CHEMICAL HAZARD INFORMATION PROFILE*
DRAFT REPORT
Ziram
137-30-4
September 30, 1983
DISCLAIMER
,oment is a preliminary draft, and has not been peer and
ratively reviewed within EPA. It should not be construed to
t Agency policy. Mention of tradenames or commercial pro not
te endorsement or recommendation for use.
cal Hazard Information Profile (CHIP) is part of the first stage in
ssment of risk by the Office of Toxic Subjstances _(OTS) of cnemicals
977 TSCA Chemical Substance Inventory, and enables OTS to decide on
ition for the subject chemical regarding level of concern and the
further assessment. The CHIP contains a summary and preliminary
•nt of readily available health, environmental effects, and exposure
n general, no in depth critical evaluation or validation of the
performed. Several levels of management and' technical review have
formed on this CHIP within the Assessment Division of OTS.
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DRAFT REPORT
CHEMICAL HAZARD INFORMATION PROFILE
Subject Ziram Prepared by 'lary Lou Daughertv
Chemical Name Zinc, bis(dimethylcarbamo- Chemical Effects Information Center
dithioato-S.S)-(T-4)-. (9 CD Oak Ridge National Laboratory
CAS No. 137-30-4
Date of Report- September 30, 1983
Rationale for Selection Carcinogenicity - NTP Bioassay (NTP 1983) .
Summary
Ziram has a relatively high, production volume (1,880,000 pounds in
the U.S. 1981) and is used primarily as a rubber accelerator and as a
fungicide on fruits and vegetables.
NIOSE projected that 27,889 workers, mainly in the rubber industry,
are exposed to ziram. The survey on which this figure was based did not
include workers in the pesticide or agriculture industries, however.
Although industrial monitoring data were not found, Russian and Italian
data document significant levels of the compound in the work environment
of ziran manufacturing facilities, suggesting that worker exposure could
occur in U.S. industry as well.
Ziram is released into the environment when applied to crops as a
fungicide, or to aquatic systems as a molluscicide. No data on release
from industrial sites was located. Experimental data suggest that, once
released, the compound is fairly stable and may retain its biological
activity for a month or more before chemical and perhaps biological
degradation are complete.
Consumers could be exposed to ziram by using the compound as a
garden fungicide or by ingesting contaminated fruits and vegetables.
However, it is possible that routine household washing of produce would
minimize exposure via ingestion.
Various types of toxicities have been demonstrated in experimental
animals, humans, and a broad spectrum of environmental species exposed to
ziram. The two most significant findings are carcinogenicity in the male
rat thyroid following oral administration of the compound, and
chromosomal abnormalities in humans exposed to the compound in the
workplace. Other effects of the compound include teratogemcity and
reproductive tczicity in rats, rabbits, mice, and chickens,
hematological changes in animals and humans, irritation of the skin,
eyes, and respiratory tract in exposed workers, and possible
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cnoliaesterase umioition in aumans. The nmtagenicity of zir in
experimental systems is equivocal. Ziram is lethal to aq.uat species at
fairly low concentrations and it inhibits the growth and me ^olic
processes of bacteria in soil and water.
The combination of factors described above for zira (high
production volume, possible release into the workplace, probable release
into the environment, and toxic effects) constitute a -otential for risk
to human health and the environment. Monitoring data for the workplace
and environment would be useful in more effectively correlating the
exposure potential and toxic effects of the chemical for a complete
assessment of the health and environmental hazards of the compound.
11
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TABLE OF CONTENTS
Chemical Hazard Information. Profile
Ziram
I. SUMMARY OF AVAILABLE DATA 1
A. Chemical Identity 1
B. Physical and Chemical Properties 1
C. Exposure 2
1. Worker Exposure Considerations 2
2. Consumer Exposure 8
3. Environmental Exposure 9
D. Human Health Effects 11
1. Metabolism 11
2. Lethality 12
3. Carcinogenicity 15
4. Mutagenicity 18
5. Teratogenicity/Reproductive Effects 20
6. Other Effects 21
E. Environmental Effects 25
F. Existing Standards 29
G. Other Relevant Information 30
II. Preliminary Risk Assessment 30
A. Exposure Assessment 30
B. Human Health Risk Assessment 36
C. Environmental Risk Assessment 38
III. References 40
A. Literature Cited . 40
B. Secondary Sources Searched 53
1. Books 53
2. Data Bases 57
C. Search Strategy 59
111
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I. Summary of Available Data
A. Chemical Identity
1. CAS Registry Number 137-30-4
2. Chemical Name: Zinc, bis(dimetliylcarbamoditii .oato-S, S'}-, (T-4)-
(9CI)
3. Synonyms' Zinc, bis (dimethyldithiocarbamato)- (SCI); Aaprotect,
Aavolex; Accelerator L, Aceto ZDED, Aceto ZDMD,
Alcobam AM, Antene, Bis (dimethyldithiocarbamato)zinc,
Carbamodithioic acid, dimethyl-, zinc salt, Carbazinc,
Corono corozate, Corozate, Crittam, Cuiaan, Cuinan L,
Cymate, Dimethylcarbamdithioic acid, zinc complex,
Dimethylcarbamodithioic acid, zinc salt,
D}.methyldithiocarbmic acid, zinc at Duprina 90,
Eptac 1, Fuel as in Ultra, Fuel as in, Fungostop, Karbam
White, Methasan, Methazate, Methyl cimate, Methyl
zimate. Methyl ziram; Mezene, Milbam. Mxlban, Molurame,
Mycronil, Orchard brand ziram, Pomarzol Z-forte, Prodaram,
Rodisan, Soxinol PZ, Tricarbamix Z, Triscabol, Vancide,
Vulcacure ZM; Vulkacit L, Vulkacite L, Z 75, Z-C Spray,
Zarlate; Zerlate, Zimate; Zinc dimethyldithiocarbamate,
Ziram, Zirberk, Zirthane,
Note: Sax (1975) lists "ziram" as a synonym for zinc
diethyldithiocarbamate. For this report, it was assumed that
"ziram", when encountered in the literature reviewed, was a
synonym for zinc dime thy Idithiocarbamate, unless otherwise
stated.
Structural Formula.
*3C\ /\/\
1— C Zn C— M
a/ VV
Molecular Formula CgHi2N2S4Zn
B. Physical and Chemical Properties
5. Molecular Weight. 305.82 (Sandiaeyer 1981)
6. Physical State. White odorless powder (Martin and Worthing 1974)
7. Melting Point (°C) 240 (Martin and Worthing 197 *)
8. Boiling Point (°C) Not found
9. Solubilities
(a)
Water - 65 ppm at 25°C (Martin and Worthing 1974),
almost insoluble (Hawley 1977)
Von-aqueous solvents -
Solubility in 1,00 ml solvent at
25"C - < 0.2 g, alcohol, < 0.5 g,
acetone, < 0.5 g, benzene, < 0.2 g,
carbon tetrachloride, < 0.2 g, ether,
0.5 g, naphtha (Windholz et al. 1976)
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(c) Other sol-vents - Soluble in dilute alkali, c
(Martin and Worthing 1974), and concentrated
(Hawley 1977)
^n disulphide
drochloric acid
Dissociation Constant
Partition Coefficient
10.
11.
12.
13.
14. Reactivity
Not found
Not found. [Bioconce .ration Factor - 59
(Kenaga 1980) (Calculated from a water
solubility of 65 pp_i)].
Density (specific gravity). 1.71 (Hawley 1977)
Volatility Vapor pressure negligible at room temperature (Hayes
1982).
The dithiocarbamates, in general, are very reactive
compounds that possess strong metal-binding
characteristics, interact with sulfhydryl compounds,
and undergo many reactions involving oxidation and loss
of sulfur. The degradation of dithaocarbamates is '
mainly influenced by oxygen and humidity (Engst and
Schnaak 1974, as reported in Fishbein 1976). Under
mild conditions, dithiocarbamate salts are oxidized to
yield thiuram disulfides. This reaction can occur on
exposure to air, as can the formation of monosulfides
with the liberation of sulfur. Ziram is stable under
normal conditions (Hayes 1982, Worthing 1979), having
good stability to moisture and dilute acids (Sittig 1980),
but can be oxidized to the tetramethyl compound, TMTD or
thiram (tetramethylthiuram disulfide) (Lowen 1961, as
reported in Fishbein 1976) which is also a fungicide.
Acid hydrolysis of ziram yields dimetylainine and carbon
disulfide as principal degradation products (Engst and
Schnaak 1974, Lowen 1961, Weed 1953, all reported in
Fishbein 1976) . Ziram can form a flammable dust
(Windholz 1976) .
15. Other.
(a) Odorless when pure (Hawley 1977)
(b) W/V Conversion (mg/m-3 approx. equal to 1 ppm) - 12.48
(Sandmeyer 1981)
(c) Soil Sorption Coefficient - 440 (Kenaga 1980) (Calculated from a
water solubility of 65 ppm).
C. Exposure
1. Worker Exposure Considerations
a. Production Volume/Manufacturers
U.S production of ziram (under the name zinc dimethyldithiocarbamate)
for the years 1977-1981 is summarized in Table 1 (USTTC 1978, 1979, 1980,
1981, 1982. all reported in USEPA 1983a)
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Table 1. U.S. Production of Ziram
(Thousands of Pounds)
1977 1978 1979 1980 1981
1.710 2,231 3,765 2,461 l.J'O
The nonconfidential file of the TSCA Chemical Substance Inventory
indicates that 5 companies reported 1977 production of ziram totalling 230-
2,300 thousand pounds. Three other companies reported 1977 production but
did not report production volumes (USEPA 1983b, as reported in DSEPA
1983a).
The following U.S. companies currently produce ziram (SRI Interna-
tional 1983a, as reported in USEPA 1983a)
Company Plant Location
Fike Chemicals, Inc. Nitro, WV
FMC Corporation
Agricultural Chemical Group Middleport, NI
The Goodyear Tire i Rubber Co.
Chemical Division Akron, OH
Uniroyal, Inc.
Uniroyal Chemical Division Naugatuck, CT
R. T. Vanderbilt Company, Inc.
Vanderbilt Chemical Corporation, subs id. Murray, KY
In addition to those listed above, with the exception of FMC Corpora-
tion, the following U.S. Companies were reported to produce ziram in 1977
(USEPA 1983b, as reported in USEPA 1983a)
Com-pa ny Plant Location
Alco Chemical Corporation Chattanooga, TN
Brin-Mont Chemicals, Inc. Greensboro, NC
Pennwalt Corporation Wyandotte, MI
Rockmart Chemical Corporation _ Aramcnee, GA
b. Imports/Importers
Separate data on imports of ziraia are not available (USEPA 1983a) .
o
The nonconfidential file of the TSCA Chemical Substance Inventory
indicates that one company imported ziram in 1977 in the range of 10,000-
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100,000 pounds (USEPA 19S3b, as reported in USEPA 1983a). I adition, two
companies imported ziram in 1977 but did not disclose the a .its, and
three companies reported that they were importers of zirap : did not
import any in 1977. laporters were not identified in USE" (1983a)
c. Technical Product and Process Type
Ziram is available in the U.S. as dusts containing 3.5-76% of the
chemical, as wettable powders containing 30-96% of the chemical, as aqueous
suspensions containing 30-40% of the chemical and as a 0.1% paste (USEPA
1973, as reported in IARC 1976).
In Japan, ziram is available as a technical grade product containing
98% of the chemical and less than 0.5% water, 0.4-0.5% sodium chloride and
1.0-1.1% other impurities (mostly zinc methyldithiocarbamate) (Japanese
Ministry of Agriculture ? Forestry 1975, as reported in IARC 1976).
The two methods for the synthesis of ziram are described below. It
is not known which of the methods is more important commercially.
Ziram may be produced by the precipitation of sodium dimethyldithio-
carbamate with zinc stil fate, zinc chloride, or zinc oxide. The sodium
dimethyldithiocarbamate is made by the reaction of carbon disulfide and
dimethylamme in aqueous sodium hydroxide at 20-30°C (IARC 1976, Sittig
1980, SRI International 1980, SRI International 1983b, all reported in
USEPA 1983a).
A more direct method involves the reaction of dimethylamme, carbon
disulfide, and water-insoluble zinc oxide or zinc hydroxide. The direct
reaction method has been claimed to have the following advantages a
shorter reaction time, more economical use of raw materials, fewer steps,
improved utilization of the heat of reaction, and much larger yield of fin-
ished product per unit of reactor volume (Sittig 1980, as reported in USEPA
1983a). *
In the direct process, zinc oxide or hydroxide is added to a jacketed
mixer and an approximately equivalent quantity of dimethylamme is added as
quickly as possible, After several minutes of very intensive mixing, an
approximately equivalent amount of carbon disulfide is added, followed by
intensive mixing. The reaction temperature is maintained at 0-150°C and
the pressure is generally maintained in the range of subatmospheric to 100
psi. After completion of the reaction, the water of reaction ana any
excess carbon disulfide or dimetaylamine are removed by vacuum distillation
(Sittig 1980, as reported in USEPA 1983a)
d. Industrial and Occupational Uses
No evidence was found for the commercial use of ziram as a chemical
intermediate. The compound i-s used mainly as a ruboer accelerator and as a
fungicide (USEPA 1983a) . It has been used as a rubber accelerator since
1943, ziram's fungicidal activity was first obvserved in 1944 (IARC 1976).
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Of tie total 2,231,000 pounds produced in the U.S. in 1978, - estimated
400,000 pounds (ISTa) were used as a fungicide on agricultur- :rops (SRI
International 1980, as reported in USEPA 1983a)
Ziram is used in the rubber-processing industry as accelerator or
promoter which functions by interacting with sulfur to .. -rease the rate of
vulcanization (IAK.C 1976). Because of its high cure rr.e, ziram is some-
tines called an ultra-accelerator (Taylor and Son 1982, as reported in
USEPA 1983a) . Ziram is a primary accelerator for cures at 120°C and a
secondary accelerator with thiazoles (Heinisch 1974, as reported in USEPA
1983a).
Ziram is used as an accelerator for the following types of rubber
isobutylene-isoprene, isoprene (natural and synthetic), nitrile-butadiene,
and sytrene-butadiene. It is also used as a curing agent for
poly(fluoroalkoxyphosphazenes), these phosphazenes are not believed to be
important commercially, however (SRI International 1983b, as reported in
USEPA 1983a).
Ziram is a protective fungicide which prevents disease—causing fungi
from entering plants, but does not kill established infestations (SRI
International 1980, as reported in USEPA 1983a) at concentrations of 0.2-
0.T"a active ingredient (Gunther and Gunther 1971). Protective fungicides
are generally applied to uninfested crops, and require frequent applica-
tions thereafter. Of the 400,000 pounds of ziram used in the U.S. for
fungicidal purposes in 1978, 300,000 pounds were used on deciduous fruits
(excluding apples and citrus fruits), and 100,000 pounds were used on
vegetables (SRI International 1980, as reported in USEPA 1983a).
Ziram is used extensively on almonds and peaches to control shot hole
(Septoria spp.), brown rot (Alternaria spp.), and peachleaf curl. It is
also used on vegetables, and as a repellent to rabbits (Personal communica-
tion to J. Leitzke from the Registration Division of the Office of Pesti-
cides). In the U.S., ziram is registered for use on 24 fruit and vegetable
crops and on several commercial and household ornamental flowers (USEPA
1973, as reported in USEPA 1983a).
Ziram is approved for use in animal glue and adhesives which are used
in food—contact articles, non—food contact paper coatings, industrial cool-
ing water, latex-coated articles, neoprene, paper and paperboard, textiles,
and plastics (polyethylene and polystyrene) (USEPA 1980, as reported in
USEPA 1983a). In 1976, one source reported that small amounts of ziram
were used for these purposes (IARC 1976).
Ziram is usea as a slimicide in paper Bills, and, in a mixture with
zinc 2-aercaptobenzothiazole, as a preservative in the textile industry and
elsewhere (Trotz and Pitts 1981, as reported in USEPA 1983a) . Ziram is an
effective molluscicide against most aquatic snails at 3-5 ppm in water
(Hadler 1982).
The classification of the commercial and possible uses of ziram in
accordance with the Chemical Use Standard Encoding System (ChemDSES) (Goen
et al. 1980, as reported in USEPA 1983a) is as follows
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321 (Accelerators)/2S.09.03 15-5 (Synthetic elastomers, s.c.)
321 (Accelerators)723.09.03 05-5 (Natural rubber)
321 (Accelerators)/28.09.03.10-0 [Polyisoprene elastc 3 (excludes
natural rubber)]
321 (Accelerators)/28.09.03.01-1 (Acrylonitrile-but- -ene elastomers)
321 (Accelerators)/28.09.03.08-8 [Styrene-butadien~ alastomers (S-type)]
326 (Fungicides)/01.01.07-9 (Fruits)
362 (Fungicides)/01.01,05-7 [Vegetables (except raises, roots, and
tubers)]
362 (Fungicides)701.01.04-6 (Roots and tubers)
362 (Fungicides)701.01.08-0 (Nuts)
166 (Animal repellants)
362 (Fungicides)01.01.12.01-5 (Ornamental nursery products)
362 (Fungicides)728.14.05-7 (Water and waste-water treatment chemicals)
362 (Fungicides)/28.13.02-3 (Organic adhesives)
362 (Fungicides)726.06.03.03-8 (Food packaging products)
362 (Fungicides)730.01.l6-7 (Rubber goods, n.e.c.)
321 (Accelerators)/28.09.03.03-3 [Chloroprene elastomers (neoprene)]
362 (Fungicides)726.02-8 (Paper)
362 (Fungicides)726.03-9 (Paperboard)
362 (Fungicides)722.02-4 (Textile goods, n.e.c.)
362 (Fungicides)730.02-2 (Plastics products)
116 (Slime preventatives)728.10.02.03-3 (Fungicides)
108 (Biocides)/28.10.12-2 (Pesticides and biocides n.e.c.)
e. Processors
The following companies are major U.S. producers of synthetic rubber,
and may process ziram during synthetic rubber manufacture (Dun's Marketing
Services 1982, as reported in USEPA 1983a).
Ashland Oil, Inc. Ashland, KY
CHR Industries New Haven, CT
Copolymer Rubber Chemical Corporation Baton Rouge, LA
Dexter Corporation Windsor Locks, CT
Eastman Kodak Company Rochester, NY
Firestone Tire ? Rubber Akron, OH
General Latex ff Chemical Corporation Cambridge, MA
Goodyear Tire ^ Ruboer Company Akron, OH
Goodyear Rubber Plantations Company Akron,OH
UCT Incorporated Louisville, KY
The following companies are major U.S. paper producers and may pro-
cess ziram danag paper manufacture (Dun's Marketing Services 1982, as
reported in USEPA 1983a).
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American Can Company Greenwich,
Consolidated Cover Company Whittier,
Crown Zellerbach Corporation San Fra- oco, CA
Hudson Pulp and Paper Corporation Danen CT
Lydall Incorporated Manchester, CT
Potlatch Corporation San Francisco, CA
Sonat Incorporated Birmingham, AL
Southwest Forest Industries Phoenix, AZ
St. Francisville Paper Company, Incorporated San Francisco, CA
Times Mirror Company Los Angeles, CA
£. Detection Methods
Methods for the detection of ziram based on polarography (Budnikov et
al. 1974, Zlisenko and Vekshtein 1973, Supin et al. 1973, all reported in
USEPA 1983a) and colorimetry (Rangswamy et al. 1970, as reported in USEPA
1983a) have been described.
Gas chromatography has been used to determine ziram residues in food
samples (McLeod and McCully 1969, as reported in USEPA 1983a). Thin layer
chromatographic methods have been described in which the presence of ziram
was shown by spraying with a sodium azide—iodine reagent (Klisenko and
Vekshtein 1973, as reported in USEPA 1983a) or with cupric chloride
hydroxylamine (Fishbein 1975, as reported in USEPA 1983a) . In another
method, ziram was hydrolyzed and the products reacted to yield strongly
fluorescent derivatives (van Hoof and Heyndrickx 1973, as reported in USEPA
1983a) which were separated by thin-layer chronatography and visualized
under ultra-violet light. This procedure was capable of demonstrating the
presence of 20 ng ziram. According to USEPA (1983a), other methods for the
chromatographic analysis of carbamates, including ziram, have been reviewed
by Fishbein and Zielinski (1967).
g. Monitoring Data/Worker Exposure
U.S. occupational monitoring data for ziram were not found. Russian
stadies, however, have demonstrated that occupational exposure can occur.
Enikeev (1968, as reported in Hayes 1982) pointed out that aerosols of
ziram in the workplace appear to constitute its principal danger. Enikeev
(1967, as reported in Chem Abstr 72.35486o) reported that Russian workers
in several ziram-producing plants were exposed to dust levels of 0.5-130
ing/in1', depending on location. Pilinskaya (1970) measured average dust lev-
els of 1.95 and 3.7 mg/m^ m the store and packing areas of a ziram plant,
with levels reaching 71.3 mg/m^ during some temporary disturbances of the
technological processes. Martson an3 Pilinskaya (1971, as reported in
USEPA 1983a) collected ziram on filters from air in a manufacturing plant.
Concentrations were determined colorimetrically to be 0.8 to 3.7 mg/m*.
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Wolf and Durhan (1966, as reported in Deichman and Ge- . 1969)
estimated tne relative acute tosicity hazard of pesticides spraymen and
ranked z iram as one of the least dangerous.
Based on. the National Occupational Hazard Survey, JOSH (1980, as
reported in USEPA 1983a) projected that 27,889 workers , .ire occnpationally
exposed to ziram. This projection is based upon the fallowing exposures
found during the survey (it should be noted that worL.rs engaged in the
production of ziram, or its use as a pesticide, were not included in this
survey)
SIC Code Name Number of Exposures
2513 Upholstered Household Furniture 2
2822 Synthetic Rubber 15
3069 Fabricated Rubber Products, n.e.c. 259
3357 Nonferrous Wire Drawing and Insulating 12
5099 Wholesalers, n.e.c. 4
2. Consumer Exposure
Documentation of consumer exposure to ziram was not found. However,
the possibility of such exposure must be considered since the compound is
commonly used as a fungicide on fruits and vegetables. Consumer contact may
occur through actual use of ziram as a pesticide or through the ingestion
of ziram-contaminated produce.
Limited data were found for the levels of pesticide residues detected
in fruits. It was demonstrated in one study that immediately after treat-
ment of peach trees with ziram, when the fruits were small and green, resi-
dues of the pesticide on the fruit exceeded 7 ppm, however, when the fruit
had matured, residues were no longer detectable, either on the skin or in
the pulp (Primo Yufera et al. 1967, as reported in Chem Abstr 67 42620r).
In another study, apples were treated with 1% ziram, according to a typical
procedure and the residues of the compound were measured in washed and
unwashed samples (Ryazanova 1967l>, as reported in Chem Abstr 71 2469z) . In
the unwashed apples, the ziram residue did not exceed 1 mg/kg, washing
reduced the residue by approximately 10—fold. Treatment with 1% ziram
resulted in bitter-tasting apples. Tolerances for residues of ziram in or
on raw agriculturel commodities in the U.S. nave been set at 7 ppm for
fruits and vegetables, and 0.1 ppm for almonds and pecans (USEPA 1980a, as
reported in DSEPA 1983a) Details are given in Section F., Standards and
Regulations.
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3. Env.ronmentai
a. Environmental Release
Environmental monitoring data were not found for zi~ other than the
levels detected on fruits treated with the compound for f .^icidal purposes
as described in section I.C.2 (Consumer Exposure). Reside levels ranged
from approximately 1 to > 7 ppm on treated fruits in tt; two studies con-
ducted in Russia and Spain (Ryazanova 19671), as reported in Chem Abstr
71 2469z, Primo Yufera et al. 1967, as reported in Cham Abstr 67 42620r).
The use of ziram as an agricultural fungicide and as a molluscicide
would be expected to result in contamination of the soil and aquatic
environments, respectively. Rain would tend to wash residues of the pesti-
cide from fruits and vegetables into the soil.
b. Environmental Fate
i. Persistence
Because of its use as an agricultural fungicide, the persistence of
ziram on or in plants treated with the compound has been of interest from
an agricultural, as well as from an environmental, viewpoint. Various stu-
dies have been performed to determine persistence of the compound under
different conditions. Ziram residues disappeared in about a month from
lettuce, carrots, and celery, grown and sprayed in a greenhouse and stored
at 4°C (Villa et al. 1976, as reported in Chem Abstr 88 16949u). Washing
of the vegetables immediately after spraying removed 92% of the pesticide.
Field persistence of the pesticide (applied at the concentration of 1820
ppm) on leaves of 12 woody plant species averaged 2.7 days and varied from
1 to 10 weeks, as determined by a cellophane bioassay technique (Neely
1970). These results were dependent upon plant species, but in 10 of the
12 woody plants species persistence was <_ 3 weeks. Generally, ziram is not
considered to be stable under environmental conditions (Nitsche et al.
1974).
Gretillat (1961, as reported in Strufe 1968) determined the per-
sistence of ziram in an aquatic environment by testing its molluscicidal
activity under laboratory conditions and in field trials. In the labora-
tory, the activity of the compound (5 and 10 ppm) decreased considerably
between the 30th and the 45th days, while in the field, a concentration of
10 ppm continued to show marked molluscicidal activity after 35 days, and
was still slightly effective after ^2 days.
The presence of inorganic salts decreases the staoility of ziram in
water (Gonnert and Strufe 1962, as reported in Strufe 1968). No explana-
tion of these results was given.
Biodegradation - Microbial degradation of ziram has been
observed. Raghu 11976, as reported in Chem Abstr 89-37937z) demonstrated
that a Pseudomonas sp., isolated from soil, was capable of degrading ziram
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10
that dimethyl dithiocarbamate— aminobutyric acid was the r ^ or polar
metabolite, Etges et al. (1965) isolated a small, gram neg- , e coccoba—
cillus from molluscicide test chambers which had contained - snail,
Australorbis glabratus,, and observed that ziram could ser- _s sole source
of nitrogen for the bacterium, provided glucose was presc as a source of
carbon and energy. It should be noted that ziram has be a shown to inhibit
growth and metabolic processes in bacteria (Section I.F 4) and may there-
fore inhibit biodegradation under certain circumstanced.
Photodegradation - In the laboratory, using aquaria exposed to
STinlight for several hours each day, Deschiens and Floch (1965, as reported
in Strufe 1968) found that active ingredient remains residually active for
45 days at a starting concentration of 5 ppm.
Hydrolysis - No data were found for ziram. However, The half
life of diethyldithiocarbamate in acid solution ranges from 2 mm at pH 4.0
to 860 mm at pH 6.6 (Hylin and Chin 1968). At pH 5.7, the approximate pH
of moist leaf surfaces, the half life was 107 mm. Hyl in and Chin (1968)
suggest that the dimethyl derivative would probably behave in a similar
manner.
Klisenko and Vekshtem (1973, as reported in Chem Abstr 82:39300r)
listed the following as degradation products of dimethyldithiocarbamate
fungicides, inclusive of ziram, in water tetramethylthiourea, dimethylam-
monium dimethyldithiocarbamate, and sulfur.
Oxidation - The oxidation of ziram to thiram has been
demonstrated in solution, but has not yet been demonstrated in the soil
(Munnecke 1967, as reported in Goring and Hamaker 1972). Thiram, in turn,
appears to be both microbially and nonbiologically degraded in soil
(Munnecke and Mickail 1967, as reported in Goring and Hamaker 1972).
Bioaccumulation - Ziram does not appear to be stored in the
tissues of rats and dogs (Vettorazzi 1979, Hodge 1956, as reported in Hayes
1982).
In a long term study rats were administered 2500 ppm ziram in the
diet for two years. At the end of the study the animals had about 4 ppm of
the compound in the liver. However, the concentration of zinc stored in
the bone increased almost linearly, corresponding to the logarithm of the
concentration of ziram in the diet, the mean zinc concentration ranged from
180 to 300 ppm of zinc in bone ash in animals maintained for 2 years on
diets containing 0 and 2500 ppm of ziram, respectively. Thus, it appears
that ziram itself is nor stored in the tissue, out the zinc metabolized
from it is stored to a slight degree (Hodge et al. 1956, as reported in
Hayes 1982)
Tewari and Singh (1979, as reported in Chem Abstr 91 33611g)
described a technique for the extraction of ziram from autopsy tissues, but
it is not clear if the material was actually found in the tissues or added
experimentally.
The bioconcentration factor for ziram was calculated from its water
-------
11
solubility (65 ppm) by Kenaga (1980) The calculated factor 59 for
ziran is not considered high (the author suggests that chea _s with a
value of over 1000 are those which need further hazard eva" .ion).
11. Transport
Air - No data were found.
Water - Paul mi (1963, as reported in Strufe 1968) investi-
gated the adsorption of ziram by mud in the laboratory, and found that 11-
30% of the active ingredient that was added to overlying water was adsorbed
within the first few minutes, and that 16-33% was adsorbed within 24 hours.
Gonnert and Strufe (1962, as reported in Strufe 1968) performed a similar
study in aqueous solution after addition of different concentrations of
pond mud (0.55%, 1.35%, 2.4%). The amount of ziram adosrbed increased with
the concentration of pond mud and with time (19% was adsorbed by 1 hour
with 0.55% mud; 96% was adsorbed by 3 hours in 2.4% mud).
Soil - The available data for the mobility of ziram through
the soil are conflicting. Munneke (1961, as reported in Singhal and Bansal
1978) and Helling et al. (1974, as reported in Singhal and Bansal 1978)
measured the mobility of ziram in soil columns and soil thin—layer chroma—
tography (TLC) plates, respectively, and found the chemical to be immobile.
Singhal and Bansal (1978), on the other hand, me-asured the mobility of
ziram using soil TLC and observed high mobility. Singhal and Bansal
applied high concentrations of ziram to tneir plates which may account for
the high mobility of their samples, thus suggesting that the concentrations
of chemicals may affect their mobility. It is not clear if the TLC tech-
niques employed by Helling et al. were the same as those used by Singhal
and Bansal, if not, this is another factor which could result in the con-
flicting observations of the two groups. ~~
Singhal and Bansal (1978) also determined that the rate of movement
of ziran through the soil was also a function of pfl and soil particle size,
but not of soil organic content. The mobility of the chemical increased as
the acidity or alkalinity of the soil increased and decreased with a
decrease in soil particle size.
D. Human Health Effects
1. Metabolism
\ thorough study of the metabolism of ziram in rats was conducted by
Veknstein and Klinsenko (1971) The compound was administered in a single
oral dose of 500 mg/kg and the animals were killed 30 minutes, 16 and 24
hours, and 2, 3, and 6 days after administration of the compound. The
organs, blood, and urine were analyzed for the presence of ziram and its
transformation products, tetramethylthiuram disulfide (TJfTD),
tetramethylthiourca, the dimethylamine salt of diiaethyldithiocarbamic acid
(DMA salt of DMDTCA) The levels of the parent compound and its
-------
12
metabolites, as detected by thin layer chromatography at the .nous tine
points, are summarized in Taole 2. The zirain was rapidly d ributed and
was completely or almost completely metabolized by day 3. metabolites,
on the other nand, persisted at significant levels in most rgans for up to
6 days. Additional analysis by a colonmetric method der ^trated that the
organs also contained large amounts of free carbon disui-u.de on the first
and second days of the experiment (56 and 115 ug/g, respectively). Carbon
disulfide accumulated in the lungs (owing to ziram in ^he other organs and
tissues) and was eliminated in expired air. In addition to carbon disul-
fide, the expired air also contained small amounts of dime thylamine.
In other studies, unspecified doses of ^^S-ziram were administered
orally to rats (Izmirova and Marinov 1972, Izmirova 1972, both reported in
Hayes 1982). The animals eliminated a portion (the amount could not be
determined from the literature) of the administered dose in the feces, 57%
of that portion was unchanged ziram, and the remainder consisted of 5
chloroform-soluble metabolites. The majority of the administered dose,
however, was metabolized to 5 water soluble metabolites which were excreted
in the urine The five chloroform—soluble metabolites were also detected in
the gastric contents (among other locations), demonstrating that a part of
the breakdown of ziram occurs before absorption (Hayes 1982) . The differ-
ences in the oral and intraperitoneal LD5Q values for the compound also
suggest this (Table 3).
Ziram and similar dithiocarbamates are probably metabolized princi-
pally by the liver microsomal mixed function oxidase (NTP 1983). Neal et
al. (1977, as reported in NTP 1983) have suggested that the known impair-
ment of microsomal drug metabolism by sulfur—containing compounds, and
especially carbon disulfide, is due to the binding of an active form of
sulfur to the microsomal and cytochrome P450 systems.
2. Lethality
Lethality data (Table 3) indicate that ziram is of moderate to high
acute oral toxicity, according to the scale of Gosselin et al . (1977) The
higher toxicity of the compound via intraperitoneal injection compared to
oral administration suggests that absorption of oral doses is relatively
slc'y and/or incomplete (Hayes 1982). In another study, 8 of 10 rats died
after being fed 6000 ppm ziram for 14 days, while only 1 of 20 died after
being fed 5000 ppm for 13 weeks (NTP 1983). Mice survived feeding of 5000
ppm for 14 days, but 10 of 10 fed 10,000 ppm died on days 5, 6, or 7 of
treatment (NT? 1983) Sixteen of 20 mice diea during weeks 3,4,5 and 3
of 13 ffeess treatment with 5000 ppm (NTP 1983)
Subchronic exposure of 8 raboits to dust containing 14 71 ^ 1.65
ziram 4 h/ day for 1 month resulted in 4 deaths (Enikeev 1967, as
reported in Chem Abstr 72 35486o) . When the concentration was reduced to 5
mg/m3 only 2 of 10 rabbits died following 4 months exposure, 4 h/day.
Ingestion of 0 5 liter of ziram was fatal to a man within a few hours.
Clinical findings included focal necrosis of the mucosa of the small
intestine, congestion ana microscopic edema of many organs, diapedetic
-------
Table 2 Distribution of 71rara. TMTD and DMA Salt of DMDTCA* In the Organs
of Albino Rats foil on Ing a Single Administration of 500 fig/kg 71mm
Time elapsed
after adminis-
tration of
tho prcfnration
10 ii i i tcs
16 houv
21 hours
2 dnys
3 days
6 days
30 minutes
16 hours
24 hours
2 d n y s
3 dnys
6 days
30 minutes
16 hours
24 hju-s -
2 dnyci
3 days
6 dnys
Intestine
9 6
35 6
48 3
2 6
2 86
0 77
0 6
3 57
7 9
7 96
5 57
4 93
4 77
3 45
+ 0 45
+ 0 67
i 1 04
± 0 27
1 0 27
±014
i 0 06
i 0 32
i 0 23
+ 0 27
+ 0 37
i 0 22
0
± 0 55
±013
0
0
0
Blood
10 » 0 96
24+0 24
3 44 + 0 41
2 8 ± 0 21
~ 0
0
0
0
0 43 ± 0 04
0 67 ± 0 02
0 5 ± 0 03
0 3 ± 0
0
4 0 ± 0 24
1 7 i 0 12
1 67 ± 0 09
1 67 ± 0 08
1 0 + 0 05
Liver
Zlram
26 2 + 072
5 35 ± 0 5«
35+03
6 8/ + 0 36
2 25 ± 0 16
1 25 ± 0 09
TKTO
0
0
5 13 ± 0 21
10 1 ± 0 35
3 84 + 0 23
3 5 ± 0 36
DMA salt of
0
1 87 ± 0 09
0
2 94 + 0 29
1 63 ±0 09
09 + 0
Spleen
. !'«/«.
6 8 ±
7 3 ±
5 8 i
. I'g/g.
60 +
10 9 +
98 +
8 86 ±
DMDTCA
0 85 +
13 +
38 9 T
8 +
5 71 7
Tetramcthylthlouren
30 minutes
16 hour*
24 hours
2 doy^
3 days
6 days
1 73
3 7
0
0
±04
± 0 55
0
0
No data
No date
No data
No data
No data
No data
0
0 8 ± 0 08
0 93 7 0 06
1 0? + 0 17
1 79 + 0 15
1 41 + 0 37
0 57 +
28 +
45 +
2 0 ^
8 57 ±
|ig/nU>
0
0
0 38
0 97
0 46
0
|ig/mL
0
0
0 39
0 97
0 44
0 25
I'g/g.l
0
0 04
0 12
1 5
0 29
0 23
Adrenals
0
0
2 38 + 0 19
35 5 + I 08
0
0
•
0
0
0
0
17 8 + 1 19
11 2 ± 0 86
ig/mlb
0
5 0 + 0 43
57+016
20 + 2 82
6 25 + 0 53
5 71 + 1 27
Kidneys
1 18 + 0 08
3 0 + 0 36
No data
0
0
03 +0
0
0
No data
6 67 + 0 74
7 15 + 0 37
2 4 ± 0 09
0
5 + 075
No dnta
0
0
1 6 ± 0 26
lungs
0
0
0
0
0
0
0
0
0
0
0
0
0
5 45 J. 1 07
47 5 ± I 41
60 8 ± 1 97
67 4 ± 7 15
™ + 2 75
Urine
No
No
No
No
No
No
22 6
34 0
1 02
Mo
5 7
3 8
0 47
data
data
data
0
0
0
data
data
data
+ 1 02
± 0 90
± 0 09
0
0
dn t a
+ 1 47
+ 07
± 0 02
content, |ig/g
0
0 0«
0 4
0 51
0 26
0 76
No dnta
No data
No data
No data
No data
No data
No data
No dirt a
No dtta
No d« t a
No d; t»
No dnta
No dita
No data
No dnta
No d n t a
Mo dn t n
No dnta
No
No
No
Ho
Ho
No
datr
dull
dati
dati
da In
da t K
TMTP " tetramethylthlnram dlsnlflde, DMA talt of DMU1CA = dimethylamlnc salt of dlmethyIdlthlocarbnmlc acid
bUn!t designations have been changed from those stated In the tianslated article (|ig/g. m,/'"g for rlrnm pg/I, |ig/ml
for DMA salt of DMDTCA) In tho belief that the translation was in error The translated unit designations for T'flD and
tetramcthyllhloorea appear to ba consistent with the dnta presented
Source Vekshtein and Khltsento 1971
-------
1-1
hemorrhages ,
alveolar and
Species
Rat
Rat
Rat, male
Rat, female
Rat
Rat
Mouse
Mouse
Mouse
Mouse, male
Mous e
Mouse
Rabbit
Raboit
Rabbit
focal atelectases, acute emphysema, and desquanr -a of
oroncaial epithelium (Bulkan 1974, as reported 3ayes 1982).
Table 3. Lethality of Ziram
Route
Oral
Oral
I. P. a
I. P.
Inj ection
Inhal.b
Oral
I.V.c
I. P.
I. P.
Inj ection
Inhal.b/2 kr
Oral
I. P.
Inj ection
LDfO (mg/kg)
500
1400
23
33
1340
1230
480
18
17
73
220
1056d
400
5-50
270
R.^ Terence
FAO/Y7HO (1965, as
reported in Fishbein
1976).
Hodge et al. (1952, as
reported in Fishbein
1976) .
Hodge et al . (1952. as
reported in Hayes 1982) ,
Hodge et al. (1952, as
reported in Hayes 1982) .
Ryazanova (1967b, as
reported in Chem Abstr
71 2469z) .
Lewis and Tatkin (1980).
Lewis and Tatkin (1980) .
Lewis and Tatkin (1980).
Kligman and Rosenweig
(1948, as reported in
Hayes 1982) .
Hodge et al . (1952, as
reported in Hayes 1982) .
Ryazanova 1967b, as
reported in Chem Abstr
71 2469z) .
Enikeev (1967, as reported
in Chem Abstr 72 35486b).
Brieger and Hodes (1949,
as reported in Hayes
1982)
Hodge et al. (1952, as
reported in Hayes 1982)
Ryazanova (1967b, as
reportea in Chem Abstr
71 2469z) .
a Intraperitoneal
b T—I. -1 * *. -._
A *Hi t* A <* «. Jk w A*
c Intravenous
-------
15
3. Carcinogenicity
a. Type of Test Carcinogenicity
Species F344/N rats, 5 weeks old, 50 males an 0 females/group
Dose/Route 0, 300, or 600 ppm 2iram in food -jr 103 weeks.
The average daily consumption of ziram by low- and
nigh—dose rats throughout the c_jor part of the study
was about 11 and 22 mg/kg for males and 13 and 26
mg/kg for females.
Results The rats were observed twice daily for signs for morbidity
or mortality, clinical signs, body weights, and feed
consumption were recorded monthly. The animals were
killed on days 729-745, and all were necropsied and
examined histopathologically. Survival, feed comsump—
tion, and mean body weights of rats of each sex were not
adversely affected by the treatment. The rats could have
possibly tolerated higher doses.
The only statistically significant tumor incidence in this
study was the increased incidence of C-cell carcinomas in
the thyroid of the high dose male rats. Fourteen percent
(7/49) of the animals of this group had the carcinomas,
compared to 4% (2/49) in the low dose group and 0% in the
control group (P < 0.05). There was also a significant
cose—related trend for male rats with with C-cell carcinomas
(P < 0.01) and for males having either C-cell carcinomas
or C-cell adenomas (P < 0.05). Neither C-cell adenomas nor
C-cell carcinomas were were significantly increased in female
rats. The high-dose females exhibited a significant decrease
in fibroadenomas of the mammary glands (P < 0.05). Also
observed in the thyroid of both males and females, but
either not dose—related or not statistically significant,
were C-cell hyperplasia, thyroglossal duct cysts, and
follicular-cell adenomas or carcinomas. The investigators
concluded that under the conditions of this study, ziram
was carcinogenic for male F344/N rats (OTP 1983a).
b. Type of Test Carcinogenicity
Ssecies Random-bred rats, 60
Dose/Routg 70 ag ziram/kg in >vater twice weekly by stomach tube
for 22 months (ziram, 90.5°o pure).
Controls Untreated, <*6 rats
Results Ten of 60 rats survived for 22 months and 4 developed
tumors (2 malignant hepatomas and 2 fibrosarcoiaas)
(p < 0.01), one of the 46 surviving controls developed a
fibrosarcoina (Andrianova and Alekseev 1970, as reported
in IARC 1976) .
-------
16
c Type of Test Carcinogenicity
Species Rats, 48 random bred
Dose/Route 15 mg z irani (90.5% pure) administer _n a
subcutaneously implanted 250 mg pa_ fin pellet.
Controls Not implanted with paraffin pellets
Results Ten rats survived 22 months and 3 developed tumors
(1 hepatoma, 1 fibrosarcoma, and 1 lymphosarcoma of
the intestine) (p < 0.02). No tumors were observed
at the site of implantation. One of 46 controls that
were still alive at 22 months developed a fibrosarooma
(Andnanova and Alekseev 1970, as reported in IARC 1976).
d. Type of Test Carcinogenicity
Species Rochester rats, 25 males, and 25 females
Dose/Route 0, 25, 250, or 2500 mg ziram/kg of
diet for 2 years (purity of ziram not specified).
Results Eleven tumors were found in the treated rats which
included 3 malignant tumors of the pituitary and
2 thyroid adenomas in the high dose group. One
animal in. the low dose group had a hyperplastic
thyroid. Seven tumors developed in the control rats,
bnt their locations were not specified (Hodge et al.
al. 1956). The tumor incidence was not dose-related
and morphologically similar tumors had been found in
the two-year old animals, therefore, the investigators
concluded that ziram is not carcinogenic.
e. Type of Test• Carcinogenicity
Species B6C3F1 mice, 6 weeks old, 50 males and 50 females/group
Dose/Route. 0, 600, or 1200 ppm ziram in feed for 103 weeks.
After the first half-year of the study the average
daily consumption of ziram was 196 mg/kg for male and
248 mg/kg for female mice of the high dose groups.
The corresponding averages for males and females
of the low dose groups were 122 and 131 mg/kg,
respectively.
Results The animals were observed twice daily for signs of
moroidity or mortality and clinical signs, body weights,
and feed consumption *ere recorded monthly. The mice
were killed on days 729-742. All animals were necropsied
and examined histopathologically Although survival of
the mice was not affected by ziram treatment, the mean
body weight gain was depressed by approximately 15—20%
in treated males throughout the study, and in high-dosed
females, after week 80. In contrast to the rats in this
study (Section l.C.S.a), the mice probably could not have
tolerated higher doses. The incidence of alveolar/
-------
17
bronchiolar adenonas was significantly (P 0 05)
increased in high dose female mice (cont ,, 2/50, 4°?>,
low-dose, 5/49, 10%, high-dose, 10/50, " ) #-ith an
equally significant dose-response trer The combined
incidence of alveolarbronchiolar ader~ > or carcinomas
in female mice of the high—dose gron^ ,as significantly
higher than that of the controls (P 0.05) (control,
4/50, 8%. low-dose, 6/49, 12%. hig -dose, 11/50, 22%),
and showed a significant positive trend (P < 0.05).
The increased incidence of lung tumors in male mice was not
statistically significant. Pulmonary adenomatous hyper-
plasia was observed in both control and treated male and
female mice. This hyperplasia, however, was consistent
with that caused by chronic Sendai infection which had been
diagnosed in untreated animals from the same animal shipment
and present in the same room as the experimental animals.
Six of the high-dose females with adenomatous hyperplasia
had pulmonary tumors, whereas 4 of the 24 high-dose females
without pulmonary adenomatous hyperplasia also had pulmonary
tumors. Also observed in females, but not in males, at
increased incidences were malignant lymphomas (not statis-
tically significant at P = 0.5), malignant lymphocytic
lymphomas (P < 0.05 increasing trend), and lymphoid
hyperplasia (controls, 0/50, high-dose, 7/50, 14%). The
investigators concluded that ziram was not carcinogenic in
male mice, and that the interpretation of the increase in
lung tumors in female mice is complicated by the intercurrent
Sendai virus infection (NTP 1983).
f. Type of Test Carcinogenicity
Species. (C57BL/6xC3H/Anf)Fi and (C57BL/6xAKR)Fl mice, 18 males
and 18 females per strain
Dose/Route 4.6 mg/kg, commercial ziram in gelatin, was
administered by gavage when animals were 7 days
of age, and the same dose, not adjusted for
increasing body weight, was administered daily for
up to 4 weeks of age. During the time that the
animals were between 4 and approximately 78 weeks
old the compound was administered orally at the
rate of 15 mg/kg of diet.
Controls Untreated or received gelatin only, 79-90 mice of each
sex and strain
Results tfhen compared to controls, tumor incidences *ere not
significantly greater (p > 0.05) for any tumor type in
any sex—strain subgroup or in the combined sexes of
either strain (Innes et al. 1969, tfTIS 1969, as
reported in IARC 1976) .
g. Type of Test Carcinogenicity
Species Strain A, 82 mice, and C57BL, 54 mice
-------
IS
Dose/Route 75 ng z iran/hg by stomach tube for 20 .^s
(purity of ziram unspecified).
Results The animals were killed 6 months after 3 beginning
of the experiment. 42/82 (51%) (stra 0 and 5/54
(7%) (C57B1) of the treated animals d eloped lung
adenomas compared to 23/54 (43%) anr j/28 of the
controls (p > 0.05) (Chernov and EL .tsenko 1969,
as reported in IARC 1976).
h. Type of Test Carcinogenicity
Species (C57BL/6xC3H/Anf)F! and (C57BL/6xAKR)Fl mice,
18 males and 18 females per strain
Dose/Route 46 4 mg commercial ziram/kg administered in a
single subcutaneous injection in gelatin on
the 28th day of life.
Controls 141, 154, 161, and 157 untreated or vehicle-
inj ected mice.
Results Animals were observed until they were approximately
78 weeks old. When compared to controls, tumor
incidences were not significantly greater (p > 0.05)
for any tumor type in any sex-strain subgroup or in
the combined sexes of either strain (NTIS 1969, as
reported in IARC 1976) . The IAJRC Working Group noted
that a negative result obtained after a single s.c.
injection may not be an adequate basis for discounting
carcinogenicity.
Hemminki et al. (1980) tested ziram for alkylating ability and found
10 activity. Both a synthetic (4-(p—nitrobenzyl)—pyridine) and a
Biological (deoxyguanosine) nucleophile were used in the alkylation
reactions, but there is no evidence that an. activation system was used.
4. Mntagenicity
z. Micrcbiai and Animal Studies
The results of mutagenicity studies on ziram are conflicting. For
example Hedenstedt et al. (1979) demonstrated the mutagenicity of ziram in
Salmonella typnimurium strains TA 1535, TA 98, and TA 100 with and without
metabolic activation, ffhile DeLorenzo et al. (1978) reported the compound
to be negative in the same strains (Table 4). The reason for tnese
differences in not clear. Both groups of investigators reported negative
mutagenicity for strains TA 1537 and TA 1538. Monya et al. (1978) also
reported, in an abstract, that ziram was mutagenic in TA 100, but not in TA
1537, TA 1538, and TA 98. Kada (1980) reported that ziram is mutagenic in
TA 1535 and TA 100, but not in TA 1537 and TA 98. There are also
conflicting reports for the mntaggiiic activity of ziram in Drosophila
(Table 4).
-------
Table 4 Mntasenlc1ty Testlag of Zlrsm
Species/
Call Systea
Salaonella tvphianrioa
TA 1535
TA 1535
TA 1537
TA 1538
TA 98
TA 98
TA 100
TA 100
TA153J TA1537
TA1538 TA98,
TA100
TA 100
TA1537 TA1535
TW8
rUOO TA1535
TA98 TA1537
TA 98
TA 98
TA 100
TA 1535
TA 1535
TA 1537
Eseherichia coll
IK hcr-
CAL as
Liquid holding
test
Strop, resist
5-JTT resist
Bacillus snbttlis
aec- assay
H17 Sao*
B45 8ec-
strain D4
Verticilllaa dial se
Honse bone
Barley seeds
Drosophila aeianocastar
Orosoohlla 2ela&ozaster
Drojooh-.il aelanoiaster
Rat tayoocytes
Zlrm
S-9 Concentration
10, 50 100 jig/plate
+ 10 50, 100 |ig/pl»te
10. 50. 100 ,ig/pl»te
10 50 100 i»g/plate
10 100 (ig/plate
+ 10, 100 fig/plate
5, 10 50 |ig/plata
+ 5. 10, 50 |ig/plata
- and * 10-1500 ilg/plate
Not itatad Not stated
Not stated Not stated
Not itatad Vot stated
Not itatad Not stated
+ 100 pg/plateb
0 3 10 100
333 tig/plate
+ ami - 33 ng/plata»
* 33 and 100 |ig/plateb
0. 3, 10. 33 100
333 |ig/plata
+ and - 0. 3 10 33
100, 333 jig/plateb
Not itatad Not stated
Vot stated Vot stated
Not stated Vot stated
Not stated Not stated
riot stated Not stated
* 06 (ig/disc
OS us/disc
500/1000 jpm (optimal or
Vot clear
ot .pp ica s ag g o 7 »j
Vot tpplieabla Vot stated
Vot applicable Vot stated
Vot applicable Vot stated
Vot applicable 0 OOJ"V
Vot applicable 1 0 and 10 pg/oL
Results
Fos (p < 0 05 s t 10 11$
p < 0 001 at 100 |ig)
Poi (p < 0 001 at 10 tig)
Nag (p > 0 05)
Veg (p > 0 05)
Pos (p < 0 05 at 100 |ig)
Pos (p < 0 001 at 10 |ig)
Pos (p < 0 001 at 5 |ig)
Pos (p < 0 001 at 5 |ig)
Nag
Poa
Nag.
Poa
Nag
Pos And Equivocal
Na,
Pos
Pos
Nag
Nag
Nag
Veg
Nag
Nag
Poi
Pos
Pos
Nag
?os
" 3t
Pos (3 5% chromosomal
aberratioua)
Poa for recessive
lethal I
lethals ^
Nag for recasaiva
lathals
62% and 99\ inhibition
respectively of Critiatad
•hynidlne uptake
Reference
Hedenstedt at al 1979
Hadenstadt at al 1979
Hedenstedt at al 1979
Hedenstedt at al. 1979
Hadanitedt «t al 19T9
Hedenstedt ot al 1979
Hedenstedt at al. 1979
Hedenstedt et al 1979
DeLorenia at al. 1978
Koriji at al 1978
Honya at al 1978
Eada at «1 1980
STada at tl 1980
NT? 1983b
HI? 1983b
NTP 1983b
NTP 1983b
tfTP 1983b
NTP 1983b
Iida at al 1930
Faarig 1974
-------
20
Kada (-1930) and Fahrig (1974) reported that ziram is nc -utagenic in
E._ coli. and Fahrig (1974) and Sieoert et al. (1970) reporte negative
results in a caitotic gene conversion test in S cerevislae
b. Human Studies
Abnormal chromosomes or chromatids were reported in 5.9% of cultured
lymphocytes of 9 workers (4 males working in a ziram store and 5 females
employed as packers of the preparation) with 3 to 5 years of occupational
exposure, compared to 0.75% abnormalities in similar cells from controls
(Pilinskaya 1970). The levels of ziram in the store and packing areas of
the workplace averaged 1.95 and 3.7 mg/m^, respectively, but reached 71.3
mg/m^ in isolated cases. Statistically significant abnormalities, were
observed in an in vitro study with cultured human lymphocytes at concentra-
tions of 0.06, 0.015, and 0.003 ppm, but not at 0.0006 ppm. These changes
were significant at the p < 0.001 level and were dose-related (Pilinskaya
1971). It was noted that at 0.003 ppm the changes were quantitatively
similar to the results found in vivo in the workers whose condition was
described by Pilinskaya (1970). Pilinskaya, in his 1971 study, stated that
the types of aberrations induced in vivo and in vitro were also similar.
Ziraia exhibited a tendency for selective damage to chromosome 2.
5. Teratogenicity/Reproductive Effects
a. Type of Test Teratogenicity/Reproductive Effects
Species Rats, male and female
Dose/Route 50 or 10 mg ziram/kg body weight per day,
orally for 2, 4, or 6 months.
Results A series of experiments was performed on the
treated rats
(1) No effect was noted on reproduction during
the first two months of treatment.
Administration for longer periods resulted
in changes in both the mothers and the
offspring. Six months after the beginning of
treatment five of the test females died, while
the two survivors became pregnant later than
the controls.
(2) The animals were mated at the end of the sixth
month of ziram treatment. \11 females treated
with 50 mg/kg were infertile, wnils treatment
with 10 mg/kg "postponed" the date of pregnancy
in some of the test females. Treated offspring
of treated parents exhibited reproductive changes
earlier than the parents.
(3) The offspring of rats treated for 2-4 months with
50 mg ziram had developmental anomalies.
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21
(4) Untreated offspring of treated parer ,vere mated
and produced 5 litters One of the offspring
had developmental anomalies and 1 _er had
decreased weight gain (Ryazanova " 57a).
The following effects of ziram were breifly described in abstracts or
reviews embryotoxic to rats at a dose of 0.03 LJ>50 (Chepinoga et al.
1970, as reported in Chem Abstr 74 123308s), embryotoxic to 97.8, 22.6, and
4.4% of the rats tested with 250, 42, and 14 ng/kg of ziram, respectively
(Antonovich et al. 1972, cursory translation), and teratogenic and gonado—
toxic to rats, mice, and rabbits at unspecified doses (Antonovich et al.
1972, as reported in Chem Abstr 73 24925s), caused testicular atrophy in
some rats fed ziram for 2 years in concentrations of 25-250 nig and 2500
mg/kg of food (Hodge et al. 1956. as reported in Stenberg and Rybakova
1967), reduced sperm motility in rabbits exposed to 5.0 mg/m^ ziram dust 4
hours per day for 4 months (Enikeev 1967, as reported in Chss: A.bstr
72 35486b), and substantially reduced the fertility and fecundity of female
mice when administered in doses of 50 mg/kg/day for 15 days according to
Ghezzo et al. (1972, as reported in IARC 1976) or for 50 days according to
Ghezzo et al. (1972, as reported in NAS 1977). No effect on the fertility
of male mice was observed. Ziram has also caused the following teratogenic
and reproductive effects in chickens: stopped egg production within 2 days
when administered in the diet at 200 ppm and caused marked ovarian atrophy
after 7 days (Weppleman et al. 1980), exhibited an LDso of 0.031 mg/kg in
chick erabryos, and caused multiple hemorrhages in the head and trunk, non-
development of the rostrum, legs, clawsr eyes, and less frequently of the
midbrain, disorders of the vascular walls, connective tissue proliferation
and changes in cartilaginous and osseous substances [Olefir and Vinogradova
1968, as reported in Medlars (TOXBACK 65) 1983]; and retarded testicular
development in chicks of domestic fowl (Thornbex's 909 cockrels) and pro-
duced degeneration in the testes of adults administered 56 mg/kg or 4 to 18
weeks (Rasul and Howell 1974) It should also be noted that the Office of
Pesticide Programs file contains a report for a negative teratogenicity
study, claimed as confidential business information by the submitting com-
pany.
6. Other Effects
a. Animals
Examples of non—oncogenic caronic, subchronic, and suoacute effects
of ziram are listed in Tables 5 and 6. Various other effects have been
described and include the inhibition of mitochondrial dehydrogenases in
yeast (Briquet et al. 1975), decreased hepatocyte cytoplasmic RNA and
decreased activity of liver oxidation-reduction enzymes in mice receiving
maximum tolerated doses (Chernov et al. 1972, as reported in Chem Abstr
79 62413b), degenerative changes in the salivary glands, kidney, and liver
of rats [Mannari et al. 1974, as reported in DIALOG (EXCERPTA MEDICA)
1983], moderate contact hypersensitivity in guinea pigs (Matsushita et al.
1978, as reported in Chem Abstr 90 34683y), moderate eye irritation in the
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Table 5 Effects of Ziiora Following Subohronio or Subacnte Exposure
Species
Roate
Treatment
Results
Reference
Rat
Rat
Rat
Orel 0, 300, 600. 1200. 2500, or
5000 ppm in diet for 13 irks
Oral Doso (not stated) administered
for 7 «k«
Oral 413 mg/kg/day for 3 days
Dody wt gain depressed more
than 16% in males receiving
1200-5000 ppm, and In females
receiving 600-5000 ppm
Ziram had toxic effect on
liver and kidneys, decreased
body wt, stimulated activity
of p-glucoronidase and aryl-
sulfatase No changes in thy-
roid
Decreased excretion of urinary
5-hydroxyindoleacetio acid
NTP 1983
1969. as
reported in Chem Abstr
71 69657c
Khaiklna ct at 1976, as
reported in Chem Abstr
85 73l18r
Hi co
Rabbit
Guinea Pig
Oral 0, 300. 600, 1200. 2500 or
5000 ppm In diet for 13 «rks
Inhalation (a) 14 7 mg/m1 dust 4 hr/day
,for 1 mo or (b) 5 mg/rn' dust 4
hr/dny for 4 mos •
Oral
4 mg/kg/day for 120 days
Dody wt gain depressed 26% or
more in males and females
receiving 2500 or 5000 ppm
50 and 20% died from exposures
(n) end (b), respectively
Survivors had increased reflex
tines and wt loss.
Increased free hlstamine in
blood. Inhibited histonminose
activity and decreased
hlstamlne-blndlng capacity of
NIT 1983
Enikccv J9fi7 as teported
in Chem Ahitr 7? 35486b
Khalklna et nl 1976, as
reported in Chem Abstr
85 73138r
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Table 6 Effects of Ziram following Chronic Exposure
Species Route
Treatment
Results
Reference
Rat
Rat
Oral
Oral
Rat
House
Oral
Oral
Rabbit
Oral
2500 and 250 ppm/day la diet
(-125 and 12 5 mg/kg/day) for
0, 300, or £00 ppm la feed for
2 yrs
2 5 rag/kg/day for 9 mos
2500 ppm produced growth retardation and
abnormal reflex Doth doses produced
non-dose-rel»tod atrophy of testes and
hypertrophy of the thyroid
Doth doses produced. In males, two-fold
Increase in incidences of thyroid C-cell
hypcrplasift anil testicnlar hypcrplasla
over those of controls. In females, both
doses produced Increased Incidences of
retlnopathy of the eye, Retlnopathy was
also seen in high dose males None of
the effects were dose-related
Transient immnnologlcal
noted
0, 600 or 1200 ppm
{wo years
in feed for,
15 or 30 mg/kg/dey in diet for
8 no s
"changes" were
In males, low dose produced increased
Incidence of corpora amylacca of the
brain (no data for high dose), in
females high dose produced Increased
incidence of cystic follicles of the
thyroid, both doses produced non-dose-
rclnted increased incidences of cystic
hyperplasla of the endonetrlal gland
Doth doses produced decreased alkaline
phosphatase
Hodge et al 1956, as reported
In Hayes 1982
NIP 19R3
Shtenbcrg et at 1972, as
reported in Hayes 19B2
NIP 19R3
GhcJTO et nl 1972, as
reported In Chen Abstr
78 93310f
Dog Oral(T) 0 5, 5 0. and 25 mg/kg/day for
1 year
25 ng/fcg produced convulsive seizures
and death
Hodge et al 1952, as reported
in Flshheln 1976
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24
rabbit (Klignan and Rosenweig, as reported in Hayes 1982), le openia in
rabbits (Korablev 1965, as reported in Pilinskaya 1971), ery~_rocytopenia
and decreased hemoglobin in rabbits and/or guinea pigs [TaL .ishvili and
Nadirashvili 1980, as reported in MEDLARS (TOSLINE) 1983], i increased
blood sugar, decreased tissue glycogen content, and loss r - mobility of
hind limbs in rats given 10 mg/kg i.p. [Daily et al. 1TJ9, as reported in
MEDLARS (Toxback 65) 1983], In addition, ziram, like mc^t dithiocarba-
mates, induces the accumulation of acetaldehyde in the olood of rats
receiving ethanol at the same time (van Logten 1972, is reported in IARC
1976) . This is not surprising, considering the structural similarity of
ziram to disulfuram (Antabuse) which is known to suppress the second step
of ethanol oxidation through blockage of aldehyde dehydrogenase (DeBruin
1976) and is used as an adjunct in combating alcohol addiction. The pos-
session of a substituted N-atom appears to be a structural requirement for
the alcohol intolerance phenomenon elicited by these compounds.
The mildew inhibitor Vancide 512 (90% ziram and 7.8% zinc salt of 2-
mercaptobenzothiazole) was tested by the U.S. Army (1969) in skin and eye
irritation tests. The commercial grade compound did not cause primary
irritation of intact or abraded skin when applied for 24 hours as either
the commercial powder or the commercial grade in acetone. When applied to
the eye, Vancide 512 powder caused severe injury to the cornea and to the
conjunctiva, a l°b suspension of commercial grade Vancide 512 in propylene
glycol caused slight to moderate eye damage.
b. Humans •
The majority of the human toxicity. and epidemiological data are from
Russian reports.
Collective-farm female workers who used a 707o formulation of ziram to
treat seed, suffered various difficulties, which included irritation of the
skin, nose, throat, and eyes, gastritis, reduced hemoglobin, vegetodys-
tonia, and slight hematological changes. Several of the women had to be
hospitalized 2-4 days following about 5 hours of exposure to the compound.
Some workers lost up to 4 days of work, but all recovered completely
[Chernov 1968, as reported in Hayes 1982, and in MEDLARS (TOXBACK 65)
1983]. Less severe irritation was induced in factory workers where levels
of ziram in the air ranged from 0 77 to 3.7 mg/m^ (Martson* and Pilinskaya
1971, as reported in Hayes 1982). Exposed workers in another study com-
plained of dermatitis, rhinitis, and conjunctivitis of an allergic nature
(Pilinskaya 1970). Of 40 Italian workers, 22 complained of ear, nose,
throat, and epigastric pains. They also had bloody sputum, nyperemia of
the mucosa, ulcerations of the nasal septum, pnlegm in the pharyngeal pas-
sage, and some had difficulty in breathing. The symptoms were attributed oy
the investigators to the irritative action of ziram powder, and not to an
allergic reaction [Anneli Ducci 1966, as reported in MEDLARS (TOXBACK 65)
1983], Another group of workers having prolonged occupational contact with
ziram had shifts in blood cholinesterase and pseudocholinesterase activi-
ties. A tendency toward accumulation of acetylcholiae in the blood, along
with changes in the bioelectric activity of the muscles during voluntary
motion, indicate that ziram may be a cholmesterase inhibitor in man and
-------
25
that tnese procedures appear to be sensitive enough to permi" -airly detec-
tion of toxic effects of zirain [Komarova and Zotkina 1971, ~ reported in
MEDLARS (TOSBACS 65) 1983] .
Aplastic anemia and pseudotumor cerebri (benign in4" ^cranial hyper-
tension) were diagnosed in a 14-year-old girl who had b~ a repeatedly
exposed to a number of herbicides and pesticides (inclining ziram) through
working in the fields of a tobacco company for several months and through
living next to a potato farm that was frequently sprayed (Jenkyn et al.
1979). Zirao was only one of the agents to which the patient was exposed,
but the diagnosis is of particular interest since the compound causes
suppression of the hematopoetic organs in animals (see Section I.D.d.a.,
Other Effects).
Seiaiconservative DNA systhesis in human lyrapnocytes was inhibited by
56% following in vitro treatment with 1 ug/ml ziram (Rocchi et al. 1980).
UV-induced unscheduled DNA synthesis was also inhibited, but only by 21°b.
Most workers in a ziram production plant had enlarged livers, and
18/29 workers had elevated alkaline phosphatase, lactic dehydrogenase,
guanase, fructose 1-phosphate aldolase, and amylase activities (Levin et
al. 1973, as reported in Cheia Abstr 83 151604q) .
E. Environmental Effects
1. Environmental Metabolism
The metabolism of ziram has been studied in papaya plants, rice
plants, and groundnut plants. Known amounts of radioactive ziram were
applied to the leaves of the papaya plant, and volatile products formed
from residues of the compound on the plant were measured over a period of
14 days (Hylin and Chin 1968). Significant amounts of radioactively
labelled carbon disulfide and carbon dioxide were measured, as were trace
amounts of trimethylamine. Although ziram (or at least its DDC ions) is
known to be absorbed by intact leaves, it was not determined in this study
if the decomposition occurred on the surface of the leaves or in the outer
cell layers of the leaf.
Kumarasamy and Raghu (1976) sprayed ziram on 25 day old rice plants
at concentrations simulating normal agricultural applications The rice
seeds were washed and cut into pieces which were extracted at different
times after application. Twenty four nours after spraying, the radioac-
tivity in the seeas was 3.3?o of the administered dose. \t eignt days, the
uptake was 8.2% of the dose. The conversion products of ziram in the seeds
at 24 hours and 8 days (with respective percentages in parentheses)
included the alanine (16.4, 9.3) and B-giucoside (16.9, 18.4) derivatives
of dimethyldithiocarfaamic acid, thiazolidine-2-thione-4-carboxylic acid
(3.8, 6.2), and an unidentified divalent sulfur compound (9.0, 11.1)
Unconverted ziras (and/or possibly thiram) accounted for 16 and 17 1% of
the radioactivity at 1 and 8 days, respectively.
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26
In another study in groundnut plants, the same degrada* :. products
were isolated (Raghu et al. 1976) Twelve days after spray 95% of the
35S taken up by the plant (1.2% of the 35S activity) was p: ,nt in the
shoots, most of wnich was identified as the alanine and B- _coside deriva-
tives of dimethyldithiocarbamic acid.
2. Lethality
Lethal doses of ziram in environmental species are listed in Table 7.
In a review of the literature, Strufe (1968) observed that, at concentra-
tions of 1-10 ppm for 12 to 72 hours, ziram kills numerous species of adult
fish in addition to those listed in Table 6. Young fish are somewhat more
sensitive (lethal doses range from 0.5-1.5 ppm) (Deschiens and Floch 1962,
Lloyd 1960, Gretillat 1961, Gretillat and Lacan 1964, all reported in
Strufe 1968). Lethal doses in aquatic fauna (crabs, crayfish, frog larvae,
dragonfly larvae, mosquito larvae) appear to be of the same order of magni-
tude (Deschiens and Floch 1962, Gretillat 1962, both reported in Strufe
1968).
Table 7. Lethality of Ziram in Environmental Species
Species
Length of Toxic Dose
Expo sure
Reference
- FISH -
Crassium
auratusa
Tilapia melanopleuraa
Epiplatus st) a
5 hrs
5-10 ppm
5 hrs LD50 5-10 ppm
5 hrs LDso 0.5-0.75 ppm
Bleak (Alburnus alburnus L.)t> 96 hrs LC(I)50° 3-4 ppm
- CRUSTACEANS -
Mitpera sinipes 96 hrs LC(I)sod 0.4 ppm
- MOLLUSCS -
Dreissena polymorpha 5 d LC5Q 1«3 ppm
Gretillat 1961, as
reported in Strufe
1968
Gretillat 1961, as
reported in Strufe
1968
Gretillat 1961, as
reported in Strufe
1968
Linden et al. 1979
Linden et al. 1979
Hoestlandt 1972
-------
27
Table 7. (continued)
Species Length of Toxic Dose Reference
Exposure
- WILD BIRDS -
Red-winged blackbird6
(Agelaius phoeniceus) LDfQ 100 mg/kg (56- Schafer 1972
178, 95% conf.
limits }
- PLANTS -
Pistia stratiotes Not stated LD^Q Gretillat 1961, as
reported in Strafe
1968
aTested an water. No other conditions stated.
^Tested in brackish water under static conditions at 10°C. Test
compound was mixture of ziram (22.5%) and carbendazim (2.5%).
C(I) = Initial concentration.
^Tested in brackish water under static conditions at 21°C. Test
compound was mixture of ziram (22.5%) and carbendazim (2.5%).
eDosed by gavage
3. Reproduction
No studies were found which would indicate the reproductive toxicity
of ziram in environmental species.
4. Behavior
No data were found.
5. Growth and Development
Ziram has been shown to be an inhibitor of growth or metabolic
processes of bacteria. Suzuki and Nakajima (1967, as reported in Chem
Abstr 70'26633d) demonstrated that 20 ppm of ziram completely inhibited the
growth of bacteria isolated from pulp white water, Hansen (1972) tested the
antibacterial effects of ziram in 211 strains of bacteria and concluded
that the compound has an innibitory effect, particularly in the gram-
positive organisms, Vaishnav and Brown (1976, as reported in Chem Abstr
-------
28
91 187939g) reported tnat ziraia (concentration not stated) re _;ed the 02
consumption of cultures of a mixture of oil—degrading bacter zo nearly
zero, and Azad et al. [1971, as reported in DIALOG (CAB Abs -cts 72-83)
1983] reported that ziram, tested at concentrations rangir_ -rom 0.00005—
0.05%, depressed both, microbial decomposition of organic _ -ter and
nitrification processes in loam soil at the higher and n -iun
concentrations.
There is also evidence that ziram reduces growta and development of
plants. George et al. (1970) treated seeds of the barley variety C 164
with ziram at concentrations of 250 and 500 ppm for 1 and 2 hours. Ziram
inhibited germination of the seeds by 60-97.5% on day 5 after treatment and
by 28-89.5"$ on day 10 after treatment. The rate of inhibition was
proportional to concentration and duration of treatment. Fifteen days
after treatment with 500 ppm, germination was inhibited by 20 and 28% for
the 1- and 2-hour treatment periods. In addition, all the ziram treatments
markedly reduced the height of the seedlings to between 8.6 and 32.9% that
of the controls. Similar, but less severe, effects were reported in a
later study in barley by Zutshi and Kaul (1975).
Ziram, at a concentration of 0.16% active ingredient, reduced the
number and size of fruits on apple trees, while the foliage remained
undamaged (Kirby et al. 1968, as reported in Chem Abstr 69 26234d), and,
when sprayed on the pollen of peach trees at 0.1 and 0.2%, reduced
germination [Pinzauti 1982, as reported in DIALOG (CAB Abstracts 72-83)
1983].
6. Population and Community Effects
No data were found.
7. Abiotic Effects
No data were found.
8. Other Effects
a. Effect on Plants
— At 10 ppm, ziram is toxic to several species of water
plants including Pistia stratiotes (Gretillat 1961, as
reported in Strufe 1968). However, ziram applied at
molluscicidal concentration [not stated in this paper, but
Hadler (1982) reports that ziram is effective against most
aquatic snails at 3-5 ppm in. water] has no effect on Lotus,
Nvm-phaea, water grasses, and reeds (Gretillat and Lacan
1964, as reported in Strufe 1968).
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29
Different species of algae are susceptible t .ram and are
danaged by the active ingredient at mollusc lal
concentration (Deschiens and Floch 1962, a sported in
Strufe 1963).
Ziram, at 0 16% active ingredient, mere ..ad russeting of
the fruits of apple trees (Kirby et al. 1968, as reported
in Chem Abstr 69 26234d).
Ziram, administered to peach trees during the vegetative
period, experimentally reproduced th.e characteristic
symptoms of external necrosis which appear from November to
January (Grosclaude et al. 1969, as reported in Chem Abstr
72.65880O .
b. Effects on Other Organisms
- Nishiuchi and Yoshida (1972, as reported in Chem Abstr
79 74562n) reported that ziram is toxic to tadpoles (no data
available), and Zazhivilov [1972, as reported in MEDLARS
(Toxback 65) 1983] found that, under experimental conditions,
the compound inhibited the function of the epithelial cilia of
the frog esophagus.
- Ziram is reportedly somewhat repellent to wild pigeons (Becker
1966, as reported in Chem Abstr 67 72803v), and reportedly to
other species of wildlife (Soyez 1981, as reported in Chem
Abstr 95 75491f).
- At the dose recommended for spraying crops, ziram was slightly
toxic to honeybees on ingestion, and more toxic on contact
[Arzone and Vidano 1980, as reported in DIALOG (CAB Abstracts
72-83) 1983]
F. Standards and Regulations
No effect levels for ziram, as demonstrated in the rat and dog, are
12.5 and 5 mg/kg body weight, respectively, and a temporary ADI (allowable
daily intake) of 0.025 mg/kg for man was established and subsequently
lowered to 0.005 mg/kg on the basis of reported teratogenic, genotoxic, and
pre—carcinogenic properties (WHO/FAO 1967, 1970, as reported in Vetorazzi
1979).
The use of ziram is permitted in the U.S. in rubber articles wnich
come in contact with food at levels not to exceed 1.5% by weight (USEPA
1980, as reported in USEPA 1983a)
Tolerances for residues of ziram (calculated as zinc ethylenebis
dithiocarbamate in or on raw agricultural commodities are established in
the U.S as follows 7 ppm in or on apples, apricots, beans, beets (with
or without tops) or beet greens alone, blackberries, blueberries
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30
(huckelbernes) , boysenbernes, broccoli, brussel sprouts, c ;age,
carrots, cauliflower, celery, cherries, collards, cranberri , cucumbers,
dewberries, eggplants, gooseberries, grapes, kale, kohlrao- .ettuce,
loganberries, melons, nectarines, onions, peaches, peanut" pears, peas,
peppers, pumpkins, quinces, radishes (with or without tor / ox radish tops,
raspberries, rutabagas (with or without tops) or rutaba; tops, spinach,
squash, strawberries, summer squash, tomatoes, turnips with or without
tops) or turnip greens, youngberries, 0.1 ppm in or or almonds, pecans
(USEPA 1980a, as reported in USEPA 1983a) .
G. Other Relevant Information
Alamanni et al. (1982, as reported in Chem Abstr 97 9056lp) state
that ethylenethiourea (ETU) was present as a contaminant in ziram between
the concentrations of 0 57 and 0.82%. ETU is reported to be a mutagen,
teratogen, and carcinogen (Lewis and Tatkin 1982) and is normally
associated with ethylene bis dithiocarbamate fungicides, not the N,N—
dimethyldithiocarbamate class of fungicides of which ziram is a member.
The possibility of an error in the abstract must be considered, especially
since this was the only reference found that links till and ziram.
The EPA Catalog of Data Supporting Pesticide Registrations (USEPA
1977) contains a listing of information or tests submitted to the USEPA
Office of Pesticide Programs Company Data Library. The catalog is indexed
according to chemical, formulation, and data type. The contents of the
ziram section of the catalog are summarized in Table 8. Listed first are
the tests submitted for ziram as the single active ingredient or for a
product containing ziram as a single active ingredient. Next are tests on
ziram mixed with a second active ingredient. The data types include
product chemistry, residue chemistry, environmental chemistry, efficacy,
phytotoxicity, human and domestic animal safety, fish and wildlife safety,
benificial insect safety, and accident exposure data. In Table 8 the
different formulations are grouped according to data type.
It should be noted that this list was compiled in 1977 and does not
include more recent information.
II. Preliminary Risk Assessment
Zinc, bis (dithmethylcaroaisodithioato-S, S')-, (T-4)-
CAS Registry Number 137-30-4
A. Exposure Assessment
Ziram is produced and used in fairly hign volumes. \ccording to the
aost recent data available, 1,880,000 pounds of ziran were produced in the
U.S. in 1981 (USITC 1982, as reported in USEPA 1983a). Production of ziram
has been declining since 1979 when the reported production volume was
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31
Taole 8 Tests Saoaitted in Support of Ziram Registz -ion
Data Type
Formulation
Descr ptorsa
Product chemistry
Physical-chemical
properties
Residue chemistry
Efficacy
-Ziram-
Technical chemical
Technical chemical
Dust
Wettable powder
Unspecified formulated
product
Wettable powder/dust
Unspecified formulated
product
Apples, cabbages,
potatoes
Figs, strawberries
Raspberries, beans
(green), cucumbers,
strawberries,
tomatoes
Almonds, beans (green),
cranberries, cucumbers,
figs, strawberries,
tomatoes
Almonds/shot hole
fungus, apricots/
brown rot, apricots/
shot hole, beans
(Blue!ake)/Sclerotina
j>. clerotiorun,
strawberries/gray
mold, strawberries/
strawberry fruit
rot, peaches/peach
leaf curl, raspber-
ries/not specified
Almonds/almond scab,
almonds/brownrot
blossom blight,
almonds/leaf blight,
almonds/peach scab, •
almonds/shot hole,
apples/bullseye rot,
blueberries/mummy
berry, blueberries
(low bush)/blossom
blight, cranberries/
cranberry fruit rot,
peaches/leaf curl,
peaches/shot hole,
pecans/pecan scab
pine trees/fusiform
rust, strawberries/
gray mold
-------
32
Taole 8 (continued)
Data Type
Formulation
Des , ptors£
Environmental
chemistry
Phytotoxicity
Efficacy
-Ziram-(continued)
Wettable powder/
dust
Unspecified formulated
product
-Ziram _in Combination with. Maneb^-
Dnspecified formulated
product
Beans (green),
cucumbers, tomatoes
Apples, peaches
Almonds/almond scab,
almonds/shot hole,
peach.es/peach leaf
curl
Efficacy
—Ziram in Combination with Ferbam0—
Wettable powder/dust
Almonds/shot hole;
celery
-Ziram in Combination with Zinc 2-Mercaptoben2othiazolate—
Product chemistry
Physical-chemical
properties
Storage stability
Efficacy
Efficacy
Sanitizer test
for non-food
contact surfaces
Unclassified
test type
Wettable powder
Wettable powder
Technical chemical (in—can
paint preservatives)
Wettable powder (in-can
paint preservatives)
Wettable powder
Wettable powder
Flowable concentrate
Unspecified bacteria
Mold, B. subtilisd.
S^ faecalis. S_
aureus, P, aerugi-
nosa
Unspecified bacteria,
mold
E. coli, S. cholerae-
suis. S.. typaosa,
S.. schottmueller,
Vf. glutinosum,
V{. audouini, S^.
fructicola, T.
gypseum, M. avreus,
A. faecalis, P_.
ammoniae
M. audouzai, S_.
fructola
Fongicidal test
Flowable concentrate
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33
Table 8. (continued)
Data Type
Formulation
Descriptors3-
—Ziram in Combination with Zinc 2—Me reap to?: enzothiazolate— (continued)
Soil burial test
on fabrics treated
with, fungicides
Fabric preservative
on wool
Fabric sanitizing
test
Paper mold—proof ing
test
Adhesive preser-
vation test
Paper mill slime
control test
Cooling water slime
control test
Fungus proofing
test for latex
coated products
Efficacy
Human and domestic
animal safety
Oral
Primary eye
irritation
Flowable concentrate
Flowable concentrate
Flowable concentrate
Flowable concentrate
Flowable concentrate
Flowable concentrate
Flowable concentrate
Flowable concentrate
Unspecified formulated
product (in—can
paint preservatives
o
Unspecified formulated
product (preservation
method)
V/ettable powder
Flowable concentrate
Wettable powder
Flowable concentrate
Flowable concentrate
Acute toxicity—
o
Subicute dermal Flowable concentrate
sensitization
Residues on paper Wettable powder
B. subtilis, P.
aeruginosa. mildew
Natural fauna
Rat
Albino rat, pigeon,
albino rabbit
Albino raboit
Albino rabbit
Albino rat
o
Guinea pig
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34
Table 8. (continued)
Data Type
Formulation
Desc"
-Ziram in Combination with Petroleum Distillate, Oi _.._, Solvent, or
Hydrocarbons, Aliphatic Hydrocarbons. Para" inic Oil-
Efficacy
Unspecified formulated
product
Blueberries/mummy
berry
-Ziram in Combination with Copper Sul.fate. Calcium Oxide-
Efficacy
Unspecified formulated
product
Pecans/pecan scab
-Ziram in Combination with Ferbam, Manganous Dimethyldithiocarbamate-
Efficacy Wettable powder Apples/not specified,
fruit trees/not
specified
Phytotoxicity Yfettable powder Apples
—Ziram in Combination wit h Zinc 2—Mercaptobenzothiazolate. Zinc Oxide-
Efficacy
Human and domestic
animal safety
Acute oral
Acute primary dermal
irritation
Acute eye irritation
Acute toxicity -
inhalation
Fish and wildlife
safety
Aquatic exposure
LC50
In—can spray pre-
servatives
Wettable powder
Wettable powder
Wettable powder
Wettable powder
Wettable powder
Unspecified bacteria
Albino rat
Albino rabbit
Albino rabbit
Rat
Fathead minnow
Descriptors are as follows
Residue chemistry — by commodity name
General efficacy - by site and pest
Phytotoxicity - by plant or crop name
°'-tanganous ethylenebisdithiocarbamate
cFemc dimethyl dithiocarbamate
organism glossary
faecal is = Al call genes, faecal is
terreus = Aspergillus terreus
subtilis = Bacillus subtilis
coli =
P.
1-
S.
ammoniac
aureus =
= Proteus ammoniae
_ Eschenchia coli
}!. aado'mni = Microsporum audouini
M. avreus = Micrococcus avreus
M. glutinosum = Metarrhizmm glutinosum
P_ aeruginosa = Pseudomonas aeruginosa
Staphlococcus aureus
choleraesuis = Salmonella choleraesuis
5>. faecal is = Streptococcus f aecalis
^. fructicola = Sclerotina fmeticola
j>. scnottmueller = Salmonella schottaueller
^. typhosa = Sa_liaone_ll_a typhosa
T. gypseum = Trichophyton gypseum
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3,765,000 pounds. Recent importation data were not availaole ^at 1977
figures indicate that at least 10,000-100,000 pounds %ere iir rted during
that year (USEPA 1983o, as reported in USEP4 1983a)
Ziram is used mainly as a rubber accelerator and a I gicide (USEPA
1983a), and in small quantities in animal glue and adhes- 33 which are used
in food-contact articles, non-food-contact paper coatin s, industrial
cooling water, latex-coated articles, neoprene, paper -zd paperboard, and
textiles and plastics (IARC 1976). Ziram is also an offective molluscicide
(Hadler 1982). There is no evidence that the compound is used as a
chemical intermediate.
Of the 2,231,000 pounds of ziram produced in 1978, approximately
400,000 pounds (18%) were used for fungicidal purposes (SRI International
1980, as reported in USEPA 1983a). Of the 400,000 pounds, 300,000 pounds
were used on deciduous fruits and 100,000 pounds were used on vegetables.
These figures suggest that probably over 1,000,000 pounds are used in the
rubber industry.
Occupational monitoring data for ziram were not found. Based on the
National Occupational hazard survey, NIOSH (1980, as reported in USEPA
1983a) projected that 27,889 workers were occupationally exposed to ziram,
the majority of whom were employed in the fabricated rubber products
industry. However, this survey did not include workers engaged in the
manufacturing of ziram or those using the compound as a pesticide, thus the
number of exposed workers could be even larger.
Inhalation and skin contamination are the most likely routes of
occupational exposure to the compound. Occupational exposure to ziram has
been demonstrated in Russian production plants where levels of ziram dust
ranging from 0.5 to 130 mg/m^ have been detected (Enikeev 1967,as reported
in Chem Abstr 72 35486b, Pilinskaya 1970, Marsten and Pilinskaya 1971, as
reported in USEPA 1983a). According to Narsten and Pilinskaya (1971), the
technological stages at which workers come in contact with ziram are in
packaging, drying, and warehousing the finished product. Until more data
is obtained, similar exposure in U.S. industry must be considered a
possibility.
Consumer exposure to ziram may occur through the use of the compound
as pesticide or through the ingestion of contaminated fruits and
vegetables. However, limited studies have demonstrated that residues of
the pesticide are easily washed off treated fruits and vegetables (Ryaznova
1967, as reported in Chem Abstr 71 2469z, Villa et al. 1976, as reported in
Chem Abstr 88 16949u), indicating that routine household washing of produce
may limit the quantities of ziram ingested.
Environmental monitoring data were not found. There was no
indication in the literature of whether or not ziram is released into the
environment from the pesticide and rubber industries. Environmental
contamination is expected, however, through the use of ziram as a fungicide
(soil contamination, primarily) and a molluscicide (*ater contamination)
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36
Once released inco the environment, ziram may persist f about a
month.. Under experimental conditions, ziraia residues disap^ red from
sprayed vegetables (stored at 4°C) in about 30 days (Villa al. 1976), in
the field, persistence on the leaves of woody plants was £_ ffeeks for 10
of the 12 species studied (Neely 1970). In water, ziram - , persist for
30-45 days, depending on pH (Gretillat 1961, as reported .a Stmfe 1968)
and other factors such as photolysis, biodegradation, s rption
characteristics and uptake by aquatic organisms.
A low concentration of ziram in water, exposed to sunlight each day,
remained biologically active for 45 days (Deschiens and Floch 1965, as
reported in Strufe 1968), indicating that photodegradation of ziram is
probably minimal. There is some evidence that ziram is biodegradable
(Raghu 1976, as reported in Chem Abstr 89 37937z, Etges et al. 1965),
however biodcgradability of the compound may be limited by its toxicity to
microorganisms (Sect- I.E.5.Growth and Development). Sorption studies have
demonstrated that in water, ziram adsorbs to mud particles in varying
degrees (Paulini 1963, Gonnert and Strufe 1962, both reported in Strufe
1968), and would therefore be available to bottom-feeding organisms, in
particular. If taken up by aquatic organisms, ziram would not be expected
to bioaccumulate (Vetorazzi 1979).
The presistence of ziram in soil would depend on factors similar to
those which govern the persistence of the compound in the water. However,
the availabile data for the mobility of ziram through the soil are
conflicting. Some investigators found the compound to be immobile in soil
(Munneke 1961, Helling et al. 1974, both, reported in Singhal and Bansal
1978; Kenaga 1980), while others observed high mobility (Singhal and Bansal
1978). Singhal and Bansal (1978) suggested that the mobility of ziram may
depend on its concentration (the excess of supersaturate would be more
mobile) since they had applied high concentrations in their assays It is
also possible that different analytical techniques could account for the
conflicting results of at least two of the studies. In any case, this
suggests the possibility of at least some leaching and subsequent
contamination of ground water by ziram.
In summary, the data suggest the possibility of the release of
significant quantities of ziram into the workplace and the environment
(especially during its use as a fungicide), with workers in the rubber and
pesticide industries and agriculture having the greatest exposure
potential. Once released into the environment, the compound would probably
not persist longer than a few weeks due to chemical and/or biological
degradation. Occupational and environmental monitoring data from the U.S.
and data on environmental releases from manufacturing and use sites are
needed for further assessment of the exposure potential of ziram.
B. Human Health Risk Assessment
Ziram is carcinogenic, mutagenic, and teratogenic in animals, and
apparently causes chromosomal abnormalities in humans. These effects.
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37
coupled with the relatively hign production volume of the co^ _nd and its
wiaespread use in industry and agriculture, constitute a po* . lal risk to
human health.
In an NTP (1983) bioassay, ziram was carcinogenic i jale, but not
female, F344/N rats, inducing a statistically significar. increase (p <
0.05) in the incidence of C-cell carcinomas of the thyr _d at an oral dose
of 22 mg/kg/day for 103 weeks. The effect was dose-re.ated. Ziram also
produced a statistically significant increase (P < 0 35) in the incidence
of alveolar adenomas in female, but not male, B6C3Fi mice (NTP 1983).
However, the interpretation of the results of the mouse study was
complicated by a respiratory (Sendai) virus infection.
These rather equivocal positive results are supported by the fact
that the thyroid is recognized as a target organ for the thiocarbdinate
compounds as a class (NTP 1983), and that unidentified metabolites of
ziram have been detected in the thyroid of female rats 24 hours after a
single dose of ziram was administered by gavage (Izmarova and Marinov 1972,
as reported in NTP 1983). In addition, tetrazaethylthiuram disulfide, a
metabolite of ziram, has been associated with squamous metaplasia in the
thyroid of rats (Lee et al. 1978, as reported in NTP 1983).
In several older studies in rats, ziram induced fibrosarcomas and
tumors of the thyroid and the liver (Section I.D.3, Carcinogenicity), some
statistically significant, some not, and in older studies in mice, the
compound was non-oncogenic. Some of these studies were considered by IARC
(1976) to be qualitatively or quantitatively inadequate, however, their
significance should be reevaluated in light of the NTP (1983) results.
The oncogenicity of ziram by the oral route is particularly relevant
to potential consumer exposure via ingestion of contaminated produce,
however the compound apparently has not been tested for oncogenicity via
inhalation or skin application, the two most probable routes of worker
exposure. This data would be useful for a more complete assessment of
occupational risk.
In experimental systems, the mutagenicity of ziram is equivocal
(Table 4) . However, abnormal chromosomes or chroiaatids were reported in
5.9% of the lymphocytes cultured from workers with known exposure to the
compound in a ziram manufacturing facility (Pilinskaya 1970), and these
effects were essentially repeated in vitro (Pilinskaya 1971). Similar
epidemiological data for U.S. workers would be useful.
Teratogenic and reproductive effects have been reported in rats,
rabbits, mice and chickens at various doses, mostly by the oral route
(Section I.4.D, Teratogenicity/Reproductive Effects). Moreover, one
inhalation study was reported in wnich raboits, exposed to 5 cig/m^ of ziram
dust 4 aours a day for 4 months, displayed testicular atrophy (Enikeev
1967, as reported in Chem Abstr 72 35486b). This exposure level was almost
in the range of the levels detected in the work atmosphere by Pilinskaya
(1970) of 1.95 and 3.7 mg/m3. However, Marsten and Pilinskaya (1971)
reviewed the clinical records of women employed in a ziram manufacturing
plant and did not detect any disturbances in reproductive functions.
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38
la animals, ziraa is of moderate to high acute oral tc ity, accord-
ing to the scale of Gossel^n st al. (1977), with, oral LDfQ -ies ranging
from 400-1400 ng/lg in various species.
Various non-oncogenic cnronic, subchronic ana suba _.e effects have
been described in animals and humans (Section I.D.6, Ot jr Effects).
Observed effects in animals include supression of the ^.amatopoetic system,
degenerative changes in the liver, kidney, and salivary glands, and contact
hypersensitivity. In humans exposed in Russian and Italian industries,
observed effects include irritation of the skin, eyes, and respiratory
tract, slight hematological changes, and enlarged livers with elevated
liver enzyme activities. One group of workers had shifts in blood cho-
linesterase and pseudocholinesterase activities (accumulation of acetylcho—
line), indicating that ziram may be a cholinesterase inhibitor in man
[Komarova and Zotkina 1971, as reported in JffiDLARS (Toxback 65) 1983].
The effects of ziram on the health of animals and humans suggest that
workers and consumers should avoid exposure to the compound. In addition
to the data needs mentioned above, monitoring data in the U.S. workplace
and in fruits and vegetables treated with ziram would be useful in further
assessment of the health risk imposed on humans by the compound.
C. Environmental Assessment
Monitoring data that would indicate the extent to which ziram is
released into the environment were not found. The probability of ziram
contamination of the environment is indicated by the use of the compound as
a fungicide which is sprayed on various crops, and as a molluscicide which
is added to aquatic systems. The high production volume and the use of the
compound in the rubber industry also suggest the possibility of industrial
release. Once released, the biological activity of ziram could persist for
as long as a month in both water and soil.
Ziram is lethal to aquatic species at concentrations of 0.5—10 ppm
depending on age and species, the young usually being more sensitive than
the adults. These species include fish, crustaceans, amphibians, insects,
molluscs, and certain aquatic plants (Deschiens and Floch 1962, Gretillat
1962, Gretillat and Lucan 1964, Lloyd 1960, all reported in Strufe 1968)
The letnal concentrations are within the range recommended for molluscici-
dal activity \vailaole data for terrestrial animals >vas limited to tne
oral LDso in the rea-wingea olackoira of 100 mg/kg (Scnafer 1972). More-
over, in experimental animals, the compound *as of moderate to nigh acute
oral toxicity (Taole 3)
Ziram has been shown to be an inhibitor of growth and metabolic
processes of bacteria in water (Suzuki and Nakajima 1967, as reported in
Chem Abstr 70 26633d) and soil [Azad et al. 1971, as reported in DIALOG
(CAB Abstracts 72-33)]. At concentrations of 0 05% (500 ppm), microoial
decomposition of organic matter and nitrification processes in loam soil
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39
were depressed. This could limit biodegradation of the comr . z.d. Ziram
also reduced growth and development of barley plants (at 25 .ad 500 ppm)
and fruit trees (at 1000-2000 ppm).
All of the effects mentioned above indicate that e ironmental
release of ziram could result in injury to a wide spect_-_a of environmental
species. Environmental monitoring data and reproducti e toxicity data for
environmental species would be particularly useful for further assessment
of the extent of the hazard.
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40
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41
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2. Data Bases
File
JEDLARS
TOXLJNE
TOX65
TOX74
CANCEELINE
CANCERPROJ
MEDLINE
IDE
RTECS
CHEMLINE
BACK77
BACK75
BACK71
BACK66
LOCKHEED/DIALOG
AGRICOLA 79-
AGRICOLA 70-78
APTIC
ASFA
BIOSIS PREVIEWS 69-76
BIOSIS PREVIEWS 77-80
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CA SEARCH 67-71
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EXCERPTA MEDICA IN-PROCESS
EXCERPTA MEDICA 74-79
EXCERPTA fffiDICA 80-
FEDERAL REGISTER
NTIS
PHARMACEUTICAL NEWS INDEX
POLLUTION ABS.
SCISEARCH 74-77
SCISEARCH 78-80
SCISEARCH 81-PRESENT
SSIE
WATERNET
Number of References
142
189
201
5
0
1
1
1
1
4
5
10
2
1
12
0
0
100
59
25
183
211
156
92
58
241
5
1
1
1
2
0
39
19
0
10
0
2
4
1
2
2
0
"ate of Search.
May 10, 1983
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File Number of References D -j of Search
ORBIT
CRECORD 0 "
SYRACUSE RESEARCH CORPORATION
DATALOG 2
CHEJfFATE 0
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C. Searcn Strategy
Ziraia
Search terns included collective index names, synon; ., CAS Registry
Number, and CHEMLINE and CHEilNAME nomenclature, ill hit- _iOm each data
base were "dumped" and the computer printouts were scar d for pertinent
references.
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