i-..,-/
i"f I
United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-6052
August, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR THIRAM
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DRAFT: DO NOT CITE OR QUOTE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 1s a preliminary draft. It has not been formally released
f» by the U.S. Environmental Protection Agency and should not at this stage be
*~ construed to represent Agency policy. It 1s being circulated for comments
^ on Us technical accuracy and policy Implications.
-> ENVMONMCNTAL PROTECTION AGENCY
WASHINGTON, D.a 20460
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C. 20460
a BBS
OFFICE OP
RESEARCH AND DEVELOPMENT
th and^nvironmental Effects Document for Thiram
H. Farlarttf, Ph.D.
-Director
Office of Health and Environmental
Assessment (RD-689)
TO: Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Waste (OS-330)
I am forwarding copies of the Health and Environmental
Effects Document (HEED) for Thiram.
The HEEDs support listings under RCRA, as well as provide
health-related limits and goals for emergency and remedial
c.ctions under CERCLA. These documents represent scientific
summaries of the pertinent available data on the environmental
fate and mammalian and aquatic toxicity of each chemical at an
extramural effort of about $10K, The attached document has been
reviewed within OHEA, by staff in OPP and OTS, and by two
external scientists.
Should you wish to see any of the files related to the
development of the HEEDs, please call Chris DeRosa at
FTS: 684-7531.
Attachment
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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
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSMER). This document series
1s 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 In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses {RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the 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
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* {U.S. EPA, 1980), 1s provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and carclno-
genlclty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification Is required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1lHy, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined In U.S.
EPA, 1984b and 1986b, respectively.
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EXECUTIVE SUMMARY
Thlram (137-26-8) Is a white crystalline solid at room temperature
(Hawley, 1981). It 1s Insoluble In water but soluble In benzene, chloroform
and carbon dlsulflde. Thlram Is manufactured by UC8 Chemicals Corp. 1n
Bucks, AL, and Goodyear Tire and Rubber In Akron, OH (SRI, 1987; USITC,
1987). During 1982, a minimum of 2.29 million pounds of thlram was consumed
In the United States (HSDB, 1988); ~97X of the thlram consumed 1n the United
States Is used as a rubber accelerator (IARC, 1976).
If released to the atmosphere, thlram Is expected to exist partly In the
vapor phase and partly In participate form (Hartley and Kldd, 1983;
Elsenrelch et al., 1981). The dominant removal mechanism for thlram 1n the
vapor phase appears to be reaction with photochemically generated hydroxyl
radicals. The half-life for this reaction has been estimated. to be 71
minuted (Atkinson, 1985; 1987). Dry deposition may be a significant route
of removal for partlculate-phase thlram. Because of Us ability to absorb
sunlight, direct photolysis 1s also a potential removal process for both
vapor- and partlculate-phase thlram. If released to water or soil, thlram
1s expected to decompose by chemical and microblal action to dlmethy1d1th1o-
carbamate (Munnecke and Mlckall. 1967; Richardson, 1954; Shirkot and Gupta,
1985; Kluge, 1969a,b; Rajagopal et al.. 1984). Under acidic conditions,
chemical processes should dominate. Under anaerobic conditions, thlram has
been found to blodegrade to dlmethylamlne, carbon dlsulflde and hydrogen
sulflde (Williams, 1977). Volatilization from water or soil surfaces Is not
expected to be an Important fate process. This compound should adsorb
moderately to suspended solids and sediments In water. In general, thlram
1s expected to have low mobility 1n soil, although potential exists for
1v
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movement through some soils (Rajagopal et al., 1984; Helling et al., 1974;
Relnbold et al., 1979). The half-life of thlram In soil has been found to
vary from <1 day to >32 weeks, with the rate of degradation depending upon
such variables as pH, humus content and Initial concentration of the
compound (Shirkot and Gupta, 1985; Griffith and Matthews, 1969; Chlnn, 1973;
Richardson, 1954; Kluge, 1969a).
Pertinent data regarding human exposure to thlram were extremely
limited. The U.S. EPA STORET data base contained no data regarding the
detection of thlram In water, aquatic biota or sediment samples. Because
t hi ram is used as a fungicide In fruit plants, It was analyzed for but not
found In samples of sweet cherries and peaches grown domestically In
Ontario, Canada, between 1983 and 1984. The detection limit for thlram In
this study was 0.01 mg/kg (Frank et al., 1987).
The 96-hour TL of thlram 1n finger!Ing channel catfish was reported
as 0.79 rag/l (McKce and Wolf, 1963). The 26-hour LD5Q of thlram to
Daphnla magna was 1.3 ppm (frear and Boyd, 1967). The 48-hour LC5Q of
thlram to Tublfex tublfex was 0.67 mg/i (Voronkln and Loshakov, 1973).
Tooby et al. (1975) reported a 96-hour LC5Q of 0.007 mg/i (based on
concentration of product) for harlequin fish, Rasbora heteromorpha. exposed
to a thlram-contalnlng product with BOX active Ingredient under flowthrough
conditions. Tooby et al. (1975) estimated a 3-month LC5_ of 0.001 mg/8.
from an extrapolation of the acute test results.
Schneider (1979) reported 96-hour LCrgS of 0.13 and 0.4 ppm for
rainbow trout, Salmo galrdnerl. exposed to solutions of thlram (99 and 7S%
active ingredient, respectively). Exposure of blueglll sunflsh, Lepomls
macrochlrus. to thlram (99 and 75X active Ingredient) generated 96-hour
LC5Qs of 0.045 and 0.28 ppm, respectively. The 96-hour LC5Qs (based on
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active Ingredients) for two products each containing an 80% level of thiram
but 20X levels of dissimilar Inactive Ingredients to the freshwater mollusc,
Lymnaea stagnalls. were 12 and 8.9 ppm for products A and B, respectively,
1n aqueous solutions (Bluzat et al., 1981). The 96-hour LC5Qs for acetone
suspensions of products A and B were 2.8 and 3.2 ppm, respectively.
Exposure of scud, Garomarus pulex. to 10, 5, 2 and 1 ppm of a commercial
product containing BOX thiram resulted In 95, 79, 48 and 25X mortality after
10 days (Bluzat et al., 1982a). Groups of scud (n=130 and 190) exposed to
0.7 ppm aqueous suspensions of thiram 1, 48 and 96 hours after preparation
of the test solutions experienced 84.6, 91.5 and SOX mortality levels,
respectively, after 96 hours of treatment. The 96-hour LC5Qs for two
commercial thiram-containing products (80X active Ingredient) to G. pulex
were 0.20 ppm and 0.13 ppm for products A and B, respectively, in aqueous
solutions {Bluzat et al., 1982b). The 96-hour LC5Qs for products A and B
In acetone were 0.22 and 0.06 ppm, respectively. The approximate median
lethal times for G. pulex exposed to 0.02, 0.025, 0.035, 0.05 and 0.08 ppm
solutions of thiram were 30, 8.5, 6.5, 4.5 and 5 days, respectively (Bluzat
and Seuge, 1983). Scud offered bean seeds treated with 3000 and 10,000 ppm
thiram demonstrated 90X survival after 3-3.5 days and 10X survival after
29-36 days. Scud offered mosses treated with 50-10,000 ppm thiram demon-
strated 90X survival after 2.4-5.4 days and 10X survival after 9-27 days.
The 96-hour LC5Qs for the flatworm, Dugesla gonocephala, the Isopod,
Asellus aquaticus. and the amphibian, Xenopus laevls. at two stages of
development {47 and 53) were 0.048, 61, 0.013 and 0.021 ppm, respectively
(Seuge et al., 1983). The 96-hour LC5Q for mayfly larvae, Cloeon
dlpterum. exposed to freshly prepared solutions of thiram was 1.01 mg/i.
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Solutions of thlram aged for 1, 7 and 36 hours produced mortality levels
among mayfly larvae of 79.5, 64.7 and 45.3%, respectively, after 96 hours of
exposure (Seuge and Bluzat, 1983).
The respective ECn, ECcn and EC,nn for Daphnla magna exposed to
U DU IUU
tetramethylthluram dlsulflde were 0.05, 0.06 and 0.8 yg/i (Knle et al.,
1983). 3ouany et al. (1985) reported 0% mortality for the water flea,
Daphnla magna. carp, Cyprlnus carplo. and zebraflsh, Brachyodanlo rerlo.
exposed to <0.1, 1.0 and 0.1 mg/i after 24 hours. Zebraflsh fed
thlram-contaminated daphnlds experienced a linear Increase In mortality from
0-100% between 4 and 8 days after the Initiation of the experiment. The
96- and 48-hour LC5Qs for gupples, Poecllla retlculata. and daphnlds,
Daphnla magna. exposed to thlram were 0.27 and 0.21 mg/l, respectively
(Van Leeuwen et al., 1985a). The 24-hour LC5Q of thlram (>98% purity) to
rainbow trout, Salmo qalrdnerl. weighing 34.0 g was 0.26 mg/i. The
24-hour LCrQ for trout weighing -47 g was 0.30 mg/l (Van Leeuwen et al.,
1986a). Exposure of trout to thlram also resulted In.significant changes 1n
several blood parameters.
The 21-day LCcn for thlram 1n the water flea, Daphnla magna. was 8
3D -
pg/l (Van Leeuwen et al., 1985b). The lowest tested concentration that
resulted 1n a decrease 1n fecundity was 10 vg/i. The lowest tested
concentration that resulted In a decrease In size of daphnlds after 21 days
was 1.8 jig/i. There were no significant effects on daphnlds exposed to
1 iig/s, of thlram over the 21-day study.
The 60-day LC for embryolarval stages of rainbow trout, Salmo
galrdnerl. exposed to thlram was 1.1 ^g/l (Van Leeuwen et al., 1986b).
The 60-day EC,.- based on mortality and teratogenesls was 0.64
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The lowest concentrations at which there were no observable effects based on
mortality, total embryotoxIcHy, length and weight were 1.0, <0.32, <0.32
and 0.56 jig/4, respectively. Exposure of juvenile rainbow trout to
thlram for 21 days resulted In a concentration-related loss of glycogen 1n
the liver at >25 yg/l and was associated with reduced body weight gain.
At 100 jig/i, thlram Induced a proliferation of bile duct epithelial
cells both with and without formation of new ductules. Cell necrosis was
observed occasionally, and hemorrhages were apparent 1n the brain and spinal
cord at 5 yg/l (Van Leeuwen et al., 1986c). Thlram Is not expected to
bloaccumulate significantly In aquatic organisms based on an estimated BCF
value of 90.8.
Hotlllty and topophototaxls of Euglena ara_c_1.11s_were Inhibited to 50% of
control organisms within 30 minutes of exposure to 10"* M solutions of
tetramethylthluram dlsulflde (Dlehn and TolHn, 1967). Cultures of the green
alga, ^cenedesmus acutus, exposed to 10 and 100 ppm tetramethylthluram
dlsulflde were dead after 1 and 3 days, respectively. The NOEL appears to
be <0.5 ppm. Gangawane and Kulkarnl (1979) reported a 25.4% reduction In
growth for cultures of Nostoe sp. exposed to 500 ppm thlram and a 14.1%
reduction In growth for cultures of TolypothMx sp. exposed to 100 ppm
thlram. Hutber et al. (1979) reported that growth of four species of blue-
green algae, Aphanocapsa (strains 6308 and 6714), Anabaena varlablUs and
Mostoc. was reduced by 50% on exposure to 50. 100, 50 'and 100 ppm thlram,
respectively. The concentrations of thlram that Inhibited growth completely
were 100, >100, 100 and >100 ppm, respectively.
The minimal active dose of thlram required to produce reductions In the
number of generations of the dilate protozoan, Cg1p1d1um campy!urn, was 0.3
mg/l (D1ve et al., 1980). The 24-hour IC5Q for Chlorella vulqarls based
V111
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on ATP levels was >2 ppm thlram (Vasseur et al., 1982). Knle et al. (1983)
reported an EC,Q of >6 mg/l for the alga, Haematococcus pluvlalls.
exposed to tetramethylthluram dlsulflde. Growth rates of the dilates,
Tetrahymena thermophlla and Tetrahymena pyr1form1s strains, were Inhibited
completely at 1.0 mg/l thlratn for all but one strain at 28°C (D1ve et al.,
1984}. Growth Inhibition of amoebae exposed to thlram was achieved at
concentrations ranging from 0.5-16 mg/l. Thlram at concentrations ranging
from 0.25-1.0 mg/l Induced a lengthening of the generation time In heat
*,
shock synchronized axenlc cultures of Tetrahymena pyrlformls (Grollere and
Dupy-Blanc. 1985).
The 72-hour IC5Q for growth of the green alga, Chlorella vulgarls.
exposed to thlram as determined by optical density at 665 nm was -5.5 mg/l
(Jouany et al., 1985). The 96-hour EC5Qs for the average specific growth
rate and effects on the time-lag until maximum population growth In
Chlorefla pyrenoldosa were 1.0 and 0.03 mg/l, respectively (Van Leeuwen et
al., 1985a). The EC5Q for assimilation of radioactive bicarbonate by £.
pyrenoldosa was 4.0 mg/l. The EC5Q for respiration of 14C by C.
pyrenoldosa was >10.0 mg/l.
Growth of a chrysomonad was Inhibited completely following exposure to
210 jiM thlram. Growth of the dilate, Cyclldlum sp., was Inhibited
completely at -180 jjM thlram (Taylor and Pace, 1987). Growth of a chloro-
phyte, Dunallella tertolectlca. was Inhibited at 4 yM thlram after 7 days.
Growth of five other phytoplankton species was Inhibited from -0.2-18.6% of
controls by exposure to 4 yH thlram for 7 days. The !5-m1nute EC5Q
value for Photobacterlum phosphoreum exposed to thlram was 0.1 mg/l (Van
Leeuwen et al., 1985a). The lowest effective concentration or minimum
Inhibiting concentration of thlram on the nitrification process of a mixed
culture of Nltrosomonas and Nltrobacter after 3 hours was 18 mg/l.
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The oral LDCfts for thlram In mallard ducks, Anas platyrhynchos. and
3U -
ring-necked pheasants, Phaslanus colchlcus. were >2800 and 673, respectively
(Tucker and Crabtree, 1970). Egberts et al. (1972) reported no statistic-
ally significant effects 1n Japanese quail, Coturnlx coturnlx. offered feed
contaminated with 10 ppm thlram for 11 weeks. Birds fed 50 ppm contaminated
feed demonstrated significant reductions In numbers of eggs laid and hatched
and shell thickness of eggs. There were also significant reductions 1n the
numbers of lymphocytes, granulocytes and monocytes of blood from birds dosed
with 50 ppm th1ram-contaminated feed. Heath et al. (1972) reported a lack
of mortality among Japanese quail, C.. coturnlx japonlca. and pheasant, £.
colchlcus. fed the highest concentration of thlram tested (5000 ppm In
feed). Mallard ducks, Anas platyrhynchos. fed mash containing 5000 ppm
thlram had 20% mortality.
Lorgue et al. (1975) reported that th1ram-contaminated feed (20 gc
Th1rban/10 kg) caused Immediate (24 hours) blockage of egg laying In quail
and regression of secondary sexual characteristics 1n males. Lorgue and
Soyez (1976) reported that thlram completely Inhibited egg laying by gray
partridges exposed to 1.6 g/kg within 48 hours. The Incidence of embryonic
mortality was Increased significantly at 4-fold lower doses. The ID and
LC5Q of thlram to Japanese quail, C. coturnlx japonlca. were 695 and
>10,000 mg/kg, respectively (Gruen et al., 1982). Hadhazy and Glavlts
(1982) reported that 100 and 200 g th1 ram/100 kg feed caused Imperfect egg
shell calcification and production of eggs with abnormal size and form In
pheasants.
Earthworms, El senla foetlda exposed to thlram by Immersion had mortality
levels ranging from 5% seven days posttreatment, to 38% one hundred and one
days posttreatment (Roark and Dale, 1979). Worms fed thlram-treated
bermudagrass clippings had mortality levels ranging from 10% after 34 days
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of treatment to 42% after 101 days. Mortality among worms reared 1n
th1ram-treated soil ranged from 21% after 10 days to 98.1% after 29 days and
99.9% after 52 days. The ALO of thlram to wild-trapped deer mice,
Peromyscus manlculatus. was reported to be 1600 mg/kg (Schafer and Bowles,
1985).
Although specific quantitative data concerning the pharmacoklnetlcs of
thlram are limited, ACGIH (1986) stated (without providing documentation)
that following absorption, thlram 1s widely distributed, and 1s predomi-
nantly excreted unchanged 1n the urine and feces. Rannug and Rannug (1984)
stated that thlram and other dlsulfldes have a tendency to participate In
redox-reactlons. Thlram Is reduced by glutathlone to d1methyld1th1ocarba-
mate, and 1t may also Interact with SH-groups of proteins, which may result
1n the Inhibition of a number of enzymes. Dalvl and Deoras (1986) reported
a dose-related Increase In the amount of carbon dlsulflde exhaled following
treatment of rats with an 1ntraper1toneal Injection of thlram.
Data regarding the toxldty of thlram following Inhalation exposure of
animals were not located. SlvlUskaya (1974, summarized by Flshbeln, 1976)
reported ophthalmologlc changes In persons occupationally exposed to thlram.
Exposure concentrations were not reported.
The most notable effect observed In animals following chronic oral
exposure to thlram 1s ataxla and hind leg paralysis observed In rats fed
thlram In the diet at >300 ppm (E.I. Du Pont de Nemours and Co., n.d.; Lee
and Peters, 1976). Neurotoxlc effects following exposure to thlram may
result from the production of carbon dlsulflde. Thuranszky et al. (1982)
found similar effects on the nervous system when rats were treated with a
single oral dose of thlram or carbon dlsulflde.
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Dietary treatment of animals with thlram has consistently resulted In
decreased food Intake and body weight gain. The study by Lowy et al.
(1980). which found that body weight gain 1n thlram treated rats was below
pair-fed controls. Indicates that the effect on body weight Is a result of
thlram treatment rather than just a result of decreased food Intake. The
lowest dietary concentration of thlram resulting In decreased body weight
gain In rats was 100 ppm (Lee et al., 1978). A study using mink and ferrets
(Hornshaw et al., 1987) did not clearly Identify levels resulting In changes
In body weight because of the small numbers of animals used, and because of
the high variability of body weight of the animals used In the study.
Thlram 1s an Inhibitor of mlcrosomal monoxygenases Including aldehyde
dehydrogenase and dopamlne Q-dehydrogenase. Combined exposure to thlram and
ethanol has been shown to result In the accumulation of acetaldehyde (Garcia
de Torres et al., 1983). Interactions between thlram and prometazlne,
meprobamate and trlhexyhenldyl have also been reported .(Fenyvesl et al.,
1985). Oral cardnogenldty studies of thlram using rats (Lee et al., 1978;
Takahashl et al., 1983; Lljlnsky, 1984) and a limited cardnogenldty study
using mice (BRL, 1968a) have not found a carcinogenic effect. Lljlnsky
(1984) found that simultaneous oral treatment of rats with thlram and sodium
nitrite significantly Increased nasal cavity and forestomach tumors. This
effect probably was due to the \n_ vivo formation of N-n1trosod1methylam1ne.
Kutagenlclty studies of thlram have yielded mixed results, with numerous
positive and negative studies available. Rannug and Rannug (1984) proposed
that mutagenlclty Induced by thlram. may result from the Inhibition of
enzymes that are Involved 1n protecting against harmful oxygen species.
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Oral teratogenldty studies using hamsters (Robens, 1969), mice (Roll,
1971; Matthlaschk, 1973; Short et al., 1976) and rats (Short et al., 1976)
have reported an Increased Incidence of resorptlons and malformations
observed prenatally and reduced viability and growth, postnatally. In some
Instances, the findings were observed In the presence of maternal toxlclty.
Oral studies concerning the effects of thlram on reproduction 1n rats
(Short et al., 1976) Indicate that at 132 mg/kg/day the 30% of the males who
survived, failed to Inseminate females and some exhibited testlcular
lesions. This dose also caused mortality. A dose of 30 mg/kg/day given to
females reduced the number of Implants/dam. Treatment at 96 mg/kg/day
resulted 1n only 1 of the 15 female survivors to mate successfully. A
cross-fostering experiment (Short et al., 1976), which found reduced
survival of offspring from untreated dams placed with treated dams Indicates
that developing rats are still sensitive to thlram postnatally. Results of
a reproductive study using mink and ferrets (Hornshaw et al., 1987)
Indicates that ferrets may be more sensitive than mink or rats to the
reproductive effects of thlram; 0/12 female ferrets produced litters at a
dose of 7 mg/kg/day.
Thlram was assigned to EPA group D: not classifiable as to human
cardnogen1c1ty. An RfO for subchronlc and chronic oral exposure of 0.006
mg/kg/day was derived from the NOAEL for reproductive effects 1n female
ferrets of 0.61 mg/kg/day 1n the study by Hornshaw et al. (1987). The
verified oral RfD of 0.005 (U.S. EPA, 1987c) 1s based on an unpublished 2-
year study In rats (E.I. Dupont de Nemours & Co. Inc., n.d.) derived from
the NOEL of 5 mg/kg/day for weakness, atoxla, varying degrees of hind 11mb
paralysis, and calcified masses In the basal gonglla and 1n the cerebellum.
X111
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Both RfDs are well below the boundary line for adverse effects when the
available data are plotted In dose/duration-effect graphs. In addition,
exposure to 2.1 ntg/kg/day produced a decrease In the number of offspring/
Utter and 1n offspring body weights. In the adult animals, there was an
Increase 1n splenic weight at 2.1 and 7 mg/kg/day and a decrease In RBCs,
hemoglobin and hematocrlt at 7 mg/kg/day.
Freshwater criteria calculated for aquatic toxldty were a Final Acute
Value of 20.4 yg/i, a Final Chronic Value of 0.0256 yg/t. and a
Final Acute-Chronic Ratio of 797.91. The Final Plant Value was estimated at
0.03 mg/l. Data were not sufficient for estimating saltwater criteria.
An RQ of 100 pounds was derived for chronic toxldty based on reproduc-
tive effects In female ferrets (Hornshaw et al.. 1987). Data were not
sufficient for derivation of a cancer-based RQ.
xW
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TABLE OF CONTENTS
Page
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 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
*»
2.1.1. Reaction with Hydroxyl Radicals 4
2.1.2. Reaction with Ozone 4
2.1.3. Photolysis 4
2.1.4. Physical Removal Processes 4
2.2. HATER 5
2.2.1. Chemical Degradation 5
2.2.2. Mlcroblal Degradation 5
2.2.3. Volatilization 5
2.2.4. Adsorption 5
2T3. SOIL 6
2.3.1. Chemical Degradation 6
2.3.2. Volatilization 6
2.3.3. Adsorption 6
2.3.4. Persistence 6
2.4. SUMMARY 8
3. EXPOSURE 10
4. ENVIRONMENTAL TOXICOLOGY 11
4.1. AQUATIC TOXICOLOGY 11
4.1.1. Acute Toxic Effects on Fauna 11
4.1.2. Chronic Effects on Fauna 16
4.1.3. Effects on Flora 18
4.1.4. Effects on Bacteria 22
4.2. TERRESTRIAL TOXICOLOGY 23
4.2.1. Effects on Fauna 23
4.2.2. Effects on Flora 25
xv
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TABLE OF CONTENTS (cont.)
Page
4.3. FIELD STUDIES 25
4.4. AQUATIC RISK ASSESSMENT 25
4.5. SUMMARY 30
5. PHARHACOKINETCS 36
5.1. ABSORPTION 36
5.2. DISTRIBUTION 36
5.3. METABOLISM 36
5.4. EXCRETION 38
5.5. SUMMARY 38
6. EFFECTS 39
6.1. SYSTEMIC TOXICITY 39
6.1.1. Inhalation Exposure 39
6.1.2. Oral Exposure 39
6.1.3. Other Relevant Information 45
6.2. CARCINOGENICITY 48
6.2.1. Inhalation 48
6.2.2. Oral. . . 48
6.2.3. Other Relevant Information 50
6.3. NUTAGENICITY 50
6.4. TERATOGENICITY 54
6.5. OTHER REPRODUCTIVE EFFECTS 58
6.6. SUMMARY 61
7. EXISTING GUIDELINES AND STANDARDS 64
7.1. HUMAN 64
7.2. AQUATIC 64
8. RISK ASSESSMENT 65
8.1. CARCINOGENICITY 65
8.1.1. Inhalation 65
8.1.2. Oral 65
8.1.3. Other Routes 66
8.1.4. Weight of Evidence 66
8.1.5. Quantitative Risk Estimates 66
8.2. SYSTEMIC TOXICITY 66
8.2.1. Inhalation Exposure 66
8.2.2. Oral Exposure 67
xvl
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TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 75
9.1. BASED ON SYSTEMIC TOXICITY 75
9.2. BASED ON CARCINOGENICITY 81
10. REFERENCES 82
APPENDIX A: LITERATURE SEARCHED 102
APPENDIX B: SUMMARY TABLE FOR THIRAM 105
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO THIRAM . . 106
xv11
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LIST OF TABLES
No. Title Page
6-1 Acute Tox1c1ty of Thlrara 46
6-2 Hutagenldty and GenotoxIcUy Testing of Thlram 51
9-1 Toxlclty Summary for Oral Exposure to Thlram 76
9-2 Composite Scores for Oral Exposure to Thlram 79
9-3 Minimum Effective Dose (MED) and Reportable Quantity (RQ) . . 80
xvlll
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LIST OF FIGURES
No. Title Page
2-1 Degradation Pathways of Thlram and Zlram 1n Soil and
\n Mlcroblal Cultures 9
4-1 Organization Chart for Listing GMAVs, GMCVs and BCFs
Required to Derive Numerical Water Quality Criteria
by the Method of U.S. EPA/OURS (1986) for the Protection
of Freshwater Aquatic Life from Exposure to Thlram 27
4-2 Example Computer Program In BASIC Language for Calculating
the Final Acute Value 28
4-3 Summary Chart for Data Required to Generate Criteria by
the Method of U.S. EPA/OWRS (1986) for Safe Levels of
Thlram In Aquatic Environments 29
5-1 Two-Step Reduction of Thlram to D1methy1d1th1ocarbamate
Ion 37
xlx
-------
LIST OF ABBREVIATIONS
AEL Adverse effect level
ALD Approximate lethal dose
ATP Adenoslne 5'-tr1phosphate
BCF Bloconcentratlon factor
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CMC Carboxymethyl cellulose
CNS Central nervous system
CS Composite score
DNSO Dimethyl sulfoxide
DNA Oeoxyrlbonuclelc add
ECso Concentration effective to 50% of recipients
~~ (and all other subscripted concentration levels)
PEL Frank effect level
GMAV Genus mean acute values
GMCV Genus mean chronic values
IC5Q Median Inhibition concentration
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to-50% of recipients
(and all other subcrlpted dose levels)
LEL Lowest effect level
1050 Dose lethal to 50% of recipients
(and all other subscripted dose levels)
LOAEL Lowest-observed-adverse-effect level
xx
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LIST OF ABBREVIATIONS (cont.)
NED Minimum effective dose
NPI Maximum permissible Intake
MTD Maximum tolerated dose
NADP N1cot1nam1de adenlne dlnucleotlde
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PCV Packed cell volume
PEL Permissible exposure level
PNS Peripheral nervous system
ppm Parts per million
RBC Red blood cell chollnesterase
RfD Reference dose
RQ Reportable quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUN8ER
Thlram 1s currently referred to by CAS as thloperoxydlcarbonlc dlamlde,
tetramethyl (SANSS, 1988). This compound 1s also known as b1s(d1methylth1o-
carbamyl)d1sulf1de, tetramethylthluram dlsulflde, thluram and THTD (Hawley,
1981). Trade names for this compound Include Arasan, Fernlde, Fernasan,
Pomarsol, Thlanosan, AAplrol AAtack, Hexathlr, Hercuram, Poraarsol forte,
Chlpco Thlram 75, Polyram-Ultra, Thlramad, Trlpomol, Tuads, Tersan 75,
Thylate, Vanclde-TM and Vanclde TM-95 (SANSS, 1988; Hartley and Kldd, 1983;
SRI, 1987; Melster, 1988)). The structure, CAS Registry number, empirical
formula and molecular weight of this compound are as follows:
CH3 S S CH3
\ n n /
N-C-S-S-C-N
/ \
CH3 CH3
Molecular weight: 240.42
Empirical formula: CgH.JI-S^
CAS Registry number: 137-26-8
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Thlram Is a white crystalline solid at room temperature, with a charac-
teristic odor (Hawley, 1981). It 1s soluble 1n water, benzene, chloroform
and carbon dlsulflde, and Insoluble 1n dilute alkali and aliphatic hydro-
carbons (IARC, 1976). Selected physical and chemical properties are as
follows:
Melting point: 155-156°C Wlndholz. 1983
146°C (commercial grade) Wlndholz, 1983
Boiling point: 129°C (20 mm Hg) IARC, 1976
0133d -1- 02/22/89
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Hater solubility:
Log Kow:
Vapor pressure:
Density:
30 mg/t (room temperature)
not available
<7.5xlO"» mm Hg (20°C)
1.29 g/cm* (20°C)
Worthing and Walker, 1983
Hartley and K1dd, 1983
Worthing and Walker, 1983
Chemically, thlram will be oxidized by strong oxidizing agents and will
decompose 1n the presence of strong adds (HSDB, 1988).
1.3. PRODUCTION DATA
Thlram Is believed to be produced commercially In the United States by
passing chlorine gas through a solution of sodium d1methyld1th1ocarbamate
(IARC, 1976). It 1s manufactured In the United States by UCB Chemicals
Corp. 1n Bucks, AL, and Goodyear T1re and Rubber In Akron, OH (SRI, 1987;
USITC, 1987). During 1982, consumption of thlram 1n the United States was a
minimum of 2.29 million pounds (HSDB, 1988).
1.4. JSE DATA
According to IARC (1976), -97% of the thlram consumed In the United
States 1s used as a primary and secondary accelerator In compounding
natural, 1sobuty1ene-1soprene, butadiene, styrene-butadlene, synthetic
Isoprene and nitrlle-butadlene rubbers. Thlram renders low sulfur and
sulfurless stock less heat-resistant, 1s nondlscolorlng and nonstalnlng, and
1s an excellent activator of guanldlnes, amines and thlazoles. Thlram 1s
also used as a cure retarder for Neoprene G rubbers (IARC, 1976). Other
applications Include use as a fungicide (on seeds, fruits, nuts, vegetables
and ornamental crops, and on paper, polyurethane foam and textiles), animal
repellent, bacterlostat 1n soap and antiseptic sprays, antl-oxldant In
polyolefln plastics, and peptlzlng agent 1n polysulphlde elastomers (IARC,
1976).
0133d
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03/21/89
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1.5. SUHMARY
Thlram (137-26-8) Is a white crystalline solid at room temperature
(Hawley, 1981). It Is Insoluble In water but soluble 1n benzene, chloroform
and carbon dlsulflde. Thlram 1s manufactured by UCB Chemicals Corp. 1n
Bucks, AL, and Goodyear Tire and Rubber In Akron, OH (SRI, 1987; USITC.
1987). During 1982, a minimum of 2.29 million pounds of thlram was consumed
In the United States (HSDB, 1988); ~97X of the thlram consumed In the United
States Is used as a rubber accelerator (IARC, 1976).
0133d -3- 02/22/89
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2. ENVIRONMENTAL FATE AND TRANSPORT
Limited experimental data regarding the environmental fate and transport
of thlram were located 1n the available literature. Therefore, predictions
concerning environmental fate and transport of this compound were based on
theoretical calculations using physical properties or molecular structure.
2.1. AIR
It can be assumed from Us vapor pressure of <7.5xlO~* mm Hg at 20°C
{Hartley and Kldd, 1983} that thlram would exist mostly In the participate
form and partly 1n the vapor form In the atmosphere (Elsenrelch et al.,
1981).
2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson
(1987), the rate constant for the reaction of thlram vapor with photo-
chemical ly generated hydroxyl radicals 1n the atmosphere Is estimated to be
3.23xl(Ti0 cma/molecule-sec at 25°C. Assuming an average ambient
hydroxyl radical concentration of S.OxlO9 molecules/cm9 (Atkinson,
1985), the hydroxyl reaction half-life 1s estimated to be 71 minutes.
2.1.2. Reaction with Ozone. Thlram Is not expected to be susceptible to
reaction with ozone molecules 1n the atmosphere (U.S. EPA, 1987a).
2.1.3. Photolysis. At a concentration of 100 mg/l In methanol, thlram
has been found to absorb UV light In the environmentally significant range
(wavelengths >290 nm) (Gore et al., 1971). This suggests that thlram may be
susceptible to direct photolysis 1n the atmosphere, although no data
regarding the rate of this reaction are available In the literature.
2.1.4. Physical Removal Processes. Dry deposition may be a route of
removal for partlculate-phase thlram 1n the atmosphere.
0133d -4- 02/22/89
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2.2. WATER
2.2.1. Chemical Degradation. Thlram is reported to decompose In acidic
media (Hartley and K1dd, 1983; Worthing and Walker, 1983). This Informa-
tion, as well as data pertaining to the persistence of thlram In soil,
suggests that chemical processes such as hydrolysis 1n acidic medium will
contribute to the decomposition of thlram In natural waters. Since thlram
absorbs light 1n the environmentally significant region (>290 mm) (HSDB,
1988), H has the potential to undergo direct photolysis In surface waters
when exposed to sunlight. Rate data that would permit estimation of
half-lives for hydrolysis and photolysis are not available In the literature.
2.2.2. Mlcroblal Degradation. Results of a study using the Japanese HITI
test protocol Indicate that thlram Is resistant to blodegradatlon under
aerobic conditions; <30% degradation was observed when 100 ppm thlram was
Incubated with 30 ppm activated sludge for 2 weeks (Sasaki, 1978; Kawasaki,
1980)." Degradation of thlram to d1methylam1ne, carbon dlsulflde and
hydrogen sulflde by rumlnal microorganisms Indicates that thlram may be
susceptible to blodegradatlon under anaerobic conditions 1n the environment
(Williams, 1977).
2.2.3. Volatilization. Henry's Law constant for thlram has been
estimated to be <7.9xlO~8 atm-mVmol based on a water solubility of 30
mg/i at room temperature and a vapor pressure of <7.5xlO~ mm Hg at
20°C. This value for Henry's Law constant'suggests that volatilization from
water surfaces would not be a significant fate process (Thomas, 1982).
2.2.4. Adsorption. A soil adsorption coefficient of 672 was estimated
for thlram using the following regression equation (Lyman, 1982): log K
= -0.55 log S + 3.64. Based on this K value, thlram Is expected to
adsorb moderately to suspended sol Ids and sediments In water.
0133d
-5-
02/22/89
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2.3. SOIL
2.3.1. Chemical Degradation. It appears that the chemical decomposition
of thlram In aerobic soil may be a significant process (Kluge, 1969a).
Because of Us ability to absorb light of wavelength >290 mm (HSD8, 1988},
direct photolysis on soil surfaces 1s a potential loss process.
2.3.2. Volatilization. Moderate adsorption of thlram to soil and a
relatively low value for Henry's Law constant (<7.9xl(T8 atm-mVmol at
20-25*0) suggest that volatilization from moist soil surfaces would not be a
significant fate process. The low vapor pressure of thlram suggests that
volatilization from dry soil surfaces also would be Insignificant.
2.3.3. Adsorption. Thlram has been found to be Immobile 1n a black clay
and a red sandy loam soil, but was more mobile In peat moss and particularly
In loamy sand soil (Rajagopal et al., 1984). These observations are In
agreement with an estimated K value of 672, which Indicates low mobility
In sofT. Helling et al. (1974) employed bloassay methods In combination
with soil TLC to study the mobility of thlram In sllty clay loam. The
overall mean Rf value for this compound was determined to be 0.73, which
Indicates moderate mobility In this soil (Relnbold et al., 1979). These
data Indicate that In general thlram has low mobility 1n soil, although H
may show moderate mobility 1n certain soils.
2.3.4. Persistence. It appears that thlram Is degraded In soil by both
blotlc and abiotic mechanisms, with the rate of degradation depending on
such variables as pH, soil type (humus content) and concentration of thlram
(Munnecke and Hlckall, 1967; Richardson, 1954; Shlrkot and Gupta, 1985;
Kluge, 1969a,b; Rajagopal et al., 1984). Thlram added to alluvial sandy
loam at an Initial concentration of 300 ppm underwent 16X degradation In
autoclaved soil and 25% In nonautoclaved soil In 24 hours (Shlrkot and
0133d -6- 02/22/89
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Gupta, 1985). In autoclaved and nonautoclaved alluvial sandy loam Inocu-
lated with Pseudomonas aeruglnosa. thlram at an Initial concentration of 300
ppm had a half-life of 8 days and underwent 90% degradation In 24 days
(Shlrkot and Gupta, 1985). At an Initial concentration of 125 ppm, thlram
had a half-life of 1 day when distributed evenly throughout a soil (45X
moisture content) (Griffith and Matthews, 1969). In contrast, the same
amount of thlram added to the soil In the form of a dressing on the surface
of 0.7 mm glass beads was much more persistent, undergoing only about 10%
degradation In 21 days (Griffith and Matthews, 1969). In a study by Chlnn
(1973), the persistence of thlram In loam soil was measured quantitatively
using a method that Incorporated some features of the cylinder-plate
technique used for assaying antibiotics. Thlram was applied to loam soil at
concentrations of 100 and 1000 ppm. Results showed that thlram at 100 ppm
had a half-life of -1 week, while at 1000 ppm H persisted longer than 32
weeks. It seems probable that thlram at 1000 ppm killed many of the soil
mlcroflora that are responsible for degradation of fungicides (Chlnn, 1973).
In other studies, thlram added to sandy soil at concentrations of 100
and 200 ppm had a half-life of <2 days; at a concentration of 50 ppm, the
half-life ranged between <2 days to -7 days, and when added to greenhouse
compost soil at a concentration of 50 ppm, thlram had a half-life of <1 day
(Richardson, 1954). The addition of thlram to soil appeared to alter the
microbiological balance of the soil. Increasing the number of bacteria and
decreasing the number of fungi over time (Richardson, 1954; Rajagopal et
al., 1984). Thlram Is reported to decompose faster In soils with greater
humus content (Mendel, 1974). In soil with humus content <1.2%, an Initial
lag 1n the decomposition of thlram was observed (Kluge, 19695). Thlram has
been found to decompose faster In soil with a lower pH. In humus sandy soil
at pH 3.5, thlram was largely decomposed after 4-5 weeks, while In the same
0133d
-7-
08/24/89
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soil at pH 7.0, thlram decomposed after 14-15 weeks (Kluge, 1969a). The
proposed degradation pathway for thlram In soil 1s shown In Figure 2-1
(Rajagopal et al., 1984).
2.4. SUMMARY
If released to the atmosphere, thlram Is expected to exist partly In the
vapor phase and partly In participate form (Hartley and K1dd, 1983;
Elsenrelch et al., 1981). The dominant removal mechanism for thlram 1n the
vapor phase appears to be reaction with photochemically generated hydroxyl
radicals. The half-life for this reaction has been estimated to be 71
minutes (Atkinson, 1985; 1987}. Dry deposition may be a significant route of
removal for partlculate-phase thlram. Because of Its ability to absorb
sunlight, direct photolysis Is also a potential removal process for both
vapor- and partlculate-phase thlram. If released to water or soil, thlram
Is expected to decompose by chemical and mlcroblal action to dlmethyldlthlo-
carbamate (Munnecke and Mlckall, 1967; Richardson, 1954; Shlrkot and Gupta,
1985; Kluge, 1969a,b; Rajagopal et al., 1984). Under acidic conditions,
chemical processes should dominate. Under anaerobic conditions, thlram has
been found to blodegrade to dlmethylamlne, carbon dlsulflde and hydrogen
sulflde (Williams, 1977). Volatilization from water or soil surfaces Is not
expected to be an Important fate process. This compound should adsorb
moderately to suspended solids and sediments In water. In general, thlram
1s expected to have low mobility In soil, although potential exists for
movement through some soils (Rajagopal et al., 1984; Helling et al., 1974;
Relnbold et al., 1979). The half-life of thlram In soil has been found to
vary from <1 day to >32 weeks, with the rate of degradation depending upon
such variables as pH, humus content and Initial concentration of the
compound (Shlrkot and Gupta. 1985; Griffith and Matthews, 1969; Chlnn, 1973;
Richardson, 1954; Kluge, 1969a).
0133d
-8-
08/23/89
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CH
CM,
Ziram
f
CH3 S 0
ODC-flf -ketcbotyrie acid
C*S) NCSCHjCHjCHCOOH
CMj s '
DOC -f tminabutyrie acid
v
S -f CNjSCHjCHjCHCOOH
NHj
Mcthipnint
*
S 4 HCHO
I
V
C02
C>CSSC
rM / I! It \ru
3 S S 1
Thiran
CH
V;$
CHj *»
Heavy rnt tal
eomplexM Hkt
CuOOCj
Oimcthyldtthioearbamatf(poO
CH
CH
DiffiftttylnitrotanMnc
FIGURE 2-1
Degradation Pathways of Thlram and Zlraro In Soil and 1n HUroblal Cultures
Source: Rajagopal et al., 1984
0133d
-9-
02/22/89
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3. EXPOSURE
Pertinent data regarding human exposure to thlram were extremely
limited. The U.S. EPA STORE! data base contained no data regarding the
detection of thlram 1n water, aquatic biota or sediment samples. Because
thlram 1s used as a fungicide In fruit plants, It was analyzed for but not
found 1n samples of sweet cherries and peaches grown domestically In
Ontario, Canada, between 1983 and 1984. The detection limit for thlram In
this study was 0.01 mg/kg (Frank et al., 1987).
Thlram Is used as a primary and secondary accelerator In compounding
rubber (IARC, 1976). In a study by Kru1s-de Vrles et al. (1987), 6 of 8
haemodlalysed patients developed subacute eczematons dermatitis In the area
surrounding the rubber arterlovenous shunt In the forearm.
It Is also possible that the dermatitis was caused by short and
Intermittent contact of the skin with rubber gloves used by the nursing
personnel. Harks and Ralney (1984) conducted a prospective study of 100
surgical patients to Identify causes of contact dermatitis. Patch testing
was performed on 11 patients with post-operative dermatitis or a history of
tape allergy. Two patients had reactions to the tests.
In two abstracts of Russian studies, workers exposed to unspecified
concentrations of thlram exhibited neural and myocardlal disorders, a
thyroid volume Increase, upper respiratory Infections and hematologlcal
alterations (Cherpak et al., 1971; Kaskevlch and Bezugly, 1973).
Although thlram was found at one superfund waste site, other data on
environmental fate and human exposure pathways were not located In the
available literature (U.S. EPA, 1987d).
0133d -10- 08/24/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. McKee and Wolf (1963) reported the
results of a toxtclty test 1n which flngerllng channel catfish were exposed
to thlraro at 19°C. The 96-hour TLffl was 0.79 mg/l.
Frear and Boyd (1967) assessed the acute toxldty of thlram to Daphnla
magna. Daphnlds were exposed singly 1n 100 ml solutions of thlram In
4-ounce bottles. The solubility of thlram In test solutions was enhanced by
use of acetone as a carrier. LD50 values were calculated from the results
of 10 definitive assays. Investigators reported a 26-hour L05(, of 1.3 ppm.
Voronkln and Loshakov (1973) reported a 48-hour LC5Q of 0.67 mg/i
for TubIfex tubJlex exposed to thlram.
Tooby et al. (1975) assessed the toxldty of thlram (80% active Ingre-
dient product) to harlequin fish, Rasbora heteromorpha. under flowthrough
conditions. The dilution water had a hardness of 20 rag/i, a pH of 8.1 and
a temperature of 20°C. Toxldty levels were calculated on the basis of
commercial product and not on active Ingredient. The 24-, 48- and 96-hour
LC5pS were 0.02, 0.012 and 0.007 mg/l, respectively. The Investigators
estimated a 3-month LC5Q of 0.001 mg/i from an extrapolation of the
results of acute studies.
Schneider (1979) reported 24-, 48- and 96-hour LC5()s of 0.138, 0.130
and 0.13 ppm for rainbow trout, Salmo galrdnerl. exposed to solutions of
thlram (99% active Ingredient). The respective LC5Qs for trout exposed to
a th1ram-conta1n1ng product with 75% active Ingredient were 0.50, 0.40 and
0.40 ppm. Exposure of blueglll sunflsh, Lepomls macrochlrus. to thlram (99%
active Ingredient) generated 24-, 48- and 96-hour LC5Qs of 0.21, 0.093 and
0.045 ppm, respectively. The respective LC5Qs for sunflsh exposed to a
0133d -11- 02/22/89
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product containing 75% thlram were 0.71, 0.31 and 0.28 ppm. Tests were
conducted under static conditions In 15 i, of reconstituted water at 12°C
for trout and 18*C for sunflsh.
Bluzat et al. (1981) assessed the acute toxUHy of two commercial
thlram-contalnlng products (product A and product B) to the freshwater
mollusc, Lymnaea staqnalls. Each product contained an 8054 level of thlram
but 20% levels of dissimilar Inactive Ingredients. Snails were exposed to
aqueous suspensions of the products In groups of four In 800 ml of water
at 230 ppm hardness and 2Q°C. The 48-, 72- and 96-hour LC^s based on
active Ingredient for product A were 35.7, 19.1 and 12 ppm, respectively,
and 38, 19.1 and 8.9 ppm, respectively, for product B. The products were
2- to 4-fold more toxic when suspensions were prepared In acetone. The
96-hour LC50s for products A and B were 2.8 and 3.2 ppm, respectively.
Bluzat et al. (1982a) assessed the effects of short-term exposures (1
hour) of scud, Gammarus pulex. to a commercial product (probably product A
as described above) containing 80% thlram. Thirty scud were exposed to
nominal concentrations of thlram ranging from 1-50 ppm In 1 I, of water for
1 hour. Animals were rinsed and transferred to aerated freshwater (hard-
ness=230 ppm, pH=7.5) for 10 days. All scud exposed to 50 ppm died within 5
days of treatment. Scud exposed to 10, 5, 2 and 1 ppm thlram experienced
95, 79, 48 and 25% mortality by the end of the 10-day observation period.
The mortality level among control scud at the end of the 10-day observation
period was 7.5%. Bluzat et al. (1982a) also assessed the dissipation of
acute toxlclty of aged thlram solutions to G. pjl_ex. Groups of scud (n=130
and 190} were exposed for 96 hours to 0.7 ppm aqueous suspensions of thlram
1, 48 and 96 hours after preparation of the test solutions. Scud had 84.6,
91.5 and 50% mortality levels for 96-hour exposures to 1-, 48- and 96-hour
aged solutions of 0.7 ppm thlram, respectively.
0133d -12- 02/22/89
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Bluzat et al. (1982b) assessed the acute toxldty of the two commercial
th1ram-conta1n1ng products (product A and product B described above) to the
freshwater scud, Garomarus pulex. Each product contained an 80% level of
thlram but 20% levels of dissimilar Inactive Ingredients. Scud were exposed
to aqueous suspensions of the products In groups of 10 In 800 ml of water
at 230 ppm hardness and 20°C. The 24-, 48-, 72- and 96-hour LCggS based
on active Ingredient for product A were 14.0, 1.21, 0.41 and 0.20 ppm,
respectively, and 4.77, 0.48, 0.2 and 0.13 ppm, respectively, for product B.
The toxldty of each product was only minimally Influenced by the solvent
used to prepare suspensions (water or acetone). The 96-hour LC5Qs for
products A and 8 In acetone were 0.22 and 0.06 ppm, respectively.
Bluzat and Seuge (1983) assessed the effects of exposure to thlram on
Gamroarus pulex by different routes of exposure (water and diet). Twenty
scud were exposed to aqueous solutions of thlram at concentrations of 0.02,
0.025, 0.035, 0.05 and 0.08 ppm. Test solutions were renewed twice weekly.
The approximate median lethal times for groups of scuds exposed to these
solutions were 30, 8.5, 6.5, 4.5 and 5 days, respectively. Alternately,
scud were offered either dried bean seeds soaked 1n, or pieces of moss
rehydrated In, aqueous suspensions of thlram ranging from 50-10,000 ppm for
48 hours at 8°C. Observations were reported 1n terms of the duration of
treatment over which 90 and 10% of the treated animals were expected to
survive. Scud offered bean seeds treated with 3000 and 10,000 ppm thlram
demonstrated 90% survival after 3-3.5 days and 10% survival after 29-36
days. Control animals survived 7.4-10 and 143-145 days, respectively. Scud
offered mosses treated with 50-10,000 ppm thlram demonstrated 90% survival
after 2.4-5.4 days and 10% survival after 9-27 days. Control animals
survived 5.9-10 and 101-121 days, respectively.
0133d -13- 03/21/89
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Seuge et al. (1983) assessed the acute toxlclty of an aqueous suspension
of thlram 1n a flatworm, Duqesla gonocephala. an Isopod, Asellus aguatlcus.
and an amphibian, Xenopus laevls. at two stages of development (47 and 53).
Organisms were exposed to nominal concentrations of thlram In 800 ml of
water at 230 ppm hardness and 20°C. The 24-, 48-, 72- and 96-hour LC5Qs
for D. gonocephala were 0.53, 0.26, 0.088 and 0.048 ppm, respectively. The
24-, 48-, 72- and 96-hour LC5Qs for A. aauatlcus were 1,882, 688, 161, and
61 ppm, respectively. The 24-, 48-, 72- and 96-hour LC5Qs for X. laevls
were 0.017, 0.014, 0.013 and 0.013 ppm, respectively, for stage 47 and
0.025, 0.022, 0.021 and 0.021 ppm, respectively, for stage 53. The Inves-
tigators noted that the slopes of the response curves were much steeper for
X. laevls than for either of the other organisms tested.
Seuge and Bluzat (1983) assessed the acute toxlclty of fresh and aged
aqueous suspensions of thlram to larvae of the mayfly, Cloeon dlpterum.
Organisms were exposed to nominal concentrations of thlram 1n 800 mi of
water at 230 ppm hardness and 20°C. Tests with larvae were begun within 2
hours of collection from the field. The 24-, 48-, 72- and 96-hour LC^.s
for larvae exposed to freshly prepared solutions of thlram were 1.92, 1.3,
1.08 and 1.01 mg/i, respectively. Tests with larvae that had been held 1n
the laboratory for 4 days before testing demonstrated a significantly
greater sensitivity (-2-fold) to thlram than larvae used Immediately upon
collection. The toxlclty of aged solutions of thlram to larvae of C.
dlpterum was assessed by exposing larvae to solutions that had been prepared
1, 7 and 36 hours before Initiation of exposure. The levels of mortality
after 24 hours were 50.4, 16.7 and 3.3X, respectively. The levels of
mortality after 48 hours were 67.3, 26.6 and 8.654, respectively. The levels
of mortality after 72 hours were 73.6, 46.7 and 22X, respectively.
0133d -14- 03/21/89
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The levels of mortality after 96 hours were 79.5, 64.7 and 45.3X,
respectively.
Kn1e et al. (1983) reported an EC5Q of 0.06 wg/l for Daphnla maqna
exposed to thlram. The respective EC. and EC10Q concentrations were
0.05 and 0.8 yg/i.
Jouany et al. (1985) assessed the toxlclty of thIrani to the water flea,
Daphnla maqna. carp, Cvprlnus carplo. and zebraflsh, Brachyodanlo rerlo.
Daphnlds were exposed to 0, 0.1 and 1 mg/l thlram 1n crystallizing dishes
containing 500 mi of test solution for 24 hours. None of the daphnlds
exposed to 1 mg/l survived, and mortality among those exposed to 0.1
mg/l was 50%. The toxlclty of thlram to carp, Cyprlnus carplo. and
zebraflsh, Brachyodanlo rerlo. was assessed under static conditions In a
synthetic dilution water. There was no mortality among fish of either
species exposed to 0.1 mg/l after 24 hours. Zebraflsh had 100% mortality
at 1.0~mg/i, while carp had no mortality at 1.0 mg/l after 24 hours.
Jouany et al. (1985) also assessed the toxlclty of thlram to zebraflsh by
passage of thlram through a simple food chain. Exponentially growing
cultures of algae were Incubated with 0.1 mg/l thlram for 48 hours. Cells
were centHfuged, washed and offered to daphnlds that were then offered to
zebraflsh. Fish were each fed 20 daphn1ds/day. Mortality among zebraflsh
rose OX at 4 days to 100% at 8 days after Initiation of the experiment.
Mortality among control fish was ~40% after 8 days.
Van Leeuwen et al. (1985a) assessed the acute toxlclty of thlram to
gupples. PoeclHa retlculata. and water fleas, D. roagna. 1n static renewal
assays using standard protocols. The 96- and 48-hour LC5Qs for gupples
and daphnlds exposed to thlram were 0.27 and 0.21 mg/l, respectively.
0133d -15- 02/22/89
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Van Leeuwen et al. (1986a) assessed the acute toxUHy of thlram (>98%
purity) to rainbow trout, Salmo qalrdnerl. F1sh {average weight of 34.0 g
and average length of 15.3 cm), were acclimatized to laboratory conditions
for 5-7 days 1n a 400 t, tank at 15°C. Diluent water used 1n the toxlclty
tests was reconstituted with a pH of 7.8 and a hardness of 50 mg/i. Fish
were fasted for 24 hours before being exposed to thlram In 10 8, tanks.
The 24-hour LC5Q (and 95% confidence limits) was 0.26 mg/l (0.24-0.32).
For flsti weighing ~47 g, the 24-hour LC5Q (and 95% confidence limits) was
0.30 mg/l (0.18-0.50).
Van Leeuwen et al. (1986a) also assessed the sublethal effects of acute
exposure of rainbow trout, S. galrdnerl. to thlram (>98% purity). Ten fish
were exposed to 0.18 mg/l of thlram for 24 hours under the conditions
described above for the lethality assays. Fish were anaesthetized at the
end of the 24-hour exposure period. Tissue samples were analyzed for a
variety of parameters. Exposure of trout to thlram resulted 1n significant
declines In blood glucose levels and IWer protein bound SH content. Inves-
tigators also noted significant Increases In liver LDH activity, percent
llpld content of liver, nonproteln bound SH content In liver, G-6-PDH
activity 1n blood, and blood osmolarlty. The Investigators concluded that
thlram should be regarded as a cytotoxlc chemical.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY Van Leeuwen et al. (1985b) assessed the chronic
effects of thlram (98% purity) on survival, reproduction and growth of the
water flea, Daphnla magna. In a 21-day study. Daphnlds were exposed to
thlram 1n 500 ml of solution 1n 800 ml vessels. Test solutions were
renewed 3 times a week from freshly prepared stock solutions of thlram.
0133d -16- 03/21/89
-------
Test concentrations were not verified by analysis. The test was conducted
at 20°C In a temperature controlled room with a photoperlod of 12 hours.
Diluent water had a hardness of 225 mg/i and a pH of 8.1. Daphnlds
starting at <24 hours old were fed dally with 3xlOB cells/I of the green
algae, Chlorella pyrenoldosa. Investigators reported a 21-day LC5Q of 8
The lowest tested concentration that resulted In a decrease In
fecundity was 10 yg/l. The lowest tested concentration that resulted 1n
a decrease In size of daphnlds after 21 days was 1.8 tig/I. There were
no significant effects on daphnlds exposed to 1 yg/l of thlram over the
21 -day study.
Van Leeuwen et al. (19865) assessed the chronic toxlclty of thlram to
embryolarval stages of rainbow trout, Sal mo galrdnerl. Eggs within 3 hours
of fertilization were exposed to 10-1 volumes of a series of thlram
concentrations In all-glass aquaria. The test temperature was 10°C. Diluent
water was reconstituted with a hardness of 50 mg/i. and a pH of 7.7. Test
solutions were renewed 3 times weekly and were aerated continuously. Thlram
stock solutions were prepared freshly at each renewal. Test concentrations
were not measured, and eggs were kept In the dark until embryogenesls, after
which a photoperlod of 12:12 hours was Imposed. Larvae were not fed during
the study. The 60-day LC (and 95% confidence limits) for embryolarval
stages of rainbow trout exposed to thlram was 1.1 yg/l (1.1-1.2). The
60-day EC5Q (and 95X confidence Tlmlts) based on mortality and teratogene-
sls was 0.64 yg/l (0.57-0,73). The most pronounced teratogenlc lesions
observed Included severe spinal and vertebral abnormalities, scollosls,
lordosls, kyphosls and dwarfed structures of the trunk. The lowest concen-
trations at which there were no observable effects based on mortality, total
embryotoxlclty, length and weight were 1.0, <0.32, <0.32 and 0.56 ug/l,
respectively.
0133d -17- 02/22/89
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Van Leeuwen et al. (1986c) assessed the effects of exposure of juvenile
rainbow trout to tMram. Trout ~5 cm In length were exposed to thlram In
reconstituted water with a hardness of 50 mg/l and a pH of 7.7 for 21
days. Exposure of trout to thlram resulted 1n a concentration-related loss
of glycogen 1n the liver at >25 yg/l and was associated with reduced
body weight gain. At 100 pg/l, thlram Induced a proliferation of bile
duct epithelial cells both with and without formation of new ductules. Cell
necrosis was observed occasionally, and hemorrhages were apparent 1n the
*.
brain and spinal cord at 5 yg/l. The Investigators concluded that the
teratogenlc action of the dithlocarbamates 1s confined to the notochord at
concentrations likely to be encountered In the environment.
4.1.2.2. BIOACCUMULATION/BIOCONCEMIRATION -- No measured steady-state
BCF value for thlram was found In the literature. Based on the regression
equation, log BCF = 2.791 - 0.564 log S (Lyman et al., 1982) and a water
solubility of 30 mg/l (see Section 1.2.), a BCF of 90.8 1s estimated for
this compound. This value suggests that thlram will not bloaccumulate
significantly In aquatic organisms.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY -- D1ehn and Tollln (1967) assessed the effects of
thlram on motnity and topophototaxls of Euqlena gracHls. Phototactlc
responses were determined In a phototaxlgraph using white light of 140
erg/cm2 second. MotllHy of E.. gradlls was determined by microscopic
observation at low levels of Illumination. The Investigators reported that
motmty and topophototaxls were Inhibited to 50% of control organisms
within 30 minutes of exposure to 10~« M solutions of tetramethylthluram
dlsulflde.
0133d
-18-
02/22/89
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KMshnakumarl (1977) assessed the toxlclty of tetramethylthluram
dlsulflde to the green alga, Scenedesmus acutus. Cultures were maintained
at a temperature of 28+1 °C, a light Intensity of 8500 lux and a pH of 7-8.
Growth of cultures was measured dally by optical density. Assays were
continued for 5 days. Cultures exposed to 10 and 100 ppm tetramethylthluram
dlsulflde were dead after 1 and 3 days, respectively. Cultures exposed to
0.5, 1, 5 and 10 ppm demonstrated 90.9, 90.9, 75 and 59% growth compared
with controls after 1 day. Cultures exposed to 0.5, 1 and 5 ppm demon-
strated 83.1, 80.3 and 56.3% growth compared with controls after 3 days.
Cultures exposed to 0.5, 1 and 5 ppm demonstrated 82.0, 77.7 and 42.8%
growth compared with controls. The NOEL for tetramethylthluram dlsulflde 1n
S. acutus appears to be <0.5 ppm.
Gangawane and Kulkarnl (1979) assessed the effect of thlram on growth of
the blue-green algae, Ngstoc sp. and Tolypothrlx sp. Cultures of these
algal species were exposed to thlram In test tubes In 10 mi of medium at
1500 lux and 25°C for 8 hours. Growth of algae was determined by the
optical density of acetone-soluble pigments. The Investigators reported a
25.4% reduction In growth for cultures of Nostoc sp. exposed to 500 ppm
thlram and a 14.1% reduction In growth for cultures of Tolypothrlx sp.
exposed to 100 ppm thlram.
Hutber et al. (1979) assessed the effect of thlram on growth of four
species of blue-green algae, Aphanocapsa (strains 6308 and 6714), Anabaena
vaMabllls and Nostoc. Cultures were maintained at 30°C at 9000 lux Illumi-
nation Intensity. Thlram was added to the cultures during the exponential
growth phase. Exposure of cultures to various concentrations of thlram
continued for 48 hours. The concentrations that reduced the exponential
0133d
-19-
02/22/89
-------
growth rate of these algae by 50% were 50, 100, 50 and 100 ppm, respec-
tively; the concentrations that Inhibited growth completely were 100, >100,
100 and >100 ppm, respectively.
Dive et al. (1980) assessed the toxldty of thlram to the dilate proto-
zoan, Colpldlum campy1urn. Protozoan cultures were cultivated monoxenlcally
on Escherlchla coll. Solutions (0.25 mi) of thlram with acetone as a
carrier were added to 50 ml of culture medium. Protozoa were counted with
a Coulter counter after 43 hours of Incubation at 20°C. The minimal active
dose of thlram required to produce reductions 1n the number of generations
of C. campy1urn was 0.3 mg/i.
Vasseur et al. (1982) assessed the toxlclty of thlram to the alga,
Chlorella vulgar Is. by monitoring the effect on ATP levels. Cultures were
swirled at a rate of 150 oscillations/minute and maintained at 20°C under
1500 lux Intensity light. The 24-hour IC__ for C. vulqarls based on ATP
levels^ias >2 ppm thlram.
Kn1e et al. (1983) reported an EC,Q of >6 mg/i for the alga,
Haematococcus pluvlalls. exposed to tetramethylthluram dlsulfIde.
D1ve et al. (1984) assessed the effects of thlram on growth of various
strains of the dilates, Tetrahymena thermophlla and Tetrahymena pyrlformls.
and various species of amoebae, dilates were exposed to thlram In sterile
cotton plugged glass tubes containing 10 ml of medium. Tests were
performed 1n an automatic blophotometer. Optical density of cultures was
monitored every 30 minutes for 3 days. Experiments were conducted at 28, 37
and 39°C. The effects of thlram on amoebae growth was achieved by exposing
amoebae to th1ram-contaminated agar plates spread with bacteria or yeast. A
drop of amoebae cyst suspension was placed 1n the center of the plate.
0133d -20- 02/22/89
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Growth of amoebae was monitored by observation of the extension of lysis of
the prey. Growth rates of dilate strains were Inhibited completely at 1.0
mg/l thlram for all but one strain cultured at 28°C. At 0.5 mg/l,
growth rates were relatively unaffected, except for a single strain.
Effects of thlram on growth of amoebae were highly variable and species- and
strain-dependent. Growth Inhibition ranged from 0.5-16 mg/l. Complete
Inhibition of growth commenced at 8 mg/l for one species but was >32
mg/t for several strains of another species.
Grollere and Dupy-Blanc (1985) reported that thlram Induced a lengthen-
ing of the generation time In heat shock synchronized axenlc cultures of
Tetrahymena pyrlformls. The effect was observed for concentrations of
thlram ranging from 0.25-1.0 mg/l applied at the end of the 6th heat shock
treatment and at various Intervals (<90 minutes) after completion of heat
shock treatments.
Jouany et al. (1985) assessed the toxlclty of thlram to the green alga,
Chlorella vulgar 1s. Algal cultures were Incubated at 20°C under 1500 lux
and a 16:8 photoperlod on a gyratory shaker at 150 rpm. Thlram was added to
exponentially growing cultures with cell concentrations of 15x10*
cells/ml. The 72-hour ICrQ for growth of algal cultures as determined
by optical density at 665 nm was -5.5 mg/l.
Van Leeuwen et al. (1985a) assessed the toxlclty of thlram to algae,
Chlorella pyrenoldosa. Algal bloassays were conducted at 20°C with an
Initial cell density of ~108 cells/l In 200 ml Erlenmeyer flasks held
on a mechanical shaker. Cells were counted with a Coulter counter. The
96-hour EC5Qs for two measures of algal density, the average specific
growth rate and effects on the time-lag until maximum population growth,
were 1.0 and 0.03 mg/l, respectively. Van Leeuwen et al. (1985a) also
0133d -21- 02/22/89
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assessed the effects of thlram on photosynthesis and respiration 1n C.
pyrenoldosa. Effects of thlram on photosynthesis was assessed by Incubating
algae with NaH14C03 1n the presence of thlram for 4 hours and determin-
ing the bicarbonate uptake by liquid scintillation. Effects of thlram on
respiration were assessed by Incubating 14C-labeled algae 1n the dark for
16 hours before determining the radioactivity remaining 1n the cells by
liquid scintillation. The ECgo for assimilation of radioactive bicarbon-
ate by algae was 4.0 mg/i. The EC5_ for respiration of 14C by algae
was >10.0 mg/l.
Taylor and Pace (1987) assessed the effect of thlram on growth of
cultures of a chrysomonad and a dilate, Cvclldlure sp. Log-phase cultures
of the chrysomonad and dilate were exposed to thlram for 24 and 48 hours,
respectively. In darkness at 22°C. Culture flasks were neither agitated nor
aerated. Growth of the chrysomonad was Inhibited completely following
exposure to 210 pH thlram. Growth of the dilate was Inhibited completely
at -80 and -1800 yM, but. was Inhibited 60% of control levels at -560 yM
thlram. Taylor and Pace (1987) also reported that 4 »ft thlram did not
Inhibit growth of a chlorophyte, Dunallella tertolectlca. after 7 days.
Growth of five other phytoplankton species were Inhibited from -0.2-18.6% of
controls by exposure to 4 pM thlram for 7 days.
4.1.3.2. BIOCONCENTRATION Pertinent data regarding the blocon-
centratlon potential of thlram 1n aquatic flora were not located 1n the
available literature cited In Appendix A.
4.1.4. Effects on Bacteria. Van Leeuwen et al. (198Sa) assessed the
toxlclty of thlram to luminescent bacteria, Photobacterlum phosphoreum. and
nitrifying bacteria, Nltrosomonas and NUrobacter. The EC value for P.
phosphoreum exposed to thlram, defined as the concentration of thlram that
0133d -22- 03/21/89
-------
produced a 50% reduction 1n bacterial luminescence after 15 minutes, was 0.1
mg/i. The effects of exposure to thlram on the nitrification process of a
mixed culture of Nltrosomonas and NUrobacter were monitored by using a
pH-1nd1cator mixture that assessed the conversion of ammonia by nitrite to
nitrate. The lowest effective concentration or minimum Inhibiting concentra-
tion of thlram on the nitrification process after 3 hours was 18 mg/i.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Tucker and Crabtree (1970) reported the results
of studies assessing the acute oral toxlclty of thlram to 3- to 4-month-old
pen-reared mallard ducks. Anas platvrhvnchos. and ring-necked pheasants,
Phaslanus colchlcus. Birds were dosed by Inserting gelatin capsules con-
taining thlram through glass tubing to the level of the crop, proventrlculus
or stomach. Birds were fasted for 16-20 hours before dosing. Two to seven
animals were employed at each of four dosage levels. Birds were observed
for 14 days post treatment. The authors reported oral LD5Qs of >2800 and
673 (95% confidence limits of 485-932) mg/kg for ducks and pheasants,
respectively.
Egberts et al. (1972) examined the oral chronic toxlclty of thlram to
Japanese quail, Coturnlx coturnlx. Four groups of quail consisting of five
hens and two cocks each were exposed to thlram 1n their diet (turkey
starter) at concentrations of 2, 10 and 50 ppm (mg/kg) for 11 weeks.
Females were housed separately but mated with one of the males each 2.5
days. There were no statistically significant effects 1n birds offered feed
contaminated with 10 ppm thlram. Birds fed 50 ppm contaminated feed demon-
strated significant reductions 1n numbers of eggs laid and hatched and shell
thickness of eggs. Investigators also demonstrated that there were signifi-
cant reductions 1n the numbers of lymphocytes, granulocytes and monocytes of
blood from birds dosed with 50 ppm ttilram-contaminated feed.
0133d -23- 03/21/89
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Heath et al. (1972) assessed the oral acute toxlclty of thlram to
Japanese quail, C. coturnlx japonlca. pheasant, P. colchlcus. and mallard
ducks, A. platyrhvnchos. All test birds were Incubator-hatched progeny of
breeding colonies. Thlram was dissolved In a carrier and added to the diet
by mixing with commercial mash In a ratio of 2 parts of solution to 98 parts
of feed by weight. Birds were offered thlram-contaminated mash for 5 days
and monitored for 3 days after termination of treatments. The Investigators
reported a lack of mortality among quail and pheasants fed the highest
concentration tested (5000 ppm 1n feed). Mallard ducks experienced 20%
mortality among birds fed mash containing 5000 ppm thlram.
Lorgue et al. (1975) also examined the oral acute toxldty of thlram to
quail. These Investigators reported that thlram-contaminated feed (20 g
Thlrban/10 kg) caused Immediate (24 hours) blockage of egg laying and
regression of secondary sexual characteristics In males. These effects were
reversible on withdrawal of contaminated feed from diet. Lorgue and Soyez
(1976) assessed the oral toxlclty of thlram to gray partridges. Thlram at
1.6 g/kg completely Inhibited egg laying within 48 hours. The Incidence of
embryonic mortality was Increased significantly at 4-fold lower doses.
Gruen et al. (1982) assessed the acute toxlclty of thlram to Japanese
quail C., coturnlx Japonlca. The Investigators reported an ID and an
LC50 of 695 and >10,000 mg/kg, respectively. Hadhazy and GlavHs (1982)
reported that 100 and 200 g thl ram/100 kg feed caused Imperfect egg shell
calcification and production of eggs with abnormal size and form 1n
pheasants. Apparently, disturbances were due to oviduct Inflammation, but
were reversible 2-3 weeks after cessation of dosing.
Schafer and Bowles (1985) reported the results of studies assessing the
ALD of thlram to wild-trapped deer mice, Peromyscus manlculatus. The ALD
(1133d -24- 02/22/89
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was obtained with a single level at each treatment that was 50% higher than
the preceding treatment. Thlram was administered by gavage with a carrier.
Mice were monitored for mortality for 3 days. Investigators reported an ALD
of 1600 mg/kg; deer mice Ingested an average of +200 mg th1 ram/kg bw/day
over the 3-day test period.
Roark and Dale (1979) assessed the toxldty of thlrara to earthworms,
E1sen1a foetlda. Worms were exposed to thlram by Immersion In a 2.0%
solution for 1 minute, as a component of their diet (bermudagrass feed
treated with a 0.1% aqueous solution), and mixed with the worms' culture
soil (0.426 g thlram In 4719 cm3 of soil). Worms exposed to thlram by
Immersion experienced mortality levels ranging from 5%, 7 days posttreat-
ment, to 38%, 101 days posttreatment. Worms fed th1ram-treated bermuda-
grass clippings experienced mortality levels ranging from 10% after 34 days
of treatment to 42% after 101 days. Mortality among worms reared In thlram-
treated~so1l ranged from 21% after 10 days to 98.1% after 29 days and 99.9%
after 52 days.
4.2.2. Effects on Flora. Ingham (1985) reviewed the effects of thlram-
contalnlng products on soil bacteria and fungi In a wide variety of test
systems. The author listed Inhibitory and stimulatory effects, as well as
the presence of tolerant populations of soil mlcroflora.
4.3. FIELD STUDIES
Pertinent data regarding the effects of thlram on flora and fauna In the
field were not located 1n the available literature cited 1n Appendix A.
4.4. AQUATIC RISK ASSESSMENT
Aquatic toxldty data for tetramethylthluram dlsulflde (thlram) were
sufficient to calculate a Final Acute Value, Final Chronic Value, final
Acute-Chronic Ratio and Final Plant Value. The lack of appropriately
0133d -25- 03/31/89
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conducted b1oconcentrat1on/b1oaccumulat1on studies prevented the estimation
of a Final Residue Value.
The Final Acute Value was calculated from GMAVs for flatworms, Dugesla
gonocephala (0.038 mg/i), blueglll sunflsh, lepomls macrochlrys (0.045
mg/i), scud, Gamma r us pulex (0.104 mg/l), and rainbow trout, Salmo
qalrdnerl (0.13 mg/l), listed In Figure 4-1 using the computer program
appearing In Figure 4-2. The Final Acute Value obtained In this manner was
20.4 tig/1 (Figure 4-3).
The Final Chronic Value was calculated from the ratio of the Final Acute
Value and the final Acute-Chronic Ratio. The Final Acute-Chronic Ratio was
calculated from the geometric mean of the ratio of results from acute and
chronic studies listed In Figure 4-1 with rainbow trout, Salmo galrdnerl
(0.13/0.00032=406.25), and the water flea, Daphnla magna (0.21/0.000134=
1567.16). The Final Acute-Chronic Ratio obtained from the geometric mean of
406.25~and 1567.16 was 797.91 (see Figure 4-3). The Final Chronic Value
obtained from the ratio of the Final Acute Value and the Final Acute-Chronic
Ratio (20.4/797.91) was 0.0256 vg/l (see Figure 4-3).
The Final Plant Value was obtained from the lowest EC obtained from
an acceptable study with freshwater algae. The Final Plant Value obtained
In this manner was 0.03 mg/l for a study with Chlorella pyrenoldosa (see
Figures 4-1 and 4-3).
The Criterion Maximum Concentration as described 1n U.S. EPA/OWRS (1986)
Is equal to 1/2 the Final Acute Value (20.4/2). The Criterion Continuous
Concentration as described In U.S. EPA/OWRS (1986) 1s equal to the lowest of
the Final Chronic Value, the Final Plant Value and the Final Residue Value.
0133d
-26-
03/31/89
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Family
*1
Chordat*
f2
Chorda!* (warmvat*r fi*h>
3
Chordat* (fi«h or amphibian)
#4
Cru«tac*an ' (planktonic)
*S
Cru*tac*an ( b*nthic >
*6
Xn**ctan
#7
non- Arthropod/ -Chorda!*
*a
H*v Zna*ctan or phylum
r*pr*a*ntativ*
f9
alga*
10
Vascular plant
TEST TYPE
GHAV
0.13*
0. 045*
0.27*
0.21*
0. 104'
0. 81*
0. 038"
0.67'
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
GttCV*
<0. 00032 J
NA
NA
0.000134"
MA
NA
NA
NA
0. 03>
NA
BCF«
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
*NA*not availabl* * 96-hr LC»« in ppm for rainbow trout Salmo Qairdn*ri
96-hr LC«* in pp* for blu»gill «unfi*h L*oomia- macrochirua- "96-hr LC«0
in mg/L for guppi** Po*cilia r*tieulata 48-hr LC*« in mg/L for th*
wat*r fl*a Daphnia maana '96-hr LC«« in mg/L for >cud Gammarus oul*x .
96-hr LC(* for th* mayfly Clo*on diotarum "96-hr LC>o for th* flatworm
Duo*eia oonoophala > 48-hr LCi* in mg/L for th* worm Tubif*x tubif*x
^ 60-day NOEC in mg/L for rainbow trout g.. oairdn*ri "21-day NOEC in
mg/L for th* wat*r fl*a £. maona >96-hr EC.* in mg/L for th* alga
Chlor*lla pvr*noido«a
FIGURE 4<1
Organization Chart for Listing GMAVs. GHCVs and
BCFs Required to Derive Numerical Water Quality Criteria
by the Method of U.S. EPA/OURS (1986) for the Protection of
Freshwater Aquatic Life from Exposure to Thlram
0133d
-27-
03/31/89
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10 REH THIS PROGRAM CALCULATES THE FAV WHEN THERE ARE LESS THAN
20 REM 59 HAVS IN THE DATA SET
30 X«0
40 X2-0
50 Y»0
60 Y2»0
70 PRINT "HOW HANY HAVS ARE IN THE DATA SET?"
80 INPUT N
90 PRINT "WHAT ARE THE FOUR LOWEST HAVS?'
100 FOR R*l TO 4
110 INPUT V
120 X«X*LOG(V)
13O X2«X2*(LOG(V»*(LOG(V»
140 P-R/(N*1)
150 Y2«Y2*P
160 Y«Y*SQR
170 NEXT R
180 S»SQR«X2-X»X/4>/(Y2-Y*Y/4)J
190 L»(X-S»Y)/4
200 A«S«SQR(O.OS)»L
2JLO F«EXP(A>
220 PRINT "FAV - »F
230 END
FIGURE 4-2
Example Computer Program In BASIC Language for Calculating the
Final Acute Value
Source: U.S. EPA/OWRS, 1986
0133d
-28-
03/31/89
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Freehwater*
Saltwater'
FAV«
20.4
ug/L
ID
FCV»
0. 0256
ug/L
ID
FACR«
797. 91
ID
FPV«
30 ug/L
ID
FRV*
ID
ID
Minimum data requiremente for generation of a Final Acute Value
(FAV) include the results of at least one accepatable teat vith
organisms in each of eight taxonomic families.
Minimum data requirement* for generation of a Final Chronic
Value (FCV) Include the result* of at leaet one acceptable teet
with organisms in each of three taxonomic familie* with at least
one fieh and one invertebrate. A freshwater criterion muat
include at least one apeclee that ia freahwater while the
remaining may be marine. A aaltwater criterion muat include at
leaat one apeciea that ia marine while the remaining may be
freahwater.
Minimum data requirement* for .generation of a Final Acute-Chronic
Ratio (FACR) include aatiafying the minimum data requirements for
- the FAV and FCV.
'The Final Plant Value (FPV)' la obtained by aelectlng the loweat plant
value from a teat with either an algae or vascular plant in which
the concentrationa of teat material were measured.
The Final Residue Value (FRV) ia obtained by aelecting the lowest of
the available residue values.
'ID»Insufficient data for calculation of a criterion.
FIGURE 4-3
Summary Chart for Data Required to Generate Criteria by the Method
of U.S. EPA/OWRS (1986) for Safe Levels of Thlram In Aquatic Environments
0133d
-29-
03/31/89
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The procedures described In U.S. EPA/OWRS (1986) Indicate that, except
possibly where a locally Important species Is very sensitive, freshwater
aquatic organisms and their uses should not be affected unacceptably 1f the
4-day average concentration of tetramethylthluram dlsulflde (thlram) does
not exceed the Criterion Continuous Concentration of <0.0256 yg/i more
than once every 3 years on the average, and 1f the 1-hour average concentra-
tion does not exceed the Criterion Maximum Concentration of 10.2 yg/J.
more than once every 3 years on the average.
The lack of pertinent data regarding the effects of exposure of marine
fauna and flora to tetramethylthluram dlsulflde (thlram) prevented the
development of a saltwater criterion.
4.5. SUMMARY
The 96-hour TL of thlram In flngerllng channel catfish was reported
as 0.79 mg/l (McKee and Wolf, 1963). The 26-hour LD5Q of thlram to
Daphnla magna was 1.3 ppm (Frear and Boyd, 1967). The 48-hour LC5Q of
thlram to Tublfex tublfex was 0.67 mg/4 (Voronkln and Loshakov, 1973).
Tooby et al. (1975) reported a 96-hour LC5Q of 0.007 rag/* (based on
concentration of product) for harlequin Hsh, Rasbora heteromorpha. exposed
to a thlram-contalnlng product with 80% active Ingredient under flowthrough
conditions. Tooby et al. (1975) estimated a 3-month LC5Q of 0.001 mg/J,
from an extrapolation of the acute test results.
Schneider (1979) reported 96-hour LC5Qs of 0.13 and 0.4 ppm for
rainbow trout, Salmo galrdnerl. exposed to solutions of thlram (99 and 75%
active Ingredient, respectively). Exposure of blueglll sunflsh, Lepomls
macrochlrus. to thlram (99 and 75% active Ingredient) generated 96-hour
LC5 s of 0.045 and 0.28 ppm, respectively. The 96-hour LC5Qs (based on
active Ingredients) for two products each containing an 80% level of thlram
0133d -30- 03/31/89
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but 20% levels of dissimilar Inactive Ingredients to the freshwater mollusc.
Lvmnaea staqnalls. were 12 and 8.9 ppm for products A and B, respectively.
In aqueous solutions (Bluzat et al., 1981). The 96-hour LC5Qs for acetone
suspensions of products A and B were 2.8 and 3.2 ppm, respectively.
Exposure of scud, Gammarus pulex. to 10, 5, 2 and 1 ppm of a commercial
product containing 80% thlram resulted 1n 95, 79, 48 and 25% mortality after
10 days {Bluzat et al., 1982a). Groups of scud (n=130 and 190} exposed to
0.7 ppm aqueous suspensions of thlram 1, 48 and 96 hours after preparation
of the test solutions experienced 84.6, 91.5 and 50% mortality levels,
respectively, after 96 hours of treatment. The 96-hour LC5_s for two
commercial thlram-contalnlng products (80% active Ingredient) to G. pulex
were 0.20 ppm and 0.13 ppm for products A and B, respectively, 1n aqueous
solutions (Bluzat et al., 1982b). The 96-hour LC5Qs for products A and B
1n acetone were 0.22 and 0.06 ppm, respectively. The approximate median
lethal times for G. pulex exposed to 0.02, 0.025, 0.035, 0.05 and 0.08 ppm
solutions of thlram were 30, 8.5, 6.5, 4.5 and 5 days, respectively (Bluzat
and Seuge, 1983). Scud offered bean seeds treated with 3000 and 10,000 ppm
thlram demonstrated 90% survival after 3-3.5 days and 10% survival after
29-36 days. Scud offered mosses treated with 50-10,000 ppm thlram deomon-
strated 90% survival after 2.4-5.4 days and 10% survival after 9-27 days.
The 96-hour LC5Qs for the flatworm, Duqesla qonocephala. the Isopod,
As ell us aquatlcus. and the amphibian, Xenqpus laey1s. at two stages of
development (47 and 53) were 0.048, 61, 0.013 and 0.021 ppm, respectively
(Seuge et al., 1983). The 96-hour LC5Q for mayfly larvae, Cloeon
dlpterum. exposed to freshly prepared solutions of thlram was 1.01 mg/1.
Solutions of thlram aged for 1, 7 and 36 hours produced mortality levels
among mayfly larvae of 79.5, 64.7 and 45.3%, respectively, after 96 hours of
exposure (Seuge and Bluzat, 1983).
0133d
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The respective EC,,, EC5Q and EC100 for Daphnla maqna exposed to
tetramethylthluram dlsulflde were 0.05, 0.06 and 0.8 yg/l, respectively
(Knle et al., 1983). Oouany et al. (1985) reported OX mortality for the
water flea, Daphnla maqna. carp, Cyprlnus carj>1o. and zebraflsh, Brachyo-
danlo rerlo. exposed to <0.1, 1.0 and 0.1 mg/i after 24 hours. Zebraflsh
fed thl ram-contaminated daphnlds experienced a linear Increase In mortality
from 0-1 00% between 4 and 8 days after the Initiation of the experiment.
The 96- and 48-hour LC5_s for gupples, Poec111a retlculata. and daphnlds,
Daphnla maqna. exposed to thlram were 0.27 and 0.21 mg/i, respectively
(Van Leeuwen et al.. 1985a). The 24-hour LC5Q of thlram (>98X purity) to
rainbow trout, Salmo qalrdnerl. weighing 34.0 g was 0.26 mg/4. The
24-hour LC50 for trout weighing -47 g was 0.30 mg/l (Van Leeuwen et al.,
1986a). Exposure of trout to thlram also resulted 1n significant changes In
several blood parameters.
The 21-day LC,.rt for thlram 1n the water flea, Daphnla maqna. was 8
50 -
iig/i. (Van Leeuwen et al., 1985b). The lowest tested concentration that
resulted In a decrease 1n fecundity was 10 yg/l. The lowest tested
concentration that resulted 1n a decrease In size of daphnlds after 21 days
was 1.8 yg/4. There were no significant effects on daphnlds exposed to
of thlram over the 21 -day study.
The 60-day LC5Q for embryolarval stages of rainbow trout, Salmo
qalrdnerl. exposed to thlram was 1.1 yg/l (Van Leeuwen et al., 1986b).
The 60-day EC based on mortality and teratogenesls was 0.64 iig/l.
The lowest concentrations at which there were no observable effects based on
mortality, total embryotox1c1tyt length and weight were 1.0, <0.32, <0.32
and 0.56 yg/l, respectively. Exposure of juvenile rainbow trout to
thlram for 21 days resulted In a concentration-related loss of glycogen In
the liver at >25 yg/l and was associated with reduced body weight gain.
0133d -32- 03/31/89
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At 100 yg/l, thlram Induced a proliferation of bile duct epithelial
cells both with and without formation of new ductules. Cell necrosis was
observed occasionally, and hemorrhages were apparent In the brain and spinal
cord at 5 v9/l (Van Leeuwen et al., 1986c). Thlram 1s not expected to
bloaccumulate significantly In aquatic organisms based on an estimated BCF
value of 90.8.
MotllHy and topophototaxls of Euqlena qracllls were Inhibited to 50% of
control organisms within 30 minutes of exposure to 10~* M solutions of
tetramethylthluram dlsulflde (D1ehn and Tollln, 1967). Cultures of the green
alga, Scenedesmus acutus. exposed to 10 and 100 ppm tetramethylthluram
dlsulflde were dead after 1 and 3 days, respectively. The NOEL appears to
be <0.5 ppm. Gangawane and Kulkarnl (1979) reported a 25.4% reduction In
growth for cultures of Nostoc sp. exposed to 500 ppm thlram and a 14.1%
reduction In growth for cultures of Tolypothrlx sp. exposed to 100 ppm
thlram. Hutber et al. (1979) reported that growth of four species of
blue-green algae, Aphanocapsa (strains 6308 and 6714), Anabaena vaMabnis
and Nostoc. was reduced by 50% on exposure to 50, 100, 50 and 100 ppm
thlram, respectively. The concentrations of thlram that Inhibited growth
completely were 100, >100, 100 and >100 ppm, respectively.
The minimal active dose of thlram required to produce reductions In the
number of generations of the dilate protozoan, Colpldlum campyTurn, was 0.3
mg/i (Dive et al., 1980). The 24-hour IC5Q for Chlorella vulgarls based
on ATP levels was >2 ppm thlram (Vasseur et al., 1982). Kn1e et al. (1983)
reported an EC,Q of >6 mg/i for the alga, Haematococcus pluvlalls.
exposed to tetramethylthluram dlsulflde. Growth rates of the dilates,
Tetrahymena thermophlla and Tetrahymena pyrlformls strains, were Inhibited
completely at 1.0 mg/i thlram for all but one strain at 28°C (Dive et al.,
0133d -33- 03/31/89
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1984). Growth Inhibition of amoebae exposed to thlram was achieved at
concentrations ranging from 0.5-16 mg/l. Thlram at concentrations ranging
from 0.25-1.0 mg/i Induced a lengthening of the generation time In heat
shock synchronized axenlc cultures of Tetrahymena pyMformls (Grollere and
Dupy-Blanc, 1985}.
The 72-hour IC5Q for growth of the green alga, Chlorella vulgar 1s.
exposed to thlram as determined by optical density at 665 nm was -5.5 mg/l
(Jouany et a!., 1985). The 96-hour EC5Qs for the average specific growth
rate and effects on the time-lag until maximum population growth 1n
Chlorella pyrenoldosa were 1.0 and 0.03 mg/l, respectively (Van Leeuwen et
a!., 1985a). The EC5Q for assimilation of radioactive bicarbonate by C.
pyrenoldosa was 4.0 mg/l. The EC5Q for respiration of 14C by C.
pyrenoldosa was >10.0 mg/l.
Growth of a chrysomonad was Inhibited completely following exposure to
210 yM thlram. Growth of the dilate, Cyclldlum sp., was Inhibited
completely at -180 jiM thlram (Taylor and Pace, 1987). Growth of a chloro-
phyte, Dunallella te.rto1ec.t1ca, was Inhibited at 4 jiH thlram after 7 days.
Growth of five other phytoplankton species was Inhibited from -0.2-18.6% of
controls by exposure to 4 yH thlram for 7 days. The 15-mlnute EC5Q
value for Photobacterlum phosphoreuro exposed to thlram was 0.1 mg/i (Van
Leeuwen et al., 1985a). The lowest effective concentration or minimum
Inhibiting concentration of thlram on the nitrification process of a mixed
culture of Nltrosomonas and NUrobacter after 3 hours was 18 mg/l.
The oral LD5Qs for thlram In mallard ducks, Anas platyrhynchos, and
ring-necked pheasants, Phaslanus colchlcus. were >2800 and 673, respectively
(Tucker and Crabtree, 1970). Egberts et al. (1972) reported no statistic-
ally significant effects 1n Japanese quail, Coturnlx coturnlx. offered feed
0133d -34- 03/31/89
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contaminated with 10 ppro thtram for 11 weeks. Birds fed 50 ppm contaminated
feed demonstrated significant reductions 1n numbers of eggs laid and hatched
and shell thickness of eggs. There were also significant reductions 1n the
numbers of lymphocytes, granulocytes and monocytes of blood from birds dosed
with 50 ppm thlram-contaminated feed. Heath et al. {1972} reported a lack
of mortality among Japanese quail, C. coturnlx japonlca. and pheasant, P.
colchlcus, fed the highest concentration of thlram tested (5000 ppm In
feed). Mallard ducks. Anas platyrhynchos. fed mash containing 5000 ppm
thlram had 20% mortality.
Lorgue et al. (1975) reported that thlram-contaminated feed (20 gc
Th1rban/I0 kg) caused Immediate (24 hours) blockage of egg laying In quail
and regression of secondary sexual characteristics In males. Lorgue and
Soyez (1976) reported that thlram completely Inhibited egg laying by gray
partridges exposed to 1.6 g/kg within 48 hours. The Incidence of embryonic
mortality was Increased significantly at 4-fold lower doses. The LD5_ and
LC50 of tn1ram to Japanese quail, C. coturnlx Japonlca. were 695 and
>10,000 mg/kg, respectively (Gruen et al., 1982). Hadhazy and Glavlts
(1982) reported that 100 and 200 g thlram/100 kg feed caused Imperfect egg
shell calcification and production of eggs with abnormal size and form In
pheasants.
Earthworms, Elsenla foetlda exposed to thlram by Immersion had mortality
levels ranging from 5%, 7 days posttreatment, to 38X, 101 days posttreatment
(Roark and Dale, 1979). worms fed thlram-treated bermudagrass clippings had
mortality levels ranging from 10% after 34 days of treatment to 42% after
101 days. Mortality among worms reared 1n thlram-treated soil ranged from
21X after 10 days to 98.IX after 29 days and 99.9X after 52 days. The ALD
of thlram to wild-trapped deer mice, Peromyscus manlcujatus. was reported to
be 1600 mg/kg (Schafer and Bowles, 1985).
0133d -35- 03/31/89
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5. PHARHACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the absorption of thlram were not located In
the available literature cited In Appendix A.
5.2. DISTRIBUTION
ACGIH (1986) stated that after absorption (respiratory, dermal, gastro-
intestinal), thlram Is widely distributed, with much of the dose excreted
unchanged 1n the urine and feces. Supporting data were not provided.
5.3. METABOLISM
In a general discussion of the reactions of the dlsulflde analogs of
dlalkyldlthlocarbamates Including thlram, Rannug and Rannug (1984) stated
that these compounds have a tendency to participate 1n redox-reactlons. For
example, thlram 1s reduced by glutathlone to d1methyld1th1ocarbamate In two
steps as Illustrated In Figure 5-1. Thlram may also Interact with SH-groups
of proteins, which could result 1n the Inhibition of a number of enzymes.
Dalvl and Deoras (1986) studied the metabolism of thlram to carbon
dlsulflde In male Sprague-Dawley rats treated by 1ntraper1tonea1 Injection.
Rats were treated with thlram 1n corn oil at doses of 15, 30 or 60 mg/kg,
and expired air was collected and analyzed for carbon dlsulflde for 5 hours
after dosing. The results indicated a dose-related Increase In the propor-
tion of the dose exhaled as carbon dlsulflde, with 0.510, 2.334 and 5.435
titnol carbon dlsulflde/g of thlram (0.012, 0.056 and 0.13% of administered
dose) exhaled at doses of 15, 30 and 60 mg/kg. respectively. Carbon
dlsulflde was detected beginning 1.5-2 hours after treatment. Pretreatment
of rats with Intraperltoneal Injections of phenobarbltal to Induce mlcro-
somal enzyme activity resulted In a nonsignificant Increase In the amount of
carbon dlsulflde exhaled from a 60 mg/kg Intraperltoneal dose of thlram.
0133d -36- 03/31/89
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s s
II II
CCH3>|,N-C-S-S-C-N(CH3>2
ThirM
$-G
Glutathionc
.1 IS
-------
Pretreatment with SKF S25-A to Inhibit mlcrosomal enzyme activity resulted
In a significant (p<0.05) decrease In the amount of carbon dlsulflde
exhaled. According to the Investigators, these results suggest the Involve-
ment of liver mlcrosomal enzymes In the metabolism of thlram. Dalvl and
Deoras (1986) noted that Merlevede and Peters (1965) detected carbon
dlsulflde 1n expired air following oral administration of thlram to humans.
5.4. EXCRETION
Without providing documentation, ACGIH (1986) stated that thlram 1s
"mainly excreted unchanged 1n urine and feces." Dalvl and Deoras (1986)
reported a dose-related Increase 1n the amount of carbon dlsulflde exhaled
following the treatment of rat.s with an Intraperltoneal Injection of thlram
(15-30 mg/kg). Other routes of excretion were not studied.
5.5. SUMMARY
Although specific quantitative data concerning the pharmacoklnetlcs of
thlram are limited, ACGIH (1986) stated (without providing documentation)
" that following absorption, thlram .Is widely distributed, and Is predomi-
nantly excreted unchanged In the urine and feces. Rannug and Rannug (1984)
stated that thlram and other bisulfides have a tendency to participate In
redox-reactlons. Thlram 1s reduced by glutathlone to d1methyld1th1ocarba-
mate, and 1t may also Interact with SH-groups of proteins, which may result
In the Inhibition of a number of enzymes. Dalvl and Deoras (1986) reported
a dose-related Increase 1n the amount of carbon dlsulflde exhaled following
treatment of rats with an Intraperltoneal Injection of thlram.
»
0133d -38- 03/31/89
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC Pertinent data regarding the toxldty of
thlram following chronic Inhalation exposure were not located 1n the
available literature cited 1n Appendix A.
6.1.1.2. CHRONIC Flshbeln (1976) summarized a report by
Slvlttskaya (1974) concerning ophthalmologlc changes In 50 workers (20-58
years old) with prolonged occupational contact (not otherwise specified)
with thlram. The predominant route of exposure and exposure concentrations
were not stated. The Initial symptoms reported were lacrlmatlon and photo-
phobia, which disappeared after prolonged Interruption of contact with
thlram. Additional symptoms reported were chronic conjunctivitis, reduced
visual acuity, delayed dark adaption, reduced corneal sensitivity, change In
the diameter of the retinal vessels and Increased tonometrlc and retinal
artery pressure.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC In a 13-week study. Lee et al. (1978) provided
groups of 20 young male CD rats with practical grade thlram In the diet at
0, 0.05, 0.1 or 0.25%. Variables evaluated Included general appearance and
behavior, food Intake, body weights, comprehensive hematology and blood
chemistry analyses, organ weights and comprehensive hlstopathologlcal exami-
nations. According to the Investigators, these diets provided thlram doses
of. 0, 30, 58 or 132 mg/kg/day. Body weight gain was 81. 64 and 22% of
controls 1n low-, middle- and high-dose rats. Statistical analysis of body
weight gain data was not performed. Food Intake was also reduced In a
dose-related manner In all treated groups compared with controls. One rat
0133d -39- 03/31/89
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treated at 58 mg/kg/day and five at 132 mg/kg/day died. At 132 mg/kg/day,
SGOT and SGPT were mildly elevated, while a mild elevation of BUN was noted
1n rats treated at 58 mg/kg/day. No changes In hematologlcal parameters
were reported. The only hlstologlcal effect observed was mild tubular
degeneration of the testes with atypical spermatlds 1n the epldldymls 1n
rats treated at 132 mg/kg/day. In another report of this study. Short et
al. (1976) stated that rough hair coats and alopecia were observed at 58 and
132 mg/kg/day. In contrast to the report by Lee et al. (1978), Short et al.
(1976) stated that 70% of the rats died at 132 mg/kg/day.
In a study by Lowy et al. (1979, 1980), groups of six young (0.080 kg)
male Ulstar rats were fed diets containing thlram (90% pure) at 0, 225, 300,
450, 600, 900 or 1200 ppm for 29 days. Similar groups of rats were
maintained as pair-fed controls. Based on food Intake and body weight data
provided by the Investigators (Lowy et al., 1980), the rats were treated
with thlram at estimated doses of 0, 33.6, 41.9, 54.7, 71.9, 106.7 or 143.4
mg/kg/day. The results Indicated that body weight gain was significantly
reduced (Flsher-Snedecor F test) compared with pair-fed controls at 300 ppm
(41.9 mg/kg/day) on study days 16 and 19, and was consistently reduced
compared with pair-fed controls at >450 ppm (>54.7 mg/kg/day). Organ weight
measurements Indicated a dose-related decrease 1n the weights of epldldymal
fat pads, and perlrenal fat pads that were significantly different from
pair-fed controls at all doses. Dose-related decreases In the weights of
the kidneys (significant at >900 ppm), testes (significant at >900 ppm) and
seminal vesicles (significant at >450 ppm) were also noted. Organ weight
data were applied to a model designed to estimate the lowest dosage that
would result In a statistically significant effect, and conventionally
derived levels of significance (p values) were not provided. Hlstologlcal
0133d -40- 03/31/89
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examinations and hematologlcal analyses were not performed. The use of
pair-fed controls 1n this study provides evidence that decreased body weight
gain 1s a result of thlram treatment rather than just a result of decreased
food Intake.
In a 28-day study, Hornshaw et al. (1987) fed groups of two male and two
female standard dark mink (5-6 months old) and groups of five male and five
female agouti-colored ferrets (6-7 months old) thlram (analytical grade) In
the diet. N1nk were fed at dietary levels of 0, 45 or 82 ppm thlram.
Additional groups of five mink/sex were fed at 147 and 265 ppm, but these
groups were terminated after 2 weeks because the minks avoided the diets.
Ferrets were fed at 0, 8, 20. 50, 125 and 312 ppm. Based on body weight and
food Intake data provided by the authors, mink were treated at doses of 0,
8.6 or 12.6 mg/kg/day for males, and 0, 6.6 or 9.5 mg/kg/day for females,
and ferrets were treated at doses of 0, 1.1, 2.8, 5.6, 14.8 or 27.5 mg/kg/
day for males and 0, 1.6, 3.3, 8.6, 16.5 or 44.8 mg/kg/day for females. No
*
treatment-related deaths were reported 1n mink, and no changes In organ
weights or gross lesions were observed at necropsy (hlstologlcal examina-
tions were not performed). Effects observed In mink at 82 ppm Included a
reduction In food consumption, loss of body weight and bloody feces.
Hematocrlt values for mink treated at 45 and 82 ppm were significantly
(p<0.01) below control values. In ferrets, all animals treated at 312 ppm
died between days 11 and 16. Signs of toxlclty observed In these animals
Included bloody feces, Inanition, Ustlessness, 1ncoord1nat1on and occa-
sional convulsions accompanied by Intense vocalization. Changes In body
weight were significantly different from controls In male ferrets at >20 ppm
(p<0.05) and In females at >125 ppm (p<0.01). At necropsy, spleen weights
were Increased In females fed at 125 ppm. No gross lesions were observed.
0133d -41- 03/31/89
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RBC counts and hemoglobin values were significantly (p<0.01) reduced 1n
ferrets compared with controls at 50 and 125 ppm, and hematocrH was also
significantly reduced (p<0.05) at 50 ppm. The Investigators stated that
based on this study, a dietary NOEL for mink was not found, while a level of
8 ppm was a dietary NOEL for ferrets. This study 1s difficult to Interpret
because body weights of mink and ferrets were highly variable, thlram
treatment decreased food Intake and group sizes were small.
6.1.2.2. CHRONIC Lee and Peters (1976) reported neurotoxlclty and
behavioral effects of thlram In CD rats. Groups of 24 rats/sex were fed
diets containing practical grade thlram at 0, 0.01, 0.04 or 0.1% for 80
weeks. The diets were adjusted during the study to maintain thlram doses at
about 0, 5.3, 20.4 and 52 mg/kg/day for males and 0, 6.1, 25.5 and 66.9
mg/kg/day for females. The rats were observed for overt signs of neuro-
behavloral toxIcHy and given experimental behavioral tests (hind leg
walking gait, Jump/climb ability, open field test). Among high-dose female
rats, eight developed hind limb ataxla or paralysis. These rats became very
emaciated near the end of the study. Hlstologlcal examinations of the
gastrocnemlus muscle, sciatic nerve and spinal cord of two ataxlc rats
revealed demyellnatlon and degeneration of the sciatic nerve, and degenera-
tion of the lumbar region of the spinal cord. Analysis of the hind leg
walking gait of female rats Indicated a significant (p<0.05) difference In
stride width and the angle between the hind feet In rats treated at >25.5
mg/kg/day and controls. Nonataxlc high-dose female rats required signifi-
cantly (p<0.01) more shocks and cleared a lower height In the jump/climb
ability test compared with control, low- and mid-dose rats. In the open-
field test, mid-dose males and high-dose males and females (Including five
ataxlc females) were hyperactive.
0133d -42- 03/31/89
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In a second part of this study, groups of 24 female rats were fed diets
containing thlram that provided dosages of 0 or 65.8 mg/kg/day for 36 weeks
(Lee and Peters, 1976). Impaired nerve conduction, peripheral neuropathy,
ataxla and paralysis were observed In 4/24. When picked up by the tall, 9
treated rats exhibited hlndfoot clasping.
Lee et al. (1978) reported additional effects observed In the 80-week
rat study described above. Alopecia was observed among ataxlc and nonataxlc
high-dose rats and 1n a few mid-dose rats. It Is not clear If hair loss
occurred only In females or In both sexes. Body weight gain was reduced
compared with controls at all doses In males and In high- and mid-dose
females. Blood and clinical analyses completed on four rats/sex/group were
similar to controls. At necropsy, results of organ weight measurements
showed Increased relative thyroid and testes weight In high-dose males, and
Increased relative liver, kidney, thyroid, ovary and brain weights In
high-dose females, with relative spleen weights Increased In both high- and
mid-dose females. Statistical analyses and actual values for blood and
clinical chemistry studies and organ weights were not provided. Hlstopatho-
logUal examinations revealed a dose-related Increase 1n the Incidence and
severity of fatty Infiltration of the pancreas 1n male rats, with 1/17,
3/13, 11/15 (p=O.OQ01, Fisher Exact test run at Syracuse Research Corpora-
tion) and 14/16 control, low-, middle- and high-dose rats affected. Fatty
Infiltration of the pancreas was found In only 1/11 high-dose female rats.
Squamous metaplasia of the thyroid was observed In 4/16 and 3/11 high-dose
male and female rats, compared with 1/17 male and 0/18 female control rats.
Specific lesions of the central and peripheral nervous systems were not
observed In nonataxlc, ataxlc or paralyzed rats, with the exception of the
lesions reported 1n two ataxlc rats (Lee and Peters, 1976).
1)133d -43- 03/31/89
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U.S. EPA (1987a) cited a 2-year Industry study (E.I. Ou Pont de Nemours
& Co., n.d.) In which groups of 24 rats (strain and sex not specified) were
fed thlram (purity not provided) 1n the diet at 0, TOO, 300, 1000 or 2500
ppro. Observations and tests reported Included body weight, mortality,
clinical signs, neurological examination and microscopic examination of
tissues. Weakness, ataxla, varying degrees of hind 11mb paralysis, and
calcified masses In the basal ganglia and cerebellum were observed at 300,
1000 and 2500 ppm. Additional Information concerning this study was not
provided.
Abstracts briefly describe 2-year Japanese studies using rats and dogs.
Malta et al. (1980) fed diets containing thlram at 0, 3, 30 or 300 ppm to
groups of 64 JCL Wlstar SPF rats of both sexes. Examinations Included
urlnalysls, hematology, blood biochemistry, ophthalmoscopy, organ weights
and hlstopathology. Interim kills of eight rats/sex/group were performed at
13, 26 and 52 weeks. Effects were restricted to the 300 ppm level and
Included reduced food consumption and growth, reduced erythrocyte count In
females during the first year of the study, and reduced muscle mass and an
Increased Incidence of muscle lesions (not specified), compared with
controls. The Investigators concluded that 30 ppm, equivalent to 1.15
mg/kg/day for males and 1.39 mg/kg/day for females, was a NOEL.
SaHo et al. (1980) treated groups of four beagle dogs/sex with thlram
1n gelatin capsules at dosages of 0, 0.4, 4 or 40 mg/kg/day. Examinations
Included hematology, blood biochemistry, urlnalysls and ophthalmoscopy at 0,
4, 13, 26, 39, 52, 78 and 104 weeks, and organ weights and hlstopathology at
termination. All dogs at 40 mg/kg/day died within 6-29 weeks. Other
effects observed at this dosage Included vomiting, salivation, convulsions,
ocular changes, a marked decrease In erythocyte counts, and altered blood
3133d -44- 03/31/89
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biochemistry Including elevated SGOT and SGPT. Some dogs at 4 mg/kg/day
exhibited vomiting, salivation and clonlc convulsions. A slight to moderate
reduction In erythrocyte count was observed during the first 13 weeks of
exposure, but not thereafter. At termination, the liver exhibited hepato-
cellular atrophy and granuloma formation with an Increase In brown pigmenta-
tion. No effects were reported at 0.4 mg/kg/day.
6.1.3. Other Relevant Information. Acute toxldty data for thlram are
summarized In Table 6-1, which Indicates that oral ID values have varied
between Investigators, with 2300 mg/kg In female NHRI mice (Matthlaschk,
1973) reported as the highest value, and 190 mg/kg In female CD rats (Lee et
al., 1978) reported as the lowest value. Studies In which male and female
rats or mice were studied separately appear to Indicate little gender-
related difference 1n sensitivity.
Thuranszky et al. (1982) studied the effect of thlram or carbon
dlsulflde on the nervous system of male Wlstar rats treated with a single
oral dose. Endpolnts examined were the "orientation of hypermotllHy"
(measured using an 1KB ANIMEX activity meter), analysis of dopamlne and the
formation of noreplnephrlne and eplnephrlne from 3H-tyros1ne (rats were
pretreated with an 1ntraper1toneal Injection of 3H-tyros1ne). The results
Indicated that thlram (240 mg/kg) or carbon dlsulflde treatment (152 mg/kg)
significantly reduced the "orientation of hypermotllHy" (not otherwise
specified), compared with untreated controls. The effect was comparable to
meprobamat, a tranqulllzer. Both thlram (60 mg/kg) and carbon dlsulflde
(152 mg/kg) resulted In an Increase In dopamlne levels and a decrease In
noreplnephrlne and eplnephrlne formation. The Investigators suggested that
the effects were consistent with a proposed mechanism of Inhibition of
0133d -45- 03/31/89
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TABLE 6-1
Acute Toxlclty of Thlram
Species/Strain
Rats /Sherman
Rat/CD
Rats/Sherman
Rat/CD ~
Mlce/CO-1
mce/CD-1
M1ce/NHRZ
Rats/M1star
Rats/Sherman
Sex
H
H
F
F
H
F
F
M,F
M,F
Route
oral
oral
oral
oral
oral
oral
oral
l.p.
dermal
LD50
(mg/kg)
640
400
620
190
400
380
2300
248
>2000
Reference
Galnes, 1969
Lee et al., 1978
Galnes, 1969
Lee et al., 1978
Lee et al., 1978
Lee et al., 1978
Hatthlaschk, 1973
PoUou et al., 1978
Galnes, 1969
1.p. = IntraperHoneal
0133d
-46-
03/31/89
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dopam1ne-B-hydroxylase activity and suggested that carbon dlsulflde may be
responsible for at least some of the nervous system effects observed
following thlram treatment.
Dalvl and Deoras (1986) treated male Sprague-Oawley rats with an
IntraperUoneal Injection of thlram In corn oil (60 mg/kg) and examined the
effect on hepatic mlcrosomal enzymes 5 and 24 hours after treatment.
Elevated serum sorbHol dehydrogenase levels and SGOT levels were observed
at 5 and 24 hours, with significant (p<0.05) Increases found 24 hours after
treatment. Liver cytochrome P-450 activity and benzphetamlne N-demethylase
activity were significantly (p<0.05) decreased at 24 hours, but not at 5
hours after dosing.
Thlram, similar In structure to Antabuse, 1s a potent Inhibitor of
mlcrosomal monoxygenases Including aldehyde dehydrogenase and dopam,1ne
8-dehydrogenase (ACGIH, 1986). Combined exposure to thlram and ethanol can
result In the accumulation of acetaldehyde. In a study by Garc'la de Torres
et al. (1983), treatment of female kllstar rats with two oral doses of thlram
at 16 or 256 pmol/kg (3.8 or 61.5 mg/kg) followed by an 1ntraper1toneal
Injection of ethanol (2 g/kg) resulted In a significant Increase 1n the
blood acetaldehyde level for <240 minutes after ethanol treatment. The
Increase In blood acetaldehyde was still detectable In rats pretreated with
thlram (16 ymol/kg) 48 hours before treatment with ethanol.
Fenyvesl et al. (1985) reported that combined oral treatment of female
Ulstar rats with thlram (10 mg/kg) and the drugs promethazlne or meprobamate
(dose not specified) resulted In a potentlatlon of the CNS effects of the
drugs. Treatment with thlram and tHhexyphenldyl resulted In an additive
effect.
0133d -47- 03/31/89
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6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carc1nogen1c1ty of
thlram following Inhalation exposure were not located In the available
literature cited In Appendix A.
6.2.2. Oral. In a cardnogenlcHy study sponsored by BRL (1968a), groups
of 18 (C57BL/6xC3H/Anf)Fl mice/sex and 18 (C57/BL/6xAKR)Fl mice/sex were
treated orally with commercial thlram (purity not reported). Gavage treat-
ment at a dose of 10 mg/kg/day In gelatin was Initiated when the mice were 7
days old. At 4 weeks of age, the mice were provided with diets containing
thlram at 26 ppra. The IARC (1976) review of this study stated that treat-
ment was an MTD for Infant and young mice, but may not have been an MTD for
adults. The number of mice surviving to 78 weeks of age, when the experi-
ment was ended, was 16 male and 18 female (C57BL/6xC3H/Anf)F1 mice and 18
male and 15 female (C57/BL/6xAKR)Fl mice. Tumor Incidences were not
significantly greater 1n thlram treated mice compared with 79-90 necropsled
negative control mice of each sex and strain, which had been treated with
gelatin or had been left untreated.
In an 80-week study. Lee et al. (1978) did not observe Increased tumor
Incidences 1n CD rats treated with thlram in the diet at concentrations that
provided doses of 0. 5.3, 20.4 and 52 mg/kg/day for males and 6.1, 25.5 and
66.9 mg/kg/day for females. Additional details of this study are presented
1n Section 6.1.1.2.
Takahashl et al. (1983) examined the potential cardnogenlcHy of thlram
In F344 rats treated for 2 years. Groups of 50 rats/sex were fed diets
containing thlram (99.76% pure) at 0, 0.05 or 0.1X (0, 500 or 1000 ppm).
Body weights of the high-dose rats were slightly depressed. No effects on
mortality, gross pathology or hlstopathology were observed. Treated male
0133d -48- 03/31/89
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and female rats exhibited a significantly lower Incidence of leukemia than
controls and historical controls. Although not significant, Incidences of
pituitary chromophore tumors 1n females and thyroid C-cell adenomas In males
were also reduced. The Investigators speculated that thlram, a known
Inhibitor of hepatic mlcrosomal monoxygenases, may alter metabolism or the
endocrine state of the animal to Inhibit spontaneous tumor development.
In a study that examined the cardnogenlclty of simultaneous treatment
with thlram and sodium nitrite, Lljlnsky (1984) fed 24 male and 24 female
F344 rats a diet containing thlram at 500 ppm and sodium nitrite at 2000 ppm
for 130 weeks. Additional groups of rats were fed the basal diet, basal
diet containing thlram (500 ppm) or basal diet containing sodium nitrite
(2000 ppm). The study began at thlram concentrations of 750 ppm, but
because of decreased food Intake the concentration was lowered to 500 ppm
after 3 weeks of treatment. Lljlnsky (1984) noted that the only biological
effect observed was the production of copious amounts of urine by rats
treated with thlram and nitrite. No explanation of this effect was avail-
able, and the kidneys did not appear to be adversely affected. Only the
survival of thlram and nitrite treated rats was affected, with deaths from
treatment-related tumors. Tumors Incidences that were Increased In thlram
and nitrite treated rats compared with controls were nasal cavity tumors
(18/24 treated males, 0/24 untreated control males; 15/24 treated females,
0/24 untreated control females) and forestomach tumors (5/24 treated males,
0/24 untreated control males; 5/24 treated females, 0/24 untreated control
females). Increased tumor Incidences were not observed In rats treated with
only thlram or nitrite. Lljlnsky (1984) noted that "although this study was
not large enough to state categorically that thlram 1s noncardnogenlc In
rats, we feel that a maximally tolerated dose was achieved, and that, there-
fore, the carcinogenic effect of thlram In rats. If any, must be very weak."
0133d -49- 03/31/89
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The carcinogenic effect of simultaneous treatment with thlram and nitrite
may be the result of the formation of N-n1trosod1methylam1ne. IARC (1976)
stated that Elespuru and. Lljlnsky (1973) and Sen et al. (1974) found that
' thlram reacts with nitrite at the acid pH 1n the stomach of guinea pigs,
resulting In the formation of N-n1trosod1methy1am1ne.
6.2.3. Other Relevant Information. BRL (1968a) treated groups of 18
(C57BL/6xC3H/Anf)Fl mice/sex and 18 (C57/BL/6xAKR)Fl mice/sex with a single
subcutaneous Injection of commercial thlram 1n gelatin at a dose of 46.4
mg/kg. The mice were treated at 28 days of age and observed until -78 weeks
of age. Tumor Incidences were not Increased compared with 141-161 untreated
or vehicle treated controls. IARC (1976) noted that "a single subcutaneous
Injection may not be an adequate basis for discounting carc1nogen1c1ty.H
Goodyear Tire & Rubber Co. (1982) reported that thlram did not Increase
the frequency of transformation 1n BALB/3T3 cells \t± vitro. The concentra-
tion range tested, 2.8-13.8 pg/mi, resulted In 12 to -90% survival. In
preliminary tests, no cells survived at concentrations >25 pg/mt.
6.3. MUTAGENICITY
Hutagenlclty data for thlram are summarized In Table 6-2. Thlram has
been tested In numerous systems with Inconsistent results. Thlram has
generally tested positive In at least one strain of Salmonella typhlmurlum
(TA100) without metabolic activation, but the available studies do not
clearly Indicate 1f S-9 Increases or decreases the mutagenlc activity of
thlram. Nixed results have been reported, for several assays In Chinese
hamster V79 cells, sex-linked recessive lethals In Drosophlla melanogaster
and mlcronucleus tests 1n mice. Tests reporting positive results for thlram
Include mutation In CHO cells and Asperqlllus nldulans. ONA damage In
Escherlchla coll.. prophage lambda Induction In E.. coll and Increases In the
0133d -50- 03/31/89
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number of abnormal sperm and chromosomal aberrations In treated mice. Tests
reporting negative results for thlram Include mutation In E_. coll. sister
chromatld exchange and the anaphase-telophase test In CHO cells, and
unscheduled DNA synthesis In thymus cells from rats and human lymphocytes.
Rannug and Rannug (1984) proposed that mutagenlclty Induced by thlram
may result from the Inhibition of enzymes Involved In protecting against
harmful oxygen species. Thlram may react with sulfhydryl groups In enzymes,
or may react to form dUhlocarbamate metal chelate complexes, decreasing the
activity of enzyme systems requiring metal Ions. Experiments by Rannug and
Rannug (1984) that found Increased mutagenlclty 1n S. typhlmurlum strain
TA100 1n the presence of Increased oxygen, copper sulfate and menadlone,
which results 1n the formation of .large amounts of singlet oxygen and
H-Op Inside the cell, support this hypothesis.
6.4. TERATOGEHICITY
Robens (1969) studied the teratogenldty of thlram 1n Syrian golden
hamsters. Groups of four to eight pregnant hamsters were treated by gavage
with thlram In DMSO or CMC at doses of 0 (vehicle control), 31, 63, 125, 250
or 500 mg/kg (DMSO) or 0 (vehicle control), 125, 250, 300 or 500 mg/kg CMC)
on gestation day 7 or 8. Dams were sacrificed on gestation day 15, and the
viability of fetuses was studied by placing them In an Incubator for 6
hours. Maternal mortality occurred In hamsters at doses >125 mg/kg, and at
500 mg/kg In hamsters treated with thlram In DMSO and CMC, respectively.
Litters were resorbed completely from one or more hamsters at >125 mg/kg
thlram In DMSO and >300 mg/kg thlram In CMC. There was a dose-related
decrease In the number of live fetuses/Utter and an Increase In percent
fetal deaths for thlram In DMSO and 1n CMC groups. In addition, there was a
dose-related decrease In fetal weight for thlram 1n DMSO groups. At 500
0133d -54- 08/24/89
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mg/kg/day thlram 1n either vehicle, there was 100% fetal death. It 1s not
clear how many fetuses were examined for visceral and skeletal effects. The
Investigator stated that "the percentage of fetuses showing terata would
probably be larger If all of the fetuses had been stained and examined for
bone anomalies.* It was difficult to assess the teratogenlc effects of
thlram In DMSO because OMSO 1s teratogenlc. Robens (1969) considered that
the teratogenlc effect of DMSO and thlram was additive or slightly more than
additive. The most common abnormalities In thlram-treated and DMSO-control
hamsters were exencephaly and fused ribs. In addition, a few fetuses In the
thlram In DMSO group were found to have heart defects, predominantly of the
great vessels. Fused ribs were the most common anomaly observed 1n fetuses
from hamsters treated with thlram In CMC. Although the effects of thlram In
CMC on the number of fetuses/litter, fetal mortality, average fetal body
weight and the number of fetuses with terata appeared to be dose-related.
statistical analyses were not performed. The Investigator concluded,
however, that thlram 1n CMC was teratogenlc at >250 mg/kg.
An abstract of a study by Roll (1971) reported that thlram was terato-
genlc to NMRI and SU mice. The mice were treated between gestation day 6
and 17 and "during other stages of gestation." There was a dose-related
Increase In resorptlons and "Impaired fetal development". Mice were most
susceptible when treated on gestation day 12 and 13. NMRI mice were more
susceptible than SU mice to the development of cleft palate. The "terato-
genlcally Ineffective dose" was estimated to be -250 mg/kg.
Matthlaschk (1973) reported Increased resorptlons and a dose-related
Incidence of malformations In fetuses from NMRI mice treated orally with
thlram at 10, 20 or 30 mg/an1maI/day on gestation days S-1S. Simultaneous
oral treatment with thlram and Intraperltoneal Injection with L-cyste1ne at
0133d -55- 08/24/89
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2.5 or 5 rag/mouse on gestation days 5-15 reduced the severity of malfor-
mations but not the number of malformations. Oral treatment with thlram (30
mg/kg) on gestation days 12-13 Increased the number of malformations
compared with treatment on gestation days 5-15. Simultaneous treatment with
thlram and L-cystelne at 10 mg/kg (days of treatment unspecified) reduced
the number of malformations.
Short et al. (1976) treated groups of 10-32 pregnant CD rats by gavage
with thlram (practical grade) 1n CMC at doses of 0, 40, 90. 136 or 164
mg/kg/day on gestation days 6-15, or at 200 mg/kg/day on gestation day 6 or
7-12. For calculation of doses, "the thlram preparation was considered to
be pure and no corrections were made for Inactive Ingredients." Rats were
sacrificed on gestation day 20; 50% of the fetuses were examined for soft
tissue anomalies; and the remaining fetuses were examined for skeletal
anomalies. At 200 mg/kg/day, only 6/18 rats survived. Body weight gain and
food consumption were significantly depressed 1n all treated groups.
Treatment resulted In a significant decrease In the number of fetuses/dam
and a corresponding Increase In resorptlons at levels >136 mg/kg/day. Fetal
body weight was significantly reduced at all doses. The Investigators
reported higher Incidences of hydrocephalus, domed cranium split or lobed
antra and decreased ossification 1n rats treated at 136 mg/kg compared with
controls, although statistical analysis of these data was not performed.
Incidences at other doses were not reported.
Short et al. (1976) also completed a teratogenlclty study In which
groups of 18-19 pregnant Swiss-Webster flilce were treated by gavage with
thlram (practical grade) In CMC at doses of 0, 100 or 300 mg/kg/day on
gestation days 6-14. Mice were sacrificed on gestation day 18. Half of the
fetuses were examined for soft tissue anomalies and half were examined for
0133d -56- 08/24/89
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skeletal anomalies. At 300 mg/kg, 4/18 mice died. No effects on body
weight gain of dams, Utter size, Incidence of resorptlons or fetal body
weights were observed. An Increased Incidence of hydrocephalus, hydro-
nephrosls, collapsed cranium, malallgned sternebrae, eye and cardiovascular
defects was observed at 300 mg/kg. Short et al. (1976) concluded that rats
were more sensitive than mice to the developmental toxic effects of thlram.
Short et al. (1976) also conducted a study regarding the effects of
perl- and postnatal thlram (practical grade) treatment In rats. In this
study, groups of 10-20 pregnant rats were provided with diets containing 0,
0.03 or 0.1% thlram from day 16 of gestation to postpartum day 21.
Practical grade thlram doses were 0, 17 and 26 mg/kg/day before birth and 0,
51 and 115 mg/kg/day after birth. A control group of food-restricted rats
was also maintained. Directly after birth, pups of six thlram-treated
dams/group were exchanged with control pups 1n a cross-fostering experiment.
Food consumption and body weights of dams were reduced 1n both treatment
groups, although at the low dose, body weights returned to normal by the end
of the experiment. Body weights of food-restricted rats were depressed
throughout lactation. Survival of pups from dams treated at 0.03% thlram
was not affected. However, pup body weights were significantly decreased
throughout the period of lactation. At 0.1% thlram, there was a significant
decrease 1n pup body weights on days 0 and 4 and In survivors on day 4
(viability Index); there were no survivors at weaning. In the cross-
fostering experiment, survival and body weights of offspring from untreated
dams placed with treated dams (0.1%) were significantly reduced; 1n
contrast, survival of prenatally exposed pups (0.1%) nursed by untreated
dams was normal, and body weights, which were Initially significantly
depressed, reached control values by day 21.
0133d -57- 08/24/89
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In a BRL (1968b) study, eight pregnant BL6 mice and seven pregnant AKR
mice were treated by subcutaneous Injection with thlram In DMSO on gestation
days 6-14 (BL6) or 6-15 (AKR). BL6 mice were treated at 10 mg/kg/day and
AKR mice were treated at 115 mg/kg/day. Maternal weight gain was signifi-
cantly (p<0.05) decreased In AKR mice. A number of abnormalities were
reported In BL6 mice, but the abnormalities were similar In type to those
observed In DMSO-treated controls. Because only one dose was studied In a
small number of mice, no conclusions can be made from this study.
6.5. OTHER REPRODUCTIVE EFFECTS
Mshbeln (1976) summarized a study by Davydova (1973) concerning the
reproductive function of female albino rats exposed to thlram by Inhalation.
Female rats (number unspecified) were exposed to thlram (purity not speci-
fied) at concentrations of 3.8+0.058 mg/m3, 6 hours/day, 5 days/week for
4.5 months. No Information concerning controls was provided. Effects noted
Included an extension of the estrous cycle at the expense of the resting
phase during the beginning of the study (the estrous cycle returned to
normal by the end of the study), reduced rate of conception, reduced
fertility and reduced body weights of fetuses. No additional Information
regarding this study was reported 1n F1shbe1n (1976).
Short et al. (1976) studied the effects of thlram on reproduction In
male and female CO rats. In the study on male reproduction, groups of 20
male rats were fed thlram In the diet at 0, 0.05, 0.1 or 0.25X for 13 weeks
before mating with untreated controls (see Section 6.1.2.1.). Based on food
Intake and body weight data, the Investigators Indicated that the rats
consumed 0, 30, 58 or 132 mg practical grade thlram/kg/day. On gestation
day 13, half of the females were sacrificed, while the remaining were
allowed to deliver; the pups were examined at birth and on postpartum days 4
0133d
-58-
08/23/89
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and 21. Thlrara at 30 and 58 mg/kg/day had no effect on the ability of males
to fertilize females. Hale animals In the 58 and 132 mg/kg/day groups
exhibited loss of hair and had rough coats; 70% of males In the latter group
died. At 132 mg/kg/day, males failed to Inseminate females. Testlcular
lesions (hypoplasla, tubular degeneration, and atypical spermatlds 1n the
epldldymls) were observed 1n <50% of the rats with Impaired breeding
performance.
In the reproductive study In female rats (Short et a!., 1976), groups of
20 virgin females were provided with thlram In the diet at 0, 0.04 or 0.2%
(0, 30 or 96 mg practical grade thlram/kg/day) for at least 14 days before
mating with untreated males. After mating, all female rats were fed the
control diet. On gestation day 13, half of the females were sacrificed,
while the remaining females were allowed to deliver; the pups were examined
at birth and on postpartum days 4 and 21. Body weights of female rats
treated with thlram at 30 or 96 mg/kg/day were 94 and 74% of the control
value after 2 weeks of treatment. At 30 mg/kg/day, significant reductions
In the number of Implants/dam (11.9 vs. 14.4 1n controls) and pups/dam (10.8
vs. 12.9 1n controls) were observed. Treatment at 96 mg/kg/day prolonged
the dlestrous phase of the estrous cycle. Only 1/20 rats at 96 mg/kg/day
was mated successfully, with 5/20 dead after 4.5 weeks of treatment. The
effect of 96 mg/kg/day thlram treatment on estrous cycle was reversible; 9/9
rats became pregnant within 9 days of being transferred to the control diet.
The number of Implants (9.5) and embryos (8.5) was reduced In this group.
although no effect on fertility Index, gestation Index or the ratio of
viable embryos to Implants was noted.
Hornshaw et al. (1987) completed reproductive studies where mink were
fed thlram for 20 weeks and ferrets were fed thlram for 24 weeks 1n the
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diet. Groups of 4 male and 12 female mink were fed thlram 1n the diet at 0,
2.5, 10 or 40 ppm, and similar groups of ferrets were fed at 0. 4, 16 or 64
ppm. Based on food Intake and body weight data during 8 weeks before the
breeding season, dosages for male mink were estimated at 0, 0.5, 1.4 and 6.1
mg/kg/day, for female mink at 0, 0.4, 1.5 or 5.7 mg/kg/day, for male ferrets
at 0, 0.6, 2.7 or 10 mg/kg/day and for female ferrets at 0, 0.61, 2.1 or 7.0
mg/kg/day. The animals were treated until the kits were weaned. After
weaning, four adult males and four adult females from each group were
necropsled, organ weights (brain, liver, spleen, kidney, heart and lung)
were recorded and hematologlc parameters were determined.
Body weight changes, reported for the first 8 weeks of the study, are
difficult to Interpret because female ferrets and, to a lesser extent, mink
tend to reduce food consumption and lose body weight as they approach
estrus. The only body weight changes that were significantly different
compared with controls were In male mink at 40 ppm and female ferrets (which
lost less weight than controls) at 64 ppm. The Investigators suggested that
In ferrets at 64 ppm the normal pre-estrus pattern may have been disrupted;
only 7/12 females were In estrus (vulvar swelling) after 8 weeks of treat-
ment. Thlram treatment did not result In signs of Intoxication or deaths In
either species. Gross lesions were not observed at necropsy, and no birth
defects were observed. The only significant effect on reproduction 1n mink
was a decrease In average birth weight at 40 ppm. At 40 ppm, only 7/12
female mink whelped compared with 10/12 controls, and 6/9 and 11/11 at 2.5
and 10.0 ppm, respectively. In ferrets, no females at 64 ppm whelped,
compared with 12/12 controls, and 9/12 and 8/12 at 4 and 16 ppm, respec-
tively. At 16 ppm, the number of ferrets/Utter was reduced (10.6/lltter,
controls; 8.2/lHter, 16 ppm); ferret Utter weights were significantly
0133d -60- 08/24/89
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reduced at birth, 3 and 6 weeks; and average kit body weights were reduced
at 3 weeks. For both mink and ferrets, the Investigators stated that kit
survival was dose-related. Kit survival was 85.0, 80.0, 73.6 and 72.2% for
control, low-, middle- and high-dose mink, and 94.1, 89.2 and 81.5% for
control, low- and middle-dose ferrets kits surviving for 6 weeks. At
necropsy, spleen weights of adults were Increased significantly compared
with controls at 40 ppm In mink, and at 16 and 64 ppm In ferrets. RBC
counts, hemoglobin concentration and hematocrlt were reduced significantly
at 40 ppm 1n mink and 64 ppm In ferrets.
6.6. SUMMARY
Data regarding the toxlclty of thUam following Inhalation exposure of
animals were not located. S1v1t1skaya (1974, summarized by Flshbeln, 1976)
reported ophthalmologlc changes In persons occupationally exposed to thlram.
Exposure concentrations were not reported.
The most notable effect observed In animals following chronic oral
exposure to thlram Is ataxla and hind leg paralysis observed In rats fed
thlram In the diet at >300 ppm (E.I. Du Pont de Nemours and Co., n.d.; Lee
and Peters, 1976). Neurotoxlc effects following exposure to thlram may
result from the production of carbon dlsulflde. Thuranszky et al. (1982)
found similar effects on the nervous system when rats were treated with a
single oral dose of thlram or carbon dlsulflde.
Dietary treatment of animals with thlram has consistently resulted In
decreased food Intake and body weight gain. The study by Lowy et al.
(1980), which found that body weight gain 1n thlram treated rats was below
pair-fed controls, Indicates that the effect on body weight Is a result of
thlram treatment rather than Just a result of decreased food Intake. The
lowest dietary concentration of thlram resulting 1n decreased body weight
gain In rats was 100 ppm (Lee et al., 1978). A study using mink and ferrets
0133d -61- 08/24/89
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(Hornshaw et al., 1987} did not clearly Identify levels resulting 1n changes
1n body weight because of the small numbers of animals used, and because of
the high variability of body weight of the animals used In the study.
Thlram Is an Inhibitor of mlcrosomal monoxygenases Including aldehyde
dehydrogenase and dopamlne B-dehydrogenase. Combined exposure to thlram and
ethanol has been shown to result In the accumulation of acetaldehyde (Garcia
de Torres et al., 1983). Interactions between thlram and prometazlne,
meprobamate and trlhexyhenldyl have also been reported (Fenyvesl et al.,
1985). Oral cardnogenldty studies of thlram In rats (Lee et al., 1978;
Takahashl et al., 1983; LlJInsky, 1984} and a limited cardnogenldty study
In mice (BRL, 1968a) have not found a carcinogenic effect. LlJInsky (1984}
found that simultaneous oral treatment of rats with thlram and sodium
nitrite significantly Increased nasal cavity and forestomach tumors. This
effect probably was due to the in vivo formation of N-n1trosod1methylam1ne.
Nutagenlclty studies of thlram have yielded mixed results, with numerous
positive and negative studies available. Rannug and Rannug (1984) proposed
that mutagenlclty Induced by thlram may result from the Inhibition of
enzymes that are Involved 1n protecting against harmful oxygen species.
Oral teratogenlclty studies 1n hamsters (Robens, 1969), mice (Roll,
1971; Matthlaschk, 1973; Short et al., 1976) and rats (Short et al., 1976)
have reported an Increased Incidence of resorptlons and malformations
observed prenatally and reduced viability and growth, postnatally. In some
Instances, the findings were observed 1n the presence of maternal toxldty.
Oral studies concerning the effects of thlram on reproduction 1n rats
(Short et al., 1976) Indicate that at 132 mg/kg/day the 30% of the males who
survived failed to Inseminate females and exhibited testlcular lesions. A
dose of 30 mg/kg/day given to females reduced the number of Implants/dam.
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Treatment at 96 mg/kg/day resulted In only 1 of the 15 female-survivors to
mate successfully. A cross-fostering experiment (Short et al., 1976), which
found reduced survival of offspring from untreated dams placed with treated
dams Indicates that developing rats are still sensitive to thlram post-
natally. Results of a reproductive study using mink and ferrets (Hornshaw
et al., 1987} Indicates that ferrets may be more sensitive than mink or rats
to the reproductive effects of thlram; 0/12 female ferrets produced Utters
at a dose of 7 mg/kg/day. In addition, exposure to 2.1 mg/kg/day produced a
decrease In the number of offspring/Utter and In offspring body weights.
In the adult animals, there was an Increase In splenic weight at 2.1 and 7
mg/kg/day and a decrease 1n RBCs, hemoglobin and hematocrU at 7 mg/kg/day.
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The OSHA (1985) PEL for thlram Is 5 mg/ma. The AC6IH (1987) TLV-TWA
was recently lowered from 5 to 1 mg/m3, based on the probability that
clinical symptoms 1n exposed workers occurred at concentrations >1.0 mg/m3.
Tolerances for thlram on raw agricultural products are 7 ppm In or on
apples, celery, peaches, strawberries, tomatoes and bananas (not more than 1
ppb shall be In the pulp after the peel Is removed and discarded), and 0.5
ppm 1n or on onions (U.S. EPA, 1986a).
U.S. EPA (1984a) determined that data were Insufficient for Identifica-
tion of a NOEL; therefore, an MPI could not be calculated. The verified
oral RfD for thlram Is 0.005 mg/kg/day (U.S. EPA, 1987c); the derivation is
discussed In Section 8.2.2.2. The RQ for thlram Is 10 pounds, based on
aquatic toxIcHy data (U.S. EPA, 1988).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to tetramethylthluram dlsulflde (thlram) were not located In the
available literature dted In Appendix A.
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8. RISK ASSESSMENT
Statements concerning available literature In this document refer to
published, quotable sources and are In no way meant to Imply that
confidential business Information (CBI), which this document could not
address, are not In existence. From examination of the bibliographies of
the CBI data, however. It was determined that CBI data that would alter the
approach to risk assessment or the risk assessment values presented herein
do not exist.
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenlcHy of
thlram following Inhalation exposure were not located 1n the available
literature cited 1n Appendix A.
8.1.2. Oral. In a BRL (1968a) study, thlram tested negative for carclno-
genldty 1n (C57BL/6xC3H/Anf)F1 mice and In (C57/8L/6xAKR)F1 mice. This
study Is limited; only one dose level was used, and 1t Is not clear If the
mice received an MTD throughout the study.
Additional oral chronic studies In rats (Lee et al., 1978; Takahashl et
al., 1983; Lljlnsky, 1984} also reported negative results for cardnogenlc-
Hy. The study by Takahashl et al. (1983) reported significantly lower
Incidences of leukemia In thlram treated rats (0, 500 or 1000 ppm In the
diet) compared with controls. The Investigators speculated that thlram, a
known Inhibitor of hepatic mlcrosomal monoxygenases, may alter metabolism to
Inhibit tumor development or may Inhibit mlcrosomal activation of other
chemical carcinogens. Lljlnsky (1984) found that thlram was not carcino-
genic when given to rats In the diet at 500 ppm, but that thlram (500 ppm)
and nitrite (2000 ppm) In the diet significantly Increased the number of
0133d -65- 08/23/89
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nasal cavity tumors and the number of forestomach tumors. The cardnogenlc-
Ity of thlram and nitrite treatment may be the result of .In. vivo formation
of N-n1tro-sod1methylam1net a potent carcinogen.
8.1.3. Other Routes. BRL (1968a) reported negative results 1n a cardno-
genlclty study 1n which 28-day-old mice were given a single subcutaneous
Injection of thlram (46.4 mg/kg) and observed until 78 weeks of age. IARC
(1976) noted that "a single subcutaneous Injection may not be an adequate
basis for discounting cardnogenlclty."
8.1.4. Height of Evidence. No data were available regarding the cardno-
genlclty of thlram In humans. The available data Indicate no evidence of a
carcinogenic effect In mice or rats treated with thlram, but the animal data
base Is Inadequate. According to U.S. EPA (1986b) guidelines, thlram can be
placed In EPA group D: not classifiable as to human cardnogenlclty.
8.1.5. Quantitative Risk Estimates. The lack of Inhalation cardnogen-
lclty data and the lack of positive oral cardnogenlclty data preclude the
derivation of carcinogenic potency factors for thlram.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Flshbeln (1976) summarized a study by
Slvltskaya (1974) that reported ophthalmologlc changes In workers with
prolonged occupational contact with thlram. Because estimates of exposure
levels were not provided, this Information 1s not useful for risk assessment.
The only Inhalation study In animals was a reproductive study using rats
(Davydova, 1973) summarized by Flshbeln (1976). In this study, effects on
reproduction (extension of the estrous cycle, reduced rate of conception,
reduced fertility and underweight fetuses) were observed In rats exposed to
thlram at a concentration of 3.8+0.058 mg/m3, 6 hours/day, 5 days/week for
4.5 months. This study was reported Inadequately for proper evaluation and
1s therefore not suitable for risk assessment.
0133d -66- 08/23/89
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The lack of Inhalation data useful for risk assessment precludes the
derivation of subchronlc and chronic Inhalation RfDs.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Lowy et al.
(1980) fed groups of six young male Wlstar rats thlram In the diet at
concentrations that provided doses of 0, 33.6, 41.9, 54.7, 71.9, 106.7 or
143.4 rag/kg/day for 29 days. Similar groups of pair-fed rats were main-
tained as controls. Body weight gain was consistently different from
pair-fed controls at >54.7 mg/kg/day. Organ weight measurements Indicated a
dose-related decrease 1n the weights of epldldymal fat pads and perlrenal
fat pads that was significant at all doses. Hlstologlcal examinations were
not completed. Because only one sex and small numbers of rats were used,
and because hematology and hlstopathology were not evaluated, this study 1s
not sufficient for risk assessment. The use of pair-fed controls In this
study provides evidence that decreased body weight gain Is a result of
thlram treatment, rather than just a result of decreased food Intake.
Lee et al. (1978) provided groups of 20 young male rats with thlram In
the diet at concentrations that provided doses of 30, 58 or 132 mg/kg/day
for 13 weeks. Food Intake was decreased and body weight gain was 81, 64 and
22X of controls at 30, 58 or 132 mg/kg/day, respectively. At 132 mg/kg/day,
18X of the rats died (Short et al.. 1976), SGOT and SGPT were mildly
elevated and mild tubular degeneration of the testes was noted. M1ld eleva-
tion of BUN was reported at 58 mg/kg/day. The lowest dose used In this
study can be considered a LOAEL, which resulted In decreased body weight
gain. This study 1s limited by the use of only male rats.
Teratogenlclty studies using hamsters (Robens, 1969). mice (Roll, 1971;
Hatthlaschk, 1973; Short et al., 1976; BRL, 1968b) and rats (Short et al.,
0133d
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1976) have reported an Increased Incidence of resorptlons and malformations
observed prenatally and reduced viability and growth, postnatally. In some
Instances, the findings were observed 1n the presence of maternal toxldty.
The studies by Robens (1969) and BRL (1968b) are confounded by the use of
DMSO, a teratogen, as the vehicle. In reproductive studies, Short et al.
(1976) found that reproduction was affected In male rats mated with
untreated females at an oral dose of 132 mg/kg/day (13 weeks), a dose that
also resulted 1n deaths, and In female rats mated to untreated males at 30
and 96 mg/kg/day (96 mg/kg/day also resulted In deaths). In a cross-
fostering experiment (Short et al., 1976), survival and body weights of
offspring from untreated rats placed with treated rats (0.1% In the diet,
115 mg/kg/day} were reduced. This experiment Indicates that developing rats
exposed to thlram postnatally are still susceptible to the developmental
effects.
Hornshaw et al. (1987) fed groups of 2 male and 2 female mink and 5 male
and 5 female ferrets thlram 1n the diet for 28 days at concentrations that
provided doses of 0, 8.6 or 12.6 mg/kg/day for male mink, 0, 6.6 or 9.5
mg/kg/day for female mink, 0, 1.1, 2.8, 5.6, 14.8 or 27.5 mg/kg/day for male
ferrets, and 0, 1.6, 3.3, 8.6, 16.5 or 44.8 mg/kg/day for female ferrets.
The only effects noted In mink were significantly decreased hematocrlt
values at both doses and a reduction In food consumption, loss of body
weight and bloody feces at the high dose (12.6 mg/kg/day males, 9.5
mg/kg/day females). All high-dose male (27.5 mg/kg/day) and female (44.8
mg/kg/day} ferrets died between days 11 and 16. Signs of toxlclty observed
In these animals Included bloody feces, Inanition, Ustlessness, Incoordlna-
tlon and occasional convulsions accompanied by Intense vocalizations.
Changes In body weights were significantly different 1n male ferrets at >2.8
0133d -68- 08/24/89
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rag/kg/day and In females at >16.5 mg/kg/day. At necropsy, spleen weights
were Increased 1n female ferrets at 16.5 mg/kg/day, and RBC counts and
hemoglobin counts were significantly reduced at 5.6 and 14.8 mg/kg/day In
males, and 8.6 and 16.5 mg/kg/ day In females.
Hornshaw et al. (1987) also completed reproductive studies where groups
of 4 male and 12 female mink (20 weeks) and similar numbers of ferrets (24
weeks) were fed thlram 1n the diet at concentrations 0, 2.5, 10 and 40 ppm
for mink and 0, 4, 16 or 64 ppm for ferrets. Based on food Intake and body
weight data for the first 8 weeks of the study, the diets provided doses of
0, 0.5, 1.4 or 6.1 mg/kg/day In male mink, 0, 0.4, 1.5 or 5.7 mg/kg/day 1n
female mink, 0, 0.6, 2.7 or 10 mg/kg/day In male ferrets and 0, 0.61, 2.1 or
7.0 mg/kg/day In female ferrets. The accuracy of these dose estimates Is
unclear; female ferrets and to a lesser extent female mink tend to reduce
feed consumption and lose body weight as they approach estrus, so actual
doses during gestation and weaning may have been higher. The animals were
treated until the kits were weaned. The Investigators suggested that 1n
female ferrets at 7 mg/kg/day, the normal pre-estrus pattern may have been
disrupted; only 7/12 females were In estrus (vulvar swelling) after 8 weeks
of treatment.
Thlram treatment did not result 1n signs of Intoxication or deaths 1n
either species. Gross lesions were not observed at necropsy, and no birth
defects were observed. The only significant effect on reproduction In mink
was a decrease 1n average birth weight at the high dose. In ferrets, no
females at 7 mg/kg/day whelped, compared with 12/12 controls and 9/12 and
8/12 at the low and middle dose, respectively. At the middle dose, (2.1
mg/kg/day In females), the number of offspring/Utter was reduced and ferret
Utter weights were reduced significantly at birth, 3 and 6 weeks, and
0133d -69- 08/23/89
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average kit body weights were reduced at 3 weeks. For both mink and ferret,
the Investigators stated that kit survival was dose-related; 85.0, 80.0,
73.6 and 72.2% survived 1n control, low-, middle- and high-dose mink kits,
and 94.1, 89.2 and 81.5% control, low- and middle-dose ferret kits surviving
for 6 weeks. Kit survival data are not considered In the Identification of
a LOAEL and NOAEL for reproduction because the data reported cannot be
statistically analyzed. This study appears to Identify a reproductive PEL
for ferrets of -1 mg/kg/day, a LOAEL of 2.1 mg/kg/day and a NOAEL of 0.61
mg/kg/day.
It appears that the ferret is the species most sensitive to thlram and
that the critical effect 1n this species Involves Impaired female reproduc-
tion. In the reproduction study by Hornshaw et al. (1987), 2.1 mg/kg/day
was a LOAEL and 0.61 mg/kg/day was a NOAEL for reproductive effects. An RfD
for subchronlc oral exposure to thlram can be derived by application of an
uncertainty factor of 100: 10 for extrapolation from animals to humans and
10 to provide additional protection for unusually sensitive humans, to the
reproduction NOAEL 1n ferrets of 0.61 mg/kg/day (Hornshaw et al., 1987).
The RfD 1s 0.006 mg/kg/day. Confidence In the data base Is medium because
the chronic, developmental and reproductive toxldty of thlram have been
Investigated In a wide range of experimental species, although no multi-
generation study has been reported. Confidence 1n the key study 1s low
because group sizes were small, hlstopathologlcal examinations were not
performed, and because variable food Intake and body weight data made
reliable estimation of dosage levels difficult. Data obtained from other
species, however, suggest that the NOAEL for reproduction In ferrets Is
below dosages 1n other species associated with CNS signs, hematologlc
effects and hlstopathologlc lesions. Confidence In the RfD Is medium.
0133d
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8.2.2.2. CHRONIC EXPOSURE The verified oral RfD (U.S. EPA, 1987c)
1s based on an unpublished study 1n rats (E.I. Du Pont de Nemours & Co.,
Inc., n.d.) In which groups of 24 rats (strain and sex unspecified) were fed
diets containing thlram at 0, 100, 300, 1000 or 2500 ppm for 2 years.
Weakness, ataxla, varying degrees of hind 11mb paralysis and calcified
masses 1n the basal ganglia and 1n the cerebellum were noted at >300 ppm.
The 300 ppm level [a dose of 15 mg/kg/day, calculated assuming a rat food
consumption factor of 0.05 (U.S. EPA, 1986c)] was considered a LOAEL and the
100 ppm level (5 mg/kg/day) was considered a NOEL. An uncertainty factor of
1000, 10 for Interspecles extrapolation, 10 for Intraspecles extrapolation,
and an additional uncertainty factor to account for the severity of the
effect and the questionable quality of the database, was used to calculate
an RfD of 0.005 mg/kg/day. Confidence In the RfD was considered low, based
on low to medium confidence In the study and low confidence In the data base.
U.S. EPA (1967b) cited the Lee and Peters (1976) 80-week study using
rats and Indicated that the dose of 6.1 mg/kg/day (female rats) 1s a NOEL
and 25.5 mg/kg/day 1s a LEL resulting In alopecia. The Lee et al. (1978)
study, which reported additional effects 1n the study described by Lee and
Peters (1976). 1s not cited.
In the 80-week study reported by Lee and Peters (1976) and Lee et al.
(1978), groups of 24 CD rats/sex were fed diets containing practical grade
thlram that provided doses of 0, 5.3, 20.4 or 52 mg/kg/day to males, and
6.1, 25.5 and 66.9 mg/kg/day to females. H1nd limb ataxla or paralysis was
observed In 8/24 high-dose female rats (Lee and Peters, 1976). Hlstologlcal
examinations of nervous tissue of two ataxlc rats revealed demyellnation and
degeneration of the sciatic nerve, and degeneration of the spinal cord (Lee
and Peters, 1976).
0133d -71- 08/23/89
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This Is In conflict with Lee et al. (1978), who stated that specific
lesions of the central and peripheral nervous systems were not observed In
nonataxlc, ataxlc or paralyzed rats. Additional nervous system effects
noted were changes In hind leg walking gait In females treated at >25.5
mg/kg/day, and hyperactlvlty 1n males at >20.4 mg/kg/day and females at 66.9
mg/kg/day (five ataxlc females were also hyperactive). Effects reported In
Lee et al. (1978) Included alopecia In middle- and high-dose rats and
decreased body weight compared with controls at all doses In males, and In
middle- and high-dose females. Body weight, presented 1n growth curves, was
consistently below controls 1n low-dose males. Statistical analyses of body
weight data were not presented. Results of organ weight measurements showed
Increased relative thyroid and testes weight 1n high-dose males and
Increased relative liver, kidney, thyroid, ovary and brain weights In
high-dose females, with relative spleen weights Increased 1n both high- and
middle-dose females. Statistical analyses and actual organ weight data were
not provided. Hlstopathologlcal examinations revealed a dose-related
Increase In the Incidence and severity of fatty Infiltration of the pancreas
In male rats, with 1/17, 3/13. 11/15 and 14/16 control, low-, middle- and
high-dose rats affected. Fatty Infiltration of the pancreas was found In
only 1/11 high-dose female rats. Squamous metaplasia of the thyroid was
observed In 4/16 and 3/11 high-dose male and female rats compared with 1/17
male and 0/18 female control rats. Based on decreased body weight gain. In
low-dose males, the 5.3 mg/kg/day dose can be considered an effect level.
Although 1t Is not clear whether decreased body weight gain should be
considered an adverse effect. It 1s an effect observed consistently In
thlram treated animals, and the subchronlc study by Lowy et al. (1979, 1980}
0133d -72- 08/23/89
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\n which body weight was decreased In thlram treated rats compared with
pair-fed controls Indicated that thlraro Itself contributes to the effect on
body weight.
In addition, It 1s known that thi ram 1s an Inhibitor of aldehyde
dehydrogenase, a biochemical effect that 1s significant to humans because of
the widespread use of ethanol. In the study by Garcia de Torres et al.
{1983), two gavage doses of thlram at 3.8 mg/kg given to female rats
followed by an Intraperltoneal Injection of ethanol (2 g/kg) significantly
Increased blood acetaldehyde levels for up to 240 minutes after treatment.
The Increases 1n blood acetaldehyde were also detectable when ethanol was
administered 48 hours after thlram treatment. Although this study Is acute,
It suggests that exposure to thlram may potentiate the action of ethanol.
Minimal toxlclty data are available In dogs. U.S. EPA (1987c) mentioned
a 1-year dog study 1n which 200 ppm (5 mg/kg/day) was considered a NOEL.
Salto et al. (1980), however, reported CNS signs and liver lesions where
dogs were treated for 2 years with thlram In gelatin capsules at 4
mg/kg/day. In addition, there was a transient reduction In erythrocyte
count at that dosage. All dogs treated at 40 mg/kg/day died. There were no
effects at 0.4 mg/kg/day.
No single chronic study with thlram clearly defines a NOAEL and LOAEL
for the critical effect 1n the most sensitive species. The NOAEL of 0.61
mg/kg/day for reproductive effects 1n the ferret (Hornshaw et al., 1987)
appears to be the most defensible basis for the RfD, because It Is below any
LOAEL for chronic toxldty In rats and dogs. Application of an uncertainty
factor of 100 (see Section 8.2.2.1.) results In an RfD for chronic oral
exposure of 0.006 mg/kg/day, the same as the RfD for subchronlc oral
exposure. Confidence 1n the RfD Is medium (see Section 8.2.2.1.).
0133d -73- 08/23/89
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A significant feature of the graphs 1s that the boundary line for
adverse effects 1s nearly without slope at human equivalent durations beyond
about 0.0025 llfespan. This feature Is consistent with the observation that
there 1s little difference between the subchronlc and chronic toxlclty of
thlram, and with the fact that the subchronlc and chronic oral RfD values
are Identical.
No one species, effect, or study figures prominently In defining the
boundary line for adverse effects, as can be seen by Identifying the FELs
and LOAELs on or near the line. The LOAEL for the major Inflection (at
0.0025 llfespan) 1s for Inhibited metabolism 1n rats treated with thlram at
3.8 mg/kg/day for 2 days (Garc'la de Torres et al., 1983). The PEL located
slightly above the line at 0.013 llfespan Is for teratogenlclty where NMRI
mice were treated at 10 mg/kg/day for 2 days, as reported In an abstract
(Matthlaschk, 1973). The LOAEL slightly above the line at 0.022 llfespan Is
for reduced body weight In male ferrets fed a diet that provided 2.8
mg/kg/day for 28 days. At 0.12 llfespan, the LOAEL on the line 1s for
reproduction In ferrets fed a diet that provided 2.1 mg/kg/day for 24 weeks
(Hornshaw et al., 1987). The LOAEL slightly above the line at 0.76 llfespan
Is for reduced body weight In male rats fed a diet that provided 5.3
mg/kg/day for 80 weeks.
The region of contradiction Is not unduly large and Is restricted to the
region between 0.0011 and 0.12 llfespan. This region probably reflects
differences In study quality and protocol rather than differences In species
sensitivity. The regions of ambiguity are also relatively small, reflecting
the rather extensive nature of the data base as well as general agreement
between studies. The subchronlc and chronic RfD value, 0.006 mg/kg/day or
0.4 mg/day for a 70 kg human, Is well below the boundary for no adverse
effects.
0133d -74- 08/23/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty of t til ram was discussed In Chapter 6. Data suitable for
the derivation of an RQ are summarized In Table 9-1. In the study using
mink and ferrets (Hornshaw et al., 1987), ferrets appeared to be more
sensitive than mink; therefore, only data concerning ferrets are presented
1n Table 9-1. In the 28-day study, male ferrets treated at a dose of 27.5
mg/kg/day died following 11-16 days of treatment. Death within such a short
period of time 1s considered an acute effect and Is not scored for CS
determination. Altered body weights were observed In males at >20 ppm (2.8
mg/kg/day) and reduced erythrocyte counts and hematocrlts were observed 1n
both sexes at >50 ppm (5.6-8.6 mg/kg/day). Only the effect on body weight
1s entered In Table 9-1, because this effect and the hematologlc effects
would both be assigned an RV of 4. Although this study was extremely
short In duration, no uncertainty factor Is applied to expand to chronic
exposure because data In other species do not show differences In subchronlc
and chronic toxldty. In the reproductive study, no offspring were produced
by ferrets treated at 7 mg/kg/day, and reduced litter, and kit weights were
reported at 2.1 mg/kg/day.
In an 80-week study (Lee and Peters, 1976; Lee et al., 1978), subtle
nervous system effects (altered gait) were noted 1n female rats treated at
>25.5 mg/kg/day, while body weights were decreased 1n males at 5.3
mg/kg/day. E.I. Du Pont de Nemours & Co. (n.d.) reported ataxla, hind limb
paralysis and calcified masses 1n the basal ganglia and cerebellum of rats
treated with thlram In the diet at doses of 15 mg/kg/day for 2 years.
Incidence data were not provided. Malta et al. (1980) reported reduced
muscle weight and the presence of hlstopathologlc lesions In the muscles of
0133d -75- 08/23/89
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rats at 300 ppm In the diet (15 mg/kg/day) for 2 years. In a 2-year study
In dogs treated with thlram In gelatin capsules, 40 mg/kg/day resulted 1n
the death of all dogs by 29 weeks, and 4 mg/kg/day was associated with CNS
effects and liver lesions.
Short et al. (1976) reported maternal and teratogenlc effects In rats
treated by gavage at 136 mg (practical grade th1ram)/kg/day on gestation
days 6-15. The only effect reported at 40 mg/kg/day was reduced fetal body
weight. In a rat reproduction study (Short et al., 1976), a dosage of 96
mg/kg/day precluded reproduction and 30 mg/kg/day was associated with
reduced number of Implants and offspring/litter.
The derivations of CS and RQ values are presented In Table 9-2. CSs
were not calculated, from studies 1n which deaths occurred shortly after the
study began (Hornshaw et al., 1987; Short et al., 1976). As Indicated In
Table 9-2, the highest CS Is calculated from the ferret study In which
reduced Utter and kit body weights were reported at a human equivalent dose
of 0.49 mg/kg/day. The CS of 25.6 corresponds to an RQ of 100 (Table 9-3).
That reproduction 1n ferrets Is the critical effect 1n the most sensitive
species Is supported by the fact that the highest CS was calculated for this
effect.
U.S. EPA (19875} derived an RQ of 100 for thlram based on an Inhalation
study of reproductive effects In rats (Davydova, 1973). In this study
(summarized by Flshbeln. 1976), reproductive effects (extension of the
estrous cycle, reduced fertility, underweight fetuses) were observed 1n rats
exposed to thlram at a concentration of 3.8±0.058 mg/m3 6 hours/day. 5
days/week for 4.5 months. A CS of 35.4 was calculated from this study based
on an Rv^ of 4.4 and an RV& of 9. Although the CS calculated from the
0133d -78- 08/23/89
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-79-
08/23/89
-------
TABLE 9-3
Thlram
Minimum Effective Dose (MED) and Reportable Quantity {RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
oral
34.3 rag/day
reproductive; reduced litter size and reduced
litter and kit body weights
Hornshaw et a!., 1987
3.2
8
25.6
100
'Equivalent human dose
0133d -80- 08/24/89
-------
Davydova (1973) study U larger than the CS calculated from the Hornshaw et
al. (1987) study, the Hornshaw et al. (1967) study 1s a more appropriate
basis for the RQ because only limited Information concerning the Davydova
(1973) study was available In the review by Flshbeln (1976).
9.2. BASED ON CARCINOGEN!CITY
Thlram has tested negative In a limited oral study using mice (BRL,
1968a) and In oral carclnogenldty studies using rats (Lee et al., 1978;
Takahashl et al., 1983). Lljlnsky (1984) found that oral treatment of rats
with thlram did not result In a carcinogenic effect, while treatment with
thlram and nitrite In the diet Increased the Incidence of nasal cavity and
forestomach tumors. Data regarding the carclnogenldty of thlram to humans
were not located.
Based on the negative animal data and the lack of human carclnogenldty
data, thlram can be classified in EPA group D - not classifiable as to human
carclnogenldty. EPA group D compounds cannot be given a hazard ranking;
therefore, an RQ based on carclnogenldty cannot be assigned.
0133d
-81-
08/23/89
-------
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0133d
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0133d
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Conner, H., K. Husgafvel-Purlalnen, D. Jenssen and A. Rannug. 1983.
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Fenyvesl, G., M. Botos and J. Ivan. 1985. Pesticide-drug Interaction In
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0133d -87- 08/24/89
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Gruen, G., H. Sadek and P. Clausing. 1982. Evaluation of acute toxUHy of
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0133d -88- 08/24/89
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0133d -89- 08/24/89
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Kaskevlch, L.M. and V.P. Bezugly. 1973. Clinical aspects of chronic thlram
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of chemical substances using four blotests. Dtsch. Gewaesserkd. Mitt.
27(3): 77-79.
Kr1shnakumar1, U.K. 1977. Sensitivity of the alga Scenedesmus acutus to
some pesticides. Life Scl. 20(9): 1525-1532.
Kruls-de Vrles, M.H., P.J. Cuenraads and J.P Nater. 1987. Allergic contact
dermatitis due to rubber chemicals 1n haemodlalysls equipment. Contact
Dermatitis. 17(5): 303-305.
Lee, C.C. and P.J. Peters, 1976. Neurotoxldty and behavioral effects of
thlram In rats. Environ. Health Perspect. 17: 35-43.
Lee, C.C., J.Q. Russell and J.L. Minor. 1978. Oral toxlclty of ferric
dlmethyldKhlocarbomate {Ferbam) and tetramethylthluram dlsulMde (Thlram)
In rodents. 0. Toxlcol. Environ. Health. 4(1): 93-106.
0133d -90- 08/24/89
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L1J1nsky, H. 1984, Induction of tumors of the nasal cavity 1n rats by
concurrent feeding of thlram and sodium nitrite. J. Toxlcol. Environ.
Health. 13(4-6): 609-614.
Lorgue, G. and D. Soyez. 1976. Study of the toxic effects of thlram, a
dlthlocarbamate fungicide, on partridges. Part II. Bull. Soc. Sd. Vet.
Med. Comp. Lyon. 78(5): 279-288.
Lorgue, G.t P. Oelatour, D. Courtot, J. Gastellu and M. Mackowlak. 1975.
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Vet. 126(3): 365-381.
Lowy, R., G. Grlffaton, L. Brlgant, B. Ardouln and F. Dupuy. 1979. The
dietary no-effect level of a dHhlocarbamate fungicide, thlram, as evaluated
from the measurement data on rats. II. The various sensitivities of the
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Lowy, R., G. Grlffaton, F. Dupuy, B. Ardouln and P. Hanchon. 1980. Dietary
no-effect level of a dUhlocarbamate fungicide, thlram, evaluated from
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Lyman, W.J. 1982. Adsorption coefficient for soils and sediments. In:
Handbook of Chemical Property Estimation Methods, W.J. Lyman, W.F. Reehl and
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0133d
-91-
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Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
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Malta, K., 1. Salto, K. Takahashl, S. Tsuda and Y. Shlrasu. 1980. Twenty
four month chronic toxlclty study with bls(dlmethylthlocarbamoyl) dlsulflde
(thlram) 1n rats. J. Toxlcol. Sc1. 5(3): 269-270.
Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
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Marks, J.G. and M.A. Ralney. 1984. Cutaneous reactions to surgical
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Matthlaschk, G. 1973. Influence of L-cyste1ne on thlram (TMlD)-lnduced
teratogenesls In NMRI-m1ce. Arch. Toxlkol. 30(3): 251-262. (CA 79:1002v)
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Co., Wllloughby, OH.
Merlevede, E. and 3. Peters. 1965. Metabolism of xanthates In man and
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0133d -92- 08/24/89
-------
MoMya, M., K. Kato, Y. Shlrasu and T. Kada. 1978. MutagenlcHy screening
of pesticides 1n mlcroblal systems. 4. HutagenUlty of dlmethyldlthlo-
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Morlya, H., T. Ohta, K. Watanabe, T. Hlyazawa, K. Kato and Y. Shlrasu.
1983. Further mutagenlclty studies on pesticides In bacterial reversion
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Munnecke, D.E and K.Y. Mckall. 1967. Thlram persistence In soil and
control of damplng-off caused by pythlum ultlmum. Phytopath. 57: 969-971.
OSHA (Occupational Safety and Health Administration). 1985. Occupational
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Poltou, P., B. Harlgnac and D. Gradlskl. 1978. Effect of tetramethyl-
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Rajagopal, B.S., G.P. Brahmaprakash, B.R. Reddy, V.D. Singh and N.
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0133d -93- 08/24/89
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Rannug, A. and U. Rannug. 1984. Enzyme Inhibition as a possible mechanism
of the mutagenldty of dlthlocarbamlc acid derivatives 1n Salmonella
typhlmurlum. Chem. 81ol. Interact. 49(3): 329-340.
Relnbold, K.A., J.J. Hassett, J.C. Means and H.L. Banwart. 1979. Adsorp-
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Richardson, L.T. 1954. The persistence of thlram 1n soil and Us relation-
ship to the microbiological balance and damplng-off control. Can. J. Bot.
32: 335-346.
Roark, J.H. and J.L. Dale. 1979. The effect of turf fungicides on earth-
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dlsulflram and thlram 1n small laboratory animals. Toxlcol. Appl.
Pharmacol. 15(1): 152-163.
Rocchl, P., P. Perocco, H. Albergh1n1, A. F1n1 and G. Prodi. 1980. Effect
of pesticides on scheduled and unscheduled DNA synthesis of rat thymocytes
and human lymphocytes. Arch. Toxlcol. 45(2): 101-108.
Roll, R. 1971. Teratologk studies with thlram (TMTD) on two strains of
mice. Arch. Toxlkol. 27(3): 173-86. (Taken from TOXBIB/71/206703)
0133d -94- 08/24/89
-------
SaHo, T., K.W. Takahashl, S. Tsuda, K. MHsumorl. K. HaHa and Y. Shlrasu.
1980. Twenty-four month chronic toxlclty study with b1s(d1methylth1o-
carbamoyl) dlsulflde (thlram) 1n beagles. 3. Toxlcol. Sc1. 5(3): 269-270.
SANSS (Structure and Nomenclature Search System). 1987. Chemical Informa-
tion System (CIS) computer data base. On-Hne: Hay 13, 1988.
Sasaki, S. 1978. The scientific aspects of the Chemical Substance Control
Law In Japan. In: Aquatic Pollutants: Transformation and Biological
Effects, 0. Hutzlnger, L.H. Letyoeld and B.C.J. Zoeteman, Ed. Pergamon
Press, Oxford, p. 283-298.
Schafer, E.W., Jr. and W.A. Bowles, Jr. 1985. Acute oral toxlclty and
repellency of 933 chemicals to house and deer mice. Arch. Environ. Contain.
Toxlcol. 14(1): 111-129.
Schneider, B.A. 1979. Toxicology handbook mammalian and aquatic data.
Book 1. Toxicology data. Office of Pesticide Programs, U.S. Environ. Prot.
Agency, Washington, DC. EPA-540-9-79-003A. NTIS PB80-196876.
Sen, N.P., B.A. Donaldson and C. Charbonneau. 1974. Formation of nltroso-
dlmethylamlne from the Interaction of certain pesticides and nitrites. In:
N-Nltroso Compounds In the Environment, P. Bogovskl and E.A. Walker, Ed.
IARC, Lyons, France. IARC Sc1. Publ. No. 9, p. 75-79. (Cited 1n IARC, 1976)
Seuge, J. and R. Bluzat. 1983. Acute toxlclty of a dlthlocarbamate fungi-
cide, thlram, In larvae of the mayfly Cloeon dlpterum: Effects of various
parameters. Hydroblologla. 101(3): 215-222. (Fre.)
0133d -95- 08/24/89
-------
Seuge, 3., D. Marchal-Segault and R. Bluzat. 1983. Acute toxUHy of the
dlthlocarbamate fungicide thlram to freshwater animals. Environ. Pollut.
Ser. A. 31(3): 177-189. (Fre.)
Shlrkot, C.K. and K.6. Gupta. 1985. Accelerated tetramethylthluram
dlsulflde (TMTO) degradation In son by Inoculation with TMTD-utlllzIng
bacteria. Bull. Environ. Contam. Toxlcol. 35: 354-361.
Short, R.D., J.Q. Russel, J.L. Minor and C. Lee. 1976. Developmental
toxldty of ferric dlmethyldUhlocarbamate and b1s(d1methylth1ocarbamoyl)-
dlsulflde In rats and mice. Toxlcol. Appl. Pharmacol. 35: 83-94.
Slvltskaya, I.I. 1974. State of the organ of vision In persons working In
contact with TMTO. Oftalmon. Z. 28: 286-388. (Cited 1n Flshbeln, 1976)
SRI (Stanford Research Institute). 1987. 1987 Directory of Chemical
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p. 047.
Szymezyk, T. 1981. Mutagenlclty of the fungicide thlram. Mutat. Res. 85:
223-224.
Takahashl, M., T. Kokubo, F. Furakawa et al. 1983. Inhibition of sponta-
neous leukemia In F-344 rats by tetramethylthluram dlsulflde (thlram).
Gann. 75(6): 821-813.
0133d
-96-
08/24/89
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Taylor, G.T. and M.t. Pace. 1987. Validity of eukaryote Inhibitors for
assessing production and grazing mortality of marine bacteMoplankon. Appl.
Environ. Mlcroblol. 53(1): 119-128.
Thomas, R.6. 1982. Volatilization from water. I_n: Handbook of Chemical
Property Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed.
McGraw Hill Book Co., New York. p. 15-1 to 15-34.
Thuranszky, K., I. Kiss, M. Botos and A. Szebenl. 1982. Effect of dHhlo-
carbamate-type chemicals on the nervous system of rats. Arch. ToxUol. 5:
135-138.
Tooby, I.E., P.A. Hursey and J.S. Alabaster. 1975. The acute toxlclty of
102 pesticides and miscellaneous substances to fish. Chem. Ind. 12:
523-526.
Tucker, R.K. and D.G. Crabtree. 1970. Handbooks of loxldty of Pesticides
to Wildlife. U.S. Fish and Wildlife Service, Bureau of Sport ElsheMer and
Wildlife, Resource Publ. No. 84. p. 1-9, 114-115.
Upshall, A. and P.E. Johnson. 1981. Thlram-lnduced abnormal chromosome
segregation In Asperglllus nldulans. Hutat. Res. 89(4): 279-301.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357,
0133d
-97-
08/24/89
-------
U.S. EPA. 1984a. Guidance for the Rereglstratlon of Pesticide Products
Containing Thlram as the Active Ingredient. Office of Pesticide Programs,
Washington, DC. NTIS PB85-102705.
U.S. EPA. 1984b. Methodology and Guidelines for Ranking Chemicals Based on
Chronic ToxIcHy Data. Prepared by the Office of Health and Environmental
Assessment. Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Thlram: tolerance levels. 40 CFR 1880.138.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986c. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). Personal
Computer Version. Fate of Atmospheric Pollutants (FAP) computer program.
April 1987. U.S. EPA, Research Triangle Park, NC.
U.S. EPA. 1987b. Reportable Quantity Document for Thlram. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial
Response, Washington, DC.
0133d
-98-
08/24/89
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U.S. EPA. 1987c. Integrated Risk Information System (IRIS): Reference Dose
(RfD) for Oral Exposure for Thlram. Online. (Revised; Verification date
04/15/87.) Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1987d. Superfund Record of Decision (EPA Region 5):
Johns-Hanvllle-Waukegan Site, Illinois (First Remedial Action), June 1987.
Final Draft Report No. EPA/ROD/R05-87/048.
U.S. EPA. 1988. Integrated Risk Information System (IRIS). Chemical File
for Thlram. Online. Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA/OWRS (Environmental Protection Agency/Office of Water Regulations
and Standards. 1986. Guidelines for Deriving Numerical National Water
Quality Criteria for the Protection of Aquatic Organisms and Their Uses.
Environmental Protection Agency, Washington, DC. 106 p.
USITC (U.S. International Irade Commission). 1987. Synthetic Organic
Chemicals, United States Production and Sales, 1986. USTIC Publ. 2009,
Washington, DC.
Van Leeuwen, C.J., J.L. Maas-Dlepeveen, G. Nlebeek, W.H.A. Vergouw, P.S.
Grlffloen and M.H. Luljen. 1985a. Aquatic toxlcologlcal aspects of dlthlo-
carbamates and related compounds. I. Short-term toxlclty tests. Aquat.
Toxlcol. 7(3): 145-164.
0133d
-99-
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Van Leeuwen, C.J., F. Roberts and G. Nlebeek. 1985b. Aquatic lexicological
aspects of dUhlocarbamates and related compounds. II. Effects on survival,
reproduction and growth of Daphnla magna. Aquat. Toxlcol. 7(3): 165-175.
Van Leeuwen, C.J., J.L. Maasdlepeveen and H.C.M. Overbeek. 1986a. Sub-
lethal effects of tetramethylthluram dlsulflde (thlram) 1n rainbow-trout.
Aqua. Toxlcol. 9(1): 13-19.
Van Leeuwen, C.J., A. Espeldoorn and F. Mol. 1986b. Aquatic toxlcologlcal
aspects of dUhlocarbamates and related compounds: III. Embryolarval studies
with rainbow trout. Aquat. Toxlcol. 9(2-3): 129-146.
Van Leeuwen C.3., T. Helder and W. Selnen. 1986c. Aquatic toxlcologlcal
aspects of dUhlorcarbamates and related compounds: IV. Teratogenlclty and
hlstopathology 1n rainbow trout. Aquat. Toxlcol. 9(2-3): 147-160.
Vasseur, P., 3.M. Jouany and J.F. Ferard. 1982. Determination of A1P as a
criterion for acute ecotoxlclty 1n algae. Colloq. Inst. Natl. Sante. Rech.
Hed. 106: 207-226.
Voronkln, A.S. and Y.T. Loshakov. 1973. Toxic effect of pesticides on
Tublfex tublfex. Eksp. Vodn. Tokslkol. 5: 169-178. [CA 86(19):134541m]
Hendel, K.G. 1974. Influence of pesticides on rhlzopshere organisms. I.
Study of TMTO (tetramethylthluram dlsulflde) In soils using a model experi-
ment. Zentralbl. Bakterlol. ParasHenk, Infertlon. Hyg., Abt.l:0r1g.,
Relhe. A. 228:141-153. (CA 81:115754)
0133d -100- 08/24/89
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Williams, P.P. 1977. Metabolism of synthetic organic pesticides by
anaerobic microorganisms. Res. Rev. 66: 63-135.
Hlndholz, M., Ed. 1983. The Merck Index, 10th ed. Herck and Co., Inc.,
Rahway, NJ. p. 1343.
Worthing, C.R and S.B. Walker, Ed. 1983. The Pesticide Manual, 7th ed.
British Crop Protection Council, p. 534.
Zdzlenlcka, M., M. Zleleska, B. Tudek and T. Szymczyk. 1979. MutagenU
activity of thlram In Ames tester strains of Salmonella typhlmurlum. Mutat.
Res. 68(1): 9-13.
Zdzlenlcka, M., M. Zleleska, M. Trojanowska and T. Szymczyk. 1981.
Mlcroblal short-term assays with thlram In vitro. Mutat. Res. 89(1): 1-7.
Zdzlenlcka, M., M. Hrynlewlcz and M. Plenkowska. 1982. Thlram-lnduced
sperm-head abnormalities 1n mice. Mutat. Res. 102(3): 261-264.
0133d
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMlINE
TSCATS
CASR online {U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research 1n Progress
These searches were conducted 1n May, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati. OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0133d -102- 08/23/89
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, N. 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.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International. Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index. 10th ed. Merck and Co..
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0133d -103- 08/23/89
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, U.W. and H.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137. Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-26960S.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0133d -104- 08/23/89
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APPENDIX C
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO THIRAM
C.I. DISCUSSION
Dose/duration-response graphs for oral exposure to thlram generated by
the method of Crockett et al. (1985) using the computer software by Durkln
and Meylan (1988) under contract to ECAO-C1nc1nnat1 are presented In Figures
C-1 and C-2. Data used to generate this (these) graph(s) are presented In
Section C.2. In the generation of this (these) f1gure(s) all responses are
classified as adverse (PEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for
plotting. If data are available for Inhalation exposure: The ordlnate
expresses concentration In either of two ways. In Hgure(s) (), the
experimental concentration expressed as mg/m3 was multiplied by the time
parameters of the exposure protocol (e.g., hours/day and days/week) and Is
presented as expanded experimental concentration [expanded exp cone
(mg/m8)]. In flgure(s) (---}, the expanded experimental concentration was
multiplied by the cube root of the ratio of the animal:human body weight to
estimate an equivalent human or scaled concentration [scaled cone (mg/m3)]
(U.S. EPA, 1980; Mantel and Schneider man', 1975).
The boundary for adverse effects (solid line) Is drawn by Identifying
the lowest-adverse-effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point an Infinite
line 1s extended upward parallel to the dose axis. The starting point Is
then connected to the lowest-adverse-effect dose or concentration at the
next longer duration of exposure that has an adverse-effect dose or
concentration equal to or lower than the previous one. This process 1s
continued to the lowest-adverse-effect dose or concentration. From this
point a line 1s extended to the right parallel to the duration axis. The
region of adverse effects lies above the adverse effects boundary.
0133d -106- 08/23/89
-------
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HUNAN EQU1U DURATION (fraction lif>sp»n>
FIGURE C-1
Dose/Duration - Effect Graph for Oral Exposure to TMram:
Envelope Method
0133d
-107-
08/23/89
-------
91
I
10000 -r
3
9
i
100-r
10--
r
r
fc
0.001
L
>f»
*-
n
I 1 llllli
0.01 0.1
HUMAN CQUIM DURATION (fraction tifcspan)
FIGURE C-2
Dose/Duration - Effect Graph for Oral Exposure to Thlram:
Censored Data Method
0133d
-108-
08/23/89
-------
Using the envelope method, the boundary for no adverse effects (dashed
line) Is drawn by Identifying the highest no-adverse-effects dose or
concentration. From this point a line parallel to the duration axis Is
extended to the dose or concentration axis. The starting point Is then
connected to the next highest or equal no-adverse-effect dose or
concentration at a longer duration of exposure. When this process can no
longer be continued, a line Is dropped parallel to the dose or concentration
axis to the duration axis. The region of no adverse effects lies below the
no-adverse-effects boundary. At both ends of the graph between the
adverse-effects and no-adverse-effects boundaries are regions of ambiguity.
The area (1f any) resulting from Intersection of the adverse-effects and
no-adverse-effects boundaries 1s defined as the region of contradiction.
In the censored data method, all no-adverse-effect points located 1n the
region of contradiction are dropped from consideration and the
no-adverse-effect boundary Is redrawn so that H does not Intersect the
adverse-effects boundary and no region of contradiction 1s generated. This
method results 1n the most conservative definition of the no-adverse-effects
region.
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Chemical Name: Thlram
CAS Number: 137-26-8
Document Title: Health and Environmental Effects Document on Thlram
Document Number: SRC-TR-88-133
Document Date: 12/22/88
Document Type: HEED
0133d -109- 08/23/89
-------
RECORD II
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Gavage
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 9
Dose: 400.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Comment :
Citation:
RECORD #2:
L050
Lee et al
Species:
Sex:
Effect:
Route:
., 1978
Rats
Female
FEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
190.000
1.0 days
1.0 days
Comment:
Citation:
RECORD |3:
LD50
Lee et al
Species:
Sex:
Effect:
Route:
.. 1978
Rats
Male
FEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
640.000
1.0 days
-1 .0 days
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
NR
NR
DEATH
BODY
9
Galnes, 1969
0133d
-110-
08/23/89
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RECORD 14:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Gavage
Galnes, 1969
Dose: 620.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
RECORD #5:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Male
FEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Lee et al., 1978
Dose: 400.000.
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
NR
NR
DEATH
BODY
9
RECORD #6:
Species:
Sex:
Effect:
Route:
Mice
Female
FEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
380.000
1.0 days
1.0 days
Comment:
Citation:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
LD50
Lee et al., 1978
NR
NR
DEATH
BODY
9
0133d
-111-
08/23/89
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RECORD #7:
Comment:
Citation:
RECORD #8:
Comment:
Citation:
RECORD #9:
Comment:
Citation:
Species: Mice
Sex: NS
Effect: FEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
1059; abstract
Matthlaschk, 1973
Species: Rats
Sex: Female
Effect: LOAEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: ENZYM
SHe of Effect: NS
Severity Effect: 2
Altered metabolism of ethanol
Garcia de Torres et al., 1983
Species: Rats
Sex: Hale
Effect: FEL
Route: Food
Number Exposed: 20
Number Responses: 14
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
2500 ppm In diet; food Intake
Lee et al.. 1978; Short et al
Dose:
Duration
Duration
Dose:
Duration
Duration
Dose:
Duration
Duration
NR
NR
HGTDC
BODY
5
2300.000
Exposure: 1.0 days
Observation: 1.0 days
3.800
Exposure: 2.0 days
Observation: 2.0 days
132.000
Exposure: 13.0 weeks
Observation: 13.0 weeks
20 20
NR NR
ENZYH DEGEN
LIVER TESTE
2 5
also reduced
., 1976
0133d
-112-
08/23/89
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RECORD #10:
Comment:
Citation:
RECORD #11:
Comment:
Citation:
RECORD #12:
Species: Rats
Sex: Male
Effect: AEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
1000 ppm In diet
Lee et al., 1978;
Species: Rats
Sex: Male
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
500 ppm In diet
Lee et al.. 1978;
Species: Rats
Sex: Male
Effect: AEL
Route: Food
20
NR
WGTOC
BODY
5
Short et
*.
20
NR
UGTDC
BODY
5
Short et
Dose:
Duration Exposure:
Duration Observation:
20
NR
ENZYM
KIDNY
2
al., 1976
Dose:
Duration Exposure:
Duration Observation:
al., 1976
Dose:
Duration Exposure:
Duration Observation:
58.000
13.0 weeks
13.0 weeks
30.000
13.0 weeks
13.0 weeks
41.900
29.0 days
29.0 days
Comment:
Citation:
Number Exposed: 6
Number Responses: NR
Type of Effect: WGTDC
Site of Effect: BODY
Severity Effect: 5
300 ppm In diet; controls were pair-fed
Lowy et al.. 1979, 1980
0133d
-113-
08/23/89
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RECORD #13:
Comment:
Citation:
RECORD #14:
Comment:
Citation:
RECORD #15:
Comment:
Citation:
Species: Rats
Sex: Male
Effect: LOAEL
Route: Food
Number Exposed: 6
Number Responses: NR
Type of Effect: HGTDC
Site of Effect: BODY
Severity Effect: 4
225 ppm In diet; controls
Lowy et al., 1979, 1980
Species: Rats
Sex: Female
Effect: FEL
Route: Food
Number Exposed: 24
Number Responses: NR
Type of Effect: FUNP
Site of Effect: PNS
Severity Effect: 8
1000 ppm 1n diet
Lee and Peters. 1976
Species: Rats
Sex: Female
Effect: LOAEL
Route: Food
Number Exposed: 24
Number Responses: NR
Type of Effect: FUND
Site of Effect: CNS
Severity Effect: 7
400 ppm 1n diet
Lee and Peters, 1976
Dose:
Duration Exposure:
Duration Observation:
were pair-fed
Dose:
Duration Exposure:
Duration Observation:
Dose:
Duration Exposure:
Duration Observation:
24
NR
FUND
PNS
7
33.600
29.0 days
29.0 days
66.900
80.0 weeks
80.0 weeks
25.500
80.0 weeks
80.0 weeks
0133d
-114-
08/23/89
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RECORD #16:
Comment :
Citation:
RECORD #17:
Comment:
Citation:
RECORD #18:
Species: Rats
Sex: Hale
Effect: AEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
400 ppm 1n diet
Lee and Peters, 1976
Species: Rats
Sex: Male
Effect: LOAEL
Route: . Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
100 ppm In diet
Lee and Peters, 1976
Species: Rats
Sex: Female
Effect: FEL
Route: Food
24
NR
FUND
CNS
6
; Lee
24
NR
WGTOC
BODY
5
; Lee
Dose:
Duration Exposure:
Duration Observation:
et al., 1978
Dose:
Duration Exposure:
Duration Observation:
et al.. 1978
Dose:
Duration Exposure:
Duration Observation:
20.400
80.0 weeks
80.0 weeks
5.300
80.0 weeks
80.0 weeks
65.800
36.0 weeks
36.0 weeks
Comment:
Citation:
Number Exposed: 24
Number Responses: NR
Type of Effect: FUNP
Site of Effect: PNS
Severity Effect: 8
Lee and Peters, 1976
0133d
-115-
08/23/89
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RECORD #19:
Comment :
Citation:
RECORD #20:
Comment:
Citation:
RECORD #21:
Species: Rats
Sex: NS
Effect: PEL
Route: Food
Number Exposed: 24
Number Responses: NR
Type of Effect: FUNP
Site of Effect: CNS
Severity Effect: 8
Briefly reported; 300 ppm In
E.I. Ou Pont de Nemours & Co.
Species: Rats
Sex: Both
Effect: LOAEL
Route: Food
Number Exposed: 64
Number Responses: NR
Type of Effect: WGTDC
Site of Effect: BODY
Severity Effect: 5
300 ppm In diet; abstract
Malta et al., I960
Species: Rats
Sex: Both
Effect: NOEL
Route: Food
Dose:
Duration Exposure:
Duration Observation:
diet
, n.d
Dose:
Duration Exposure:
Duration Observation:
64 64
NR NR
HE MAT DEGEN
BLOOD HSKEL
3 5
Dose:
Duration Exposure:
Duration Observation:
15.000
2.0 Years
2.0 Years
15.000
2.0 years
2.0 years
1.150
2.0 years
2.0 years
Comment:
Citation:
Number Exposed: 64
Number Responses: NR
Type of Effect: WGTDC
Site of Effect: BODY
Severity Effect: 5
30 ppm In diet; abstract
Malta et al.. 1980
0133d
-116-
08/23/89
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RECORD #22:
Comment:
Citation:
RECORD #23:
Comment:
Citation:
RECORD #24:
Species: Dogs
Sex: Both
Effect: PEL
Route: Capsul
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Abstract; beagles
SaHo et al., 1980
Species: Dogs
Sex: Both
Effect: LOAEL
Route: Capsul
Number Exposed: 8
Number Responses: NR
Type of Effect: FUND
Site of Effect: CNS
Severity Effect: 7
Abstract, beagles
SaHo et al., 1980
Species: Dogs
Sex: Both
Effect: NOEL
Route: Capsul
Dose:
Duration Exposure:
Duration Observation:
Dose:
Duration Exposure:
Duration Observation:
8
NR
HE HAT
BLOOD
2
Dose:
Duration Exposure:
Duration Observation:
40.000
6.0 weeks
6.0 weeks
4.000
2.0 years
2.0 years
0.400
2.0 years
2.0 years
Comment:
Citation:
Number Exposed:
Number Responses:
Type of Effect:
SUe of Effect:
Severity Effect:
Abstract, beagles
SaHo et al., 1980
NR
NR
FUND
CNS
7
0133d
-117-
08/23/89
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RECORD |25:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
AEL
Oral (NOS)
Dose: 240.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: BEHAV
Site of Effect: CNS
Severity Effect: 6
Reduced "orientation of hypermotmty*
Thuranszky et al.f 1982
RECORD #26:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Oral (NOS)
Dose: 60.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: ENZYH
SHe of Effect: CNS
Severity Effect: 2
Altered neurotransmUter levels In unspecified tissue
Thuranszky et al., 1982
RECORD #27:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Minks
Female
LOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose:
Duration Exposure:
Duration Observation;
2
NR
HEMAT
BLOOD
2
6.600
28.0 days
28.0 days
45 ppm In diet; dosage 1n males was 8.6 mg/kg/day
Hornshaw et al., 1987
0133d
-118-
08/23/89
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RECORD #28:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Ferrets
Hale
PEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
27.500
11.0 days
11.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Comment:
Citation:
RECORD #29:
312 ppm; females at this
also died
Hornshaw et al. , 1987
Species: Ferrets
Sex: Male
Effect: LOAEL
Route: Food
dietary level (44.8
mg/kg bw/day)
Dose: 2.800
Duration Exposure: 28.0 days
Duration Observation: 28.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: HGTDC
Site of Effect: BODY
Severity Effect: 5
Comment:
Citation:
RECORD |30:
20 ppm
bw/day) r
Hornshaw
Species:
Sex:
Effect:
Route:
In diet; female;
tot affected
et al., 1987
Ferrets
Female
LOAEL
Food
\ at this dietary level
Dose:
Duration Exposure:
Duration Observation:
(3.
16
28
28
3 mg/kg
.500
.0 days
.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 5
125 ppm 1n diet
Hornshaw et al., 1987
0133d
-119-
08/23/89
-------
RECORD #31
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Ferrets
Male
LOAEL
Food
Dose: 5.600
Duration Exposure: 28.0 days
Duration Observation: 28.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: HEHAT
Site of Effect: BLOOD
Severity Effect: 2
Comment:
Citation:
RECORD #32:
50 ppm In
bw/day)
Hornshaw et
Species:
Sex:
Effect:
Route:
diet; effect
al.. 1987
Ferrets
Male
NOEL
Food
also observe
Dose:
Duration
Duration
d In females
Exposure:
Observation:
(8.6 mg/kg
1.100
28.0 days
28.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: HEHAT
SHe of Effect: BLOOD
Severity Effect: 2
8 ppm In diet; no effects In females (1.6 mg/kg bw/day}
Hornshaw et al., 1987
RECORD #33:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Hamsters
Female
FEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
500.000
1.0 days
1.0 days
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
4
NR
DEATH
BODY
9
Given In carboxymethylcellulose (CMC)
Robens, 1969
0133d
-120-
08/23/89
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RECORD f34:
Comment:
Citation:
RECORD #35:
Comment:
Citation:
RECORD |36:
Species: Hamsters
Sex: Female
Effect: FEL
Route: Gavage
Number Exposed: 4
Number Responses: NR
Type of Effect: TERAD
SHe of Effect: FETUS
Severity Effect: 8
Given 1n CMC; statistical
Robens, 1969
Species: Hamsters
Sex: Female
Effect: NOAEL
Route: Gavage
Number Exposed: 4
Number Responses: NR
Type of Effect: TERAD
Site of Effect: FETUS
Severity Effect: 8
Given 1n CMC; statistical
Robens, 1969
Species: Mice
Sex: Female
Effect: NOAEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: TERAO
Site of Effect: FETUS
Severity Effect: 8
Dose:
Duration Exposure:
Duration Observation:
analysis not performed
Dose:
Duration Exposure:
Duration Observation:
analysis not performed
Dose:
Duration Exposure:
Duration Observation:
250.000
1.0 days
1.0 days
125.000
1.0 days
1.0 days
250.000
2.0 days
2.0 days
Comment: Abstract; NHRI mice more sensitive than SW mice.
Teratogenlclty was observed at higher unspecified doses; no
maternal toxlclty
Citation: Roll, 1971
0133d
-121-
08/23/89
-------
RECORD 137:
Comment:
Citation:
RECORD #38:
Species: Mice
Sex: Female
Effect: FEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: TERAD
Site of Effect: FETUS
Severity Effect: 8
Abstract; NMRI mice
Matthlaschk, 1973
Species: Rats
Sex: Female
Effect: LOAEL
Route: Gavage
Dose: 10.000
Duration Exposure: 11.0 days
Duration Observation: 11.0 days
Dose: 40.000
Duration Exposure: 10.0 days
Duration Observation: 10.0 days
Comment:
Citation:
Number Exposed: 10
Number Responses: NR
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 8
Comment :
Citation:
RECORD #39:
Maternal
Identify
Short et
Species:
Sex:
Effect:
Route:
food Intake
NOAEL
a!., 1976
Mice
Female
LOAEL
Gavage
and bw gain r
Dose:
Duration
Duration
educed; study
Exposure:
Observation:
does not
300.000
9.0 days
9.0 days
Number Exposed: 18
Number Responses: NR
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 7
Slight evidence of fetotoxldty; statistical analysis not
performed; 4/18 dams died; SW mice
Short et al., 1976
0133d
-122-
08/23/89
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RECORD #40:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
NOAEL
Gavage
Dose: 100.000
Duration Exposure: 9.0 days
Duration Observation: 9.0 days
Number Exposed: 18
Number Responses: NR
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 7
Comment:
Citation:
RECORD #41:
SH mice;
Short et
Species:
Sex:
Effect:
Route:
no evidence
al.. 1976
Rats
Hale
FEL
Food
of maternal or fetal toxlclty
Dose:
Duration
Duration
Exposure:
Observation:
132.000
13.0 weeks
13.0 weeks
Number Exposed: 20
Number Responses: NR
Type of Effect: REPRO
Site of Effect: NS
Severity Effect: 8
2500 ppm In diet; males failed to Inseminate control females;
<50X of males with Impaired breeding performance had
testlcular lesions
Short et al.t 1976
RECORD #42:
Species:
Sex:
Effect:
Route:
Rats
Male
NOAEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
58.000
13.0 weeks
13.0 weeks
Comment:
Citation:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1000 ppm 1n diet
Short et al., 1976
20
NR
REPRO
NS
8
0133d
-123-
08/23/89
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RECORD #43:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose: 30.000
Duration Exposure: 14.0 days
Duration Observation: 14.0 days
Number Exposed: 20
Number Responses: NR
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 7
Comment :
Citation:
RECORD #44:
400 ppm
Short et
Species:
Sex:
Effect:
Route:
1n diet; lowest
al., 1976
Rats
Female
LOAEL
Food
dosage tested
Dose:
Duration Exposure:
Duration Observation:
95
27
27
.200
.0 days
.0 days
Number Exposed: 10
Number Responses: NR
Type of Effect: SURVI
Site of Effect: OTHER
Severity Effect: 9
Comment:
Citation:
RECORD #45:
Reduced viability and growth of offspring; 1000 ppm In diet
Short et
Species:
Sex:
Effect:
Route:
al.. 1976
Rats
Female
NOAEL
Food
Dose:
Duration Exposure:
Duration Observation:
43.400
27.0 days
27.0 days
Number Exposed: 10
Number Responses: NR
Type of Effect: SURVI
Site of Effect: OTHER
Severity Effect: 9
No effect on survival of offspring
Short et al., 1976
0133d
-124-
08/23/89
-------
RECORD |46:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Minks
Female
AEL
Food
Dose:
Duration Exposure:
Duration Observation:
5.700
20.0 weeks
20.0 weeks
Number Exposed: 12
Number Responses: NR
Type of Effect: SURVI
Site of Effect: OTHER
Severity Effect: 9
Decreased average birth weight, possibly decreased kit
survival; 40 ppm
Hornshaw et al., 1987
RECORD #47:
Comment :
Citation:
RECORD #48:
Species: Minks
Sex: Female
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Probably decresed
Hornshaw et al..
Species: Minks
Sex: Female
Effect: NOAEL
Route: Food
12
NR
SURVI
OTHER
9
Dose:
Duration Exposure:
Duration Observation:
1.500
20.0 weeks
20.0 weeks
kit survival; 10 ppm In diet
1987
Dose:
Duration Exposure:
Duration Observation:
0.400
20.0 weeks
20.0 weeks
Comment:
Citation:
Number Exposed: 12
Number Responses: NR
Type of Effect: SURVI
SHe of Effect: OTHER
Severity Effect: 9
No effect on reproduction
Hornshaw et al., 1987
0133d
-125-
08/23/89
-------
RECORD #49:
Comment:
Citation:
RECORD #50:
Species: Ferrets
Sex: Female
Effect: FEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose:
Duration Exposure:
Duration Observation:
12
NR
REPRO
OTHER
8
7.000
24.0 weeks
24.0 weeks
Reproduction precluded at 64 ppm 1n diet
Hornshaw et al., 1987
Species: Ferrets
Sex: Female
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose:
Duration Exposure:
Duration Observation:
12
NR
REPRO
OTHER
8
2.100
24.0 weeks
24.0 weeks
Comment: 16 ppm: reduced number of offspring/litter, Utter weight
and offspring body weight at 3 weeks postpartum; survival of
offspring reduced
Citation: Hornshaw et al., 1987
RECORD #51:
Species:
Sex:
Effect:
Route:
Ferrets
Female
NOAEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
0.610
24.0 weeks
24.0 weeks
Comment:
Citation:
Number Exposed: 12
Number Responses: NR
Type of Effect: REPRO
Site of Effect: OTHER
Severity Effect: 8
No effects on reproduction
Hornshaw et al., 1987
NR = Not reported
0133d
-126-
08/23/89
-------
|