Derivation of Potency Factor (F) for DUMocarb
Reference:
Exposure route:
Species:
Strain:
Vehlrle or physical state:
Body weight:
Dura Ion of treatment:
DuraiIon 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 ppra In diet for 74 weeks
0 94.9
8/79 7/17
4.28916xlO~2 (nig/kg/day)'1
1.2918 (mg/kg/day)-*
00790
-49-
12/28/87
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JasVn, S. and H. Tjaelve. 1984b. Effect of sodium dlethyldUhlocarbamate
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Jasln, S. and H. Tjaelve. 1986. Mobilization of nickel by potassium ethyl-
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105:C73997b)
Jaslm, S., 8.R. Danlelsson, H. Tjaelve and L. Oencker. 1985. Distribution
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d1th1?carbamate treatment. Acta Pharmacol. Toxlcol. 57: 262-270.
KaneDeek, H.H., A.6. Rauws, N. ten Ham, A.N.P. van Heljst. 1971. Dangerous
red1s:r1bf$*«ft of thallium by treatment with sodium dlethyldlthlocarbamate.
Acta lied. Scand. 189: 149-154.
0079d -56- 12/28/87
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Kaufman, D.O. 1967. Degradation of carbamate herbicides In soil. J.
AgMc. Food Chem. 15: 582-591.
Klhlman, B.A. 1957. Experimentally Induced chromosome aberrations In
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K1mu-a, Y., T. Tadano, K. Sakal, A. Miyamoto and K. Klsara. 1980a. Changes
of ejaculation due to suppression of noradrenallne biosynthesis by dlethyl-
dlth ocarbamate. Andrologla. 12: 85-91.
Klmura, Y., T. Tadano, K. Sakal, A. Miyamoto and K. Klsara. 1980b. Changes
of e.aculatlon due to suppression of noradrenallne biosynthesis by dlethyl-
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King, E.F. and H.A. Painter. 1985. The effect of acclimatization on the
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Klaasien, C.D., M.P. Uaalkes and L.R. Cantilena, Jr. 1984. Alteration of
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0079d -57- 12/28/87
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Unj, J.H., F. Oberllng, A. Aleks1Jev1c, A. Falkenrodt and S. Mayer. 1985.
Immunomodulatlon with dlethyldlthlocarbamate 1n patients with AIDS related
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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 In
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Neveu, P.J.. D. Perdoux and L. Lafleur. 1982. In. vivo enhancement of
m1to
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-------
Rasul, A.R. and J.M. Howell. 1973a. Response of the peripheral and central
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Rasul, A.R. and J.M. Howell. 1973b. A comparison of the effect of sodium
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Rasu , A.R. and J.H. Howell. 1974b. The toxlclty of some dlthlocarbamate
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0079d -60- 12/28/87
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Rencux, M., J.P. 61roud, I. Florentln, J.H. Gulllaumln, D. Oegenne and G.
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Roseiikranz, H.S. and 2. Lelfer. 1980. Determining the DNA-modlfyIng
activity of chemicals using DAN polymerase-def Iclent Escherlchla coll.
Chem. Mutagens. 6: 109-147.
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dHhlocarbamate on ejaculatory Inhibition and change monoamlne levels of
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Sax, il.I. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van
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Slegeis, C-P., J. Larsellle and M. Younes. 1982. Effects of dlthlocarb and
dextrc-catechln on mlcrosomal enzyme activities of rat Hver. Res. Commun.
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0079d -61- 12/28/87
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Strjnme, J.H. 1965. Metabolism of cMsulflram and dlethyldUhlocarbamate In
rat; with demonstration of an U» vivo ethanol-lnduced Inhibition of the
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carb
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0079d -63- 01/22/88
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U.S. EPA. 1985a. Integrated Risk Information System (IRIS). Reference
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Van Leeuwen, C.J., F. Roberts and G. Nlebeek. 1985b. Aquatic toxlcologlcal
aspects of dithlocarbamates and related compounds. II. Effects on survival,
reproduction and growth of Daphnla maqna. Aquat. Toxlcol. 7: 165-175.
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Wattmberg, L.W., L.K.T. Lam, A.V. fladmoe and P. Borchert. 1977.
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Hlndfolz, M., Ed. 1983. The Merck Index. An Encyclopedia of Chemicals.
Drug* and Blologlcals, 10th ed. Merck and Co., Inc., Rahway, NJ. p. 1234.
Zemaltls, M.A. and F.E. Greene. 1979. In vivo and in vUro effects of
thluram dlsulfldes and dithlocarbamates on hepatic mlcrosomal drug metabo-
lism In the rat. Toxlcol. Appl. Pharmacol. 48(2): 343-350.
0079d
-65-
01/22/88
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASK 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:
A:GIH (American Conference of Governmental Industrial Hyglenlsts).
1)86. Documentation of the Threshold Limit Values and Biological
E (posure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
I'i87. TLVs: Threshold Limit Values for Chemical Substances In the
W< irk Environment adopted by ACGIH with Intended Changes for
1( 87-1988. Cincinnati, OH. 114 p.
C ay ton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hjgt«flt and Toxicology, 3rd rev. ed., Vol. 2A. John Ulley and
2878 p.
6.0. 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
Sots, NY. p. 3817-5112.
0079d -66- 12/28/87
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Grayson, H. 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, MA. 575 p.
[ARC {International Agency for Research on CancerJ. IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
)aber, H.M., H.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
I984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
I PA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
I'ark, CA.
DTP (National Toxicology Program). 1987. Toxicology Research and
"estlng Program. Chemicals on Standard Protocol. Management
Status.
(uellette, 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 In the Special Review
P-ogram, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
U»ITC (U.S. International Trade Commission). 1986. Synthetic
0 ganlc Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1U92, Washington, DC.
Vnrschueren, 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.
Biltlsh Crop Protection Council. 695 p.
, M., Ed. 1983. The Merck Index, 10th ed. Herck and Co.,
y, HJ.
0079d -67- 12/28/87
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In addition, approximately 30 compendia of aquatic toxldty data were
rev'ewed, 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 Tox1c1ty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
ToxIcHy Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
IcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Jrepared for the Resources Agency of California, State Water
JualHy Control Board. Publ. No. 3-A.
I'lmental, D. 1971. Ecological Effects of Pesticides on Non-Target
:;pedes. 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 80-196676.
0079d -68- 12/28/87
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APPENDIX B
Cancer Data Sheet for Derivation of qi* for Oral Exposure
Conpound: OUhlocarb
Reference: BRL,' 1968a
Sp?c1es/strain/sex: m1ce/B6C3Fl/males
Rojte/vehlcle: oral, by gavage 1n distilled water for 3 weeks then In diet
for 74 weeks
Length of exposure (le) * 77 weeks
Length of experiment (Le) * 77 weeks
Lltespan of animal (L) « 104 weeks (assumed)
Bocy weight = 0.037 kg (measured)
Tun or site and type: liver, hepatoma
Exposure
thei 692 ppm In diet for
74
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
0
215 mg/kg/day for 3 weeks,
0
94.9+
8/79
7/17
Unadjusted qi* » 8.8250x10'" (mg/kg/day)'1
Hunvn q^ « 2.6893X10'1 (mg/kg/day)"1
tAssuming that mice consume the equivalent of 13% of their body weight
da'ly as food, dietary exposure to 692 ppm of dlthlocarb corresponds to 90.0
mg/kq/dty *»d the TWA dosage for the entire experiment Is 94.9 mg/kg/day.
0079 J
-69-
12/28/87
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