QoOf
EPA/60O/8-9O/O21
August 1789
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CACODYLIC ACID
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ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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TECHNICAL REPORT DATA
(Ptetae reed Instruction* on the reverse before completing)
1. REPORT NO.
EPA/600/8-90/021
2.
3. RECIPIENT'S ACCESSION NO.
PB91-216473
4. TITLE AND SUBTITLE
Health and Environmental Effects Document for
Cacodylic Acid
6. REPORT DATE
6. PERFORMING ORGANIZATION COOE
7. AUTHOH(S)
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS .
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268 „___
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
Health and Environmental Effects Documents (HEEDS) are prepared for the Office of
Solid Waste and Emergency Response (OSWER). This document series is intended to
support listings under the Resource Conservation and Recovery Act (RCRA) as well as
to provide health-related limits and goals for emergency and remedial actions under
the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and information obtained from Agency Program Office files
are evaluated as they pertain to potential human health, aquatic life and environmen-
tal effects of hazardous waste constituents.
Several quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these include Reference Doses (RfDs) for chronic
and subchronic exposures for both the inhalation and oral exposures. In the case of
suspected carcinogens, RfDs may not be estimated. Instead, a carcinogenic potency
factor, or q *, is provided. These potency estimates are derived-for both oral and
inhalation exposures where possible. In addition, unit risk estimates for air and
drinking water are presented based on inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxicity and carcinogenicity are.
derived. The RQ is used to determine the quantity of a hazardous substance for
which notification is required in the event of a release as specified under CERCLA.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
COSATi Field/Group
18. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (Thit Report!
Unclassified
21. NO. OF PAGES
101
20. SECURITY CLASS (Thispage>
Unclassified
22. PRICE
EPA Pan 2220.1 (R»». 4-77) PREVIOUS COITION i* OBSOLETE
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs} based on both chronic toxlclty 'and cardno-
genldty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification Is required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). Jhese two RQs (chronic toxlclty and cardno-
genlclty) represent two of s1x^ scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for, chronic toxlclty and cancer based RQs are defined In U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMHARY
Cacodyllc add 1s a colorless and odorless solid at ambient tempera-
tures. It Is soluble 1n water and ethanol, but Insoluble 1n ethyl ether
(Woolson, 1976; Worthing, 1983). Cacodyllc add 1s an add and forms both
catlonlc and anlonlc compounds. The chemical Is produced commercially by
the reaction of monosodlum methylarsonlc add with methyl chloride and
sulfur .dioxide at 80°C and 5 ps1 pressure (Woolson, 1976). It Is manufac-
tured In the United States by Vlneland Chemical Co., Vlneland, NJ, and
Drexel Chemical Co., Tunica, MS (SRI, 1987). Data regarding U.S. production
volume are not available. It Is estimated that a maximum of 4.8 million
pounds of cacodyllc acid was consumed In the United States In 1987.
Cacodyllc add 1s used as a herbicide, as a desUcant and defoliant for
cotton, for killing unwanted trees and thinning forest, and for controlling
Insects and fungi that attack trees (Woolson, 1976, 1986; Worthing, 1983).
The fate of cacodyllc add 1n the atmosphere Is not well understood. It
Is likely to be present 1n the participate phase of aerodynamic diameter of
<4 ym, with a concentration maximum at aerodynamic diameter of 0.5 ^m
(Tanaka et al., 1984). The oxidation of partlculate cacodyllc add by HO-
1n the atmosphere Is likely, but the kinetic data for this reaction, which
will allow the estimation of Us residence time 1n air, are not available.
Some of the partlculate cacodyllc add may be removed by dry and wet
deposition. Since this compound Is quite stable towards oxidation/
reduction (Braman and Foreback, 1973), it may have a long residence time 1n
the air, which will allow It to transport long distances. No data were
found In the literature to Indicate that cacodyllc acid will undergo
significant abiotic reaction In water. Blodegradatlon of cacodyllc add 1n
1v
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water and sediment has been reported, and arsenate Is the primary product,
although small amounts of arsenlte, CO- and probably alkylarslnes are also
formed. The half-life of this compound In water Is >1 month (Lemmo et al.',
1983; Holm et al., 1980). Significant volatilization of this compound from
water 1s not expected. Sorptlon onto sediments will cause some cacodyllc
add In water to be lost, and the sorptlon will Increase with Increase of pH
and aluminum and Iron content of the sediment; however, the sorptlon of this
compound on sediments Is weakest of all the arsenlcals (Holm et al., 1980;
Lemmo et al., ,1983). Bloconcentratlon of this compound 1n lower food chain
organisms will'be significantly higher than In higher food chain organisms.
Therefore, significant bloconcentratlon in edible fish may not occur
(Isensee et al., 1973). In aerobic soils, cacodyllc add will undergo
blodegradatlon ,w1th the formation of primarily arsenate. The blodegradatlon
rate may depend on the nature of soil, with 90H degradation observed In two
soils compared 'with <5% degradation In another soil (Woolson, 1976; Odanaka
et al., 1985a). Conflicting data are available on the degradation products
1n soils under anaerobic conditions. While one group of researchers
(Woolson and Kearney, 1973; Woolson, 1976) reported organoarsenlcals as the
primary product, another group (Odanaka et al., 1985b) reported Inorganic
arsenic as the primary product. The sorptlon of this compound In soil will
depend on clay and Iron oxide content of the soil, but the sorptlon capacity
may be lower than both arsenate and methylarsonate. Therefore, leaching of
this compound particularly from sandy soils may be more prevalent (Wauchope,
1975; Woolson, 1976). No detectable transport or translocatlon of the
herbicide within cotton seeds was observed as a result of application 1n a
cotton field (Mastradone and Woolson, 1983).
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Limited monitoring data on the ambient levels of cacodyllc add In any
environmental medium are available. The concentration of this compound In
air sampled at sites In Japan ranged from 7-270 pg/ma. A seasonal varia-
tion In airborne cacodyllc add levels was observed, with maximum levels
during summer when the biological activities In aquatic and terrestrial
media were maximum (Tanaka et al., 1984; Mukal et al., 1986). The concen-
trations of this chemical In a few surface waters sampled In the United
States were <0.02-1 iig/fi., but H was not detected In Tampa tap waters
(Braman and Foreback, 1973). Urine samples of presumably unexposed people
averaged 15 ug/l, with values as high as 1.8 mg arsenlc/i In appli-
cators using monosodlum methanearsonate and cacodyllc add. The later level
corresponds to an exposure of >0.036 mg arsenic/kg bw/24-hour day (Braman
and Foreback, 1973; Morris, 1985).
The 96-hour LC5Qs for mosqultoflsh and southern toad tadpoles were
estimated to be between 100 and 1000 mg/l (Oliver et al., 1966). The
96-hour LC,.Qs for bluegllls, amphlpods and shrimp were 17, 140 and 135 and
28 mg/l, respectively (Mayer and Ellersleck, 1986). Cockell and Hilton
(1988) reported that the NOEC for cacodyllc add In juvenile rainbow trout
was >1497 ng As/g diet. Mortality was 42.5-97.554 1n terrestrial snails
given baits containing 1.5-2.4J4 cacodyllc add.
Uptake of cacodyllc add by organisms In laboratory aquatic ecosystems
was greatest In algae, aquatic plants and daphnlds. followed by snails, fish
and crayfish. Bloconcentratlon ratios In these organisms ranged from a high
of -1650 for algae and daphnlds to -1-15 for fish and crayfish (Isensee et
al., 1973; Schuth et al., 1974). Stary et al. (1982) demonstrated that
uptake of cacodyllc add by gupples from water was negllble after a few days
of exposure and that 95% of the tissue residues from Ingested cacodyllc acid
vl
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was depurated within hours. Calculated BCFs estimated from log K and
water solubility were <1, suggesting that cacodyllc add was not likely to
accumulate In the tissues of aquatic organisms.
Algal productivity was reduced by 50% In the presence of 55.3 ppm
cacodyllc acid for 48 hours (Oliver et al., 1966). Reproduction In brown
algae was Inhibited by 35 mM of the sodium salt of cacodyllc acid (Roederer,
1986).
Field studies revealed low to moderate effects on vegetation from three
terrestrial communities exposed to 2 Ibs/acre of cacodyllc acid. Treatment
levels of 30 Ibs/acre were highly detrimental to the survival of vegetation
1n those communities (Oliver et al., 1966).
Cacodyllc acid appears to be asorbed rapidly and virtually completely
from the respiratory tract of Intratracheally treated rats, with a half-time
of 2.2 minutes.' Gastrointestinal absorption In rats Is considerably slower,
with an estimated half-time of 248 minutes (Stevens et al., 1977).
Excretion data: 1n rats (Stevens et al., 1977), hamsters (Yamauchl and
Yamamura, 1984; Harafante et al., 1987) and mice (Marafante et al., 1987)
Indicate that GI absorption ranges from -60-70% In these species. Urinary
excretion data; In humans (Marafante et al., 1987; Buchet et al., 1981)
suggest a GI absorption factor for humans of -80%.
Distribution data obtained from rats treated Intravenously with high
(200 mg/kg) and low (33 vg) doses Indicate that the rat R8C has an
affinity for cacodyllc acid (Stevens et a I.. 1977). Among other tissues,
highest concentrations were found 1n the liver > kidney > lung > spleen >
brain. The magnitude of the dose had no effect on tissue distribution.
Plasma elimination was trlphaslc, with a terminal half-life of 3.42 hours.
vll
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Tissue distribution appeared to be similar In hamsters, except that the
hamster RBC did not appear to have a particular affinity for cacodyllc add
(Yamauchl and Yamamura,. 1984).
The metabolism of cacodyllc add has been studied by quantifying" Its
metabolites In tissue, expired air and excreta of treated rats, mice,
hamsters and humans (Stevens et al., 1977; Yamauchl and Yamamura, 1984;
Marafante et al., 1987). Excretion data In hamsters, mice and humans
suggest that metabolism Is not nearly as Important as excretion In the
elimination of cacodyllc add (Marafante et al., '1987). Demethylatlon to
methylarsonlc acid, Inorganic arsenic and carbon dioxide appears to be a
minor metabolic pathway (Yamauchl and Yamamura, 1984; Stevens et al., 1977).
The most Important blotransformatlon pathway appears to be methylatlon to a
trlmethyl compound, probably to a tdmethylarslne oxide conjugate (Yamauchl
and Yamamura, 1984; Marafante et al., 1987). Complexatlon with thlo-
contalnlng compounds may be an Intermediate step In the formation of
tMmethylarslne oxide.
Excretion of a parenteral dose Is primarily through the kidney, with
minor amounts expired as CO. and excreted through the bile (Stevens et
al., 1977; Marafante et al., 1987). Fecal excretion of an oral dose
probably represents largely unabsorbed compound. A plasma half-life In rats
of 3.42 hours was estimated for the terminal phase of a trlphaslc decay
function (Stevens et al., 1977). In hamsters and mice, urinary and fecal
excretion together accounted for 97.5 and 96.8X of an oral dose after 48
hours, suggesting that excretion In these species 1s fairly rapid (Marafante
et al., 1977). In humans, -80% of an oral dose was recovered from the urine
within 3 days of treatment (Marafante et al., 1987; Buchet et al., 1981).
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Oral L05Q values 1n rats range from 644-1433 mg/kg, with Uttle
apparent difference In magnitude regardless of age or gender (see Table
6-1). Inhalation and Intraperltoneal single exposure data Indicate Uttle
difference1 In the sensitivity of rats compared with mice. Intraperltoneal
L05Q values In both species ranged from 500-1000 mg/kg.- In a 20-day
dietary study1 using rats, testlcular effects were observed, at 180 mg/kg
bw/day, but not at 140 mg/kg bw/day (Nees, 1960). A dietary concentration
of 184 ppm was a NOEL In rats In a 30- to 90-day dietary study (Nees, 1968)
and 30 ppm was a NOEL Vn a 90-day study using dogs (Derse, 1968). It Is not
»
clear whether the testls was examined In these longer-term studies.
Data regarding the toxlclty of cacodyllc add In humans were not
located; however, workers applying arsenic-containing sllvlcldes had higher
urinary concentrations of arsenic compounds, Including cacodyllc add, than
did nonexposed controls. The levels of cacodyllc add 1n the urine did not
appear to rise with Increased duration of exposure. Near normal levels were
observed on Monday mornings.
Cacodyllc add did not yield evidence of cardnogenlclty In an 18-month
gavage/dletary study In which mice were exposed to 46.4 mg/kg/day by gavage
from 7-28 days of age and 121 ppm In the diet after 28 days of age (BRL,
1968; Innes eta!.. 1969). In a different BRL (1968) experiment with mice.
a single subcutaneous Injection at 464 mg/kg of cacodyllc add In distilled
water did not produce a significant Increase 1n tumor Incidence compared
with controls. A drinking water study produced equivocal evidence that
cacodyllc acid may promote liver tumors 1n partially hepatectomlzed rats
Initiated with DENA (Johansen et al., 1984). Results of mutagenldty
testing were mixed. Tests In prokaryotes (Simmon et al., 1977; Jones et
al., 1984; Andersen et al., 1972) and Drosophllla (Ramel and Magnusson,
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1979; Valencia, 1981) were negative, but tests In Saccharomyces were
positive (Simmon et al., 1977; Jones et al., 1984). Mixed results were
obtained 1n various mammalian test systems (Simmon et al., 1977; Jones et
al., 1984; Taylor et al., 1984). The compound 1s not scheduled for testing
by the NTP (1988).
Developmental toxlclty studies (Rogers et al., 1981; Kavlock et al.,
1985; Chernoff and Kavlock, 1982) suggest that rats are more sensitive than
mice. In a gavage study using rats, 40 mg/kg/day was associated with
retarded maternal weight gain, reduced fetal body weights and retarded
ossification (Rogers et al., 1981). An Increased Incidence of Irregular
palatine rugae was observed at 30 mg/kg/day. There were no significant
effects at 15 mg/kg/day. In mice treated by gavage, 200 mg/kg/day resulted
1n adverse body weight effects on both the dam and the fetus; 400 mg/kg/day'
resulted 1n an Increased Incidence of cleft palate (Rogers et al., 1981).
An Interim RfO of 0.03 mg/kg/day was derived for subchronlc oral
exposure to cacodyllc add based on the NOEL of 9.2 mg/kg/day for rats In
the 907day dietary study by Nees (1968). An Interim RfD of 0.003 mg/kg/day
was derived from the same data for chronic oral exposure. The RfD values
are well below the line for adverse effects In a dose/duration-response plot
of the oral toxldty data. An RQ of 1000 pounds was derived based on mild
teratogenlc effects In rats In a developmental toxlclty study (Rogers et
al., 1981). Based on Inadequate data concerning the carclnogenlclty of
cacodyllc add, H was assigned to EPA Group D, not classifiable as to human
carclnogenlclty. A cancer-based RQ was not derived.
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2, PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 3
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT ; . . . . 4
2.1. AIR 4
2.2. WATER 5
2.3. SOIL 6
2.4. SUMMARY 8
3. EXPOSURE. 10
3.1. SUMMARY 11
4. ENVIRONMENTAL TOXICOLOGY 13
4.1. AQUATIC TOXICOLOGY 13
4.1.1. Acute Toxic Effects on fauna. 13
4.1.2. Chronic Effects on Fauna 13
4.1.3. Effects on Flora 16
4.1.4. Effects on Bacteria 17
4.2. TERRESTRIAL TOXICOLOGY 17
4.2.1. Effects on Fauna 17
4.2:.2. Effects on Flora 18
4.3. FIELD STUDIES 18
4.4. AQUATIC RISK ASSESSMENT 19
4.5. SUMMARY 19
5. PHARMACOKINETCS 22
5.1. ABSORPTION 22
5.2. DISTRIBUTION 25
5.3. METABOLISM 28
5.4. EXCRETION 32
5.5. SUMMARY.- 33
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TABLE OF CONTENTS (cent.)
Page
6. EFFECTS 35
6.1. SYSTEMIC TOXICITY . 35
6.1.1. Inhalation Exposure 35
6.1.2. Oral Exposure 35
6.1.3. Other Relevant Information 36
6.2. CARCINOGENICITY 38
6.2.1. Inhalation 38
6.2.2. Oral 38
6.2.3. Other Relevant Information 39
6.3. MUTAGENICITY 40
6.4. TERATOGENICITY 44
6.5. OTHER REPRODUCTIVE EFFECTS 47
6.6. SUMMARY 47
7. EXISTING GUIDELINES AND STANDARDS 49
7.1. HUMAN 49
7.2. AQUATIC 49
8. RISK ASSESSMENT 50
8.1. CARCINOGENICITY 50
8.1.1. Inhalation 50
8.1.2. Oral 50
8.1.3. Other Routes 50
8.1.4. Weight of Evidence 51
8.1.5. Quantitative Risk Estimates 51
8.2. SYSTEMIC TOXICITY 51
8.2.1. Inhalation Exposure 51
8.2.2. Oral Exposure 51
9. REPORTA8LE QUANTITIES 54
9.1. BASED ON SYSTEMIC TOXICITY 54
9.2. BASED ON CARCINOGENICITY 58
10. REFERENCES 59
APPENDIX A: LITERATURE SEARCHED 73
APPENDIX B: SUMMARY TABLE FOR CACODYLIC ACID 76
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
CACODYLIC ACID 77
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LIST OF TABLES
No. Title Page
5-1 Tissue Distribution of 14C 105 Days After Administration
of 14C-Cacodyl1c Acid to Adult Male Sherman Rats by
Various Routes 27
5-2 Excretion of Metabolites of Cacodyllc Acid In the Urine
Following Oral Administration 30
5-3 Excretion of Metabolites of Cacodyllc Add In the Feces
Following Oral Administration 31
6-1 Acute Lethal Toxlclty of Cacodyllc Add 37
6-2 MutagenkHy Testing of Cacodyllc Add 41
9-1 Toxlclty Summary for Cacodyllc Acid 55
9-2 Composite Scores for Cacodyllc Add 56
9-3 Minimum Effect Dose (MED) and Reportable Quantity (RQ). ... 57
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LIST OF ABBREVIATIONS
BCF
bu
CAS
CBI
CS
DENA
DNA
PEL
GI
LOAEL
MEO
NOAEL
NOCEL
NOEC
NOEL
PEL
ppm
RBC
RfD
RQ
Bloconcentratlon factor
Body weight
Chemical Abstract Service
Confidential Business Information
Composite score
DlethylnHrosamlne
Deoxyrlbonuclelc acid
Frank-effect level
Gastrointestinal
Soil sorptlon coefficient standardized
with respect to organic carbon
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
No-observed-adverse-effect level
No-observed-carclnogenlcity-effect level
No-observed-effect concentration
No-observed-effect level
Permissible exposure level
Parts per million
Red blood cell
Reference dose
Reportable quantity
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RVd
RVe
TLV
TMA
TMAO
LIST OF ABBREVIATIONS (cent.)
Dose-rating value
Effect-rating value
Threshold limit value
Trlmethylarslne
Trtmethylarslne oxide
xv
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1. INTRODUCTION
1.1.' STRUCTURE AND CAS NUMBER
The common chemical name for'cacodyllc acid Is d1methylars1n1c add. It
Is also known as hydroxyd1methylars1ne oxide. Some of the common trade
names of this chemical are Ansar 138, Bolls-eye, Phytar 138 and Sllvlsar 510
(HSDB, 1988; Worthing, 1983). The structure, molecular formula, molecular
weight and CAS Registry number for cacodyllc add are as follows:
CH3 0
\lt
As-OH
/
CH3
Molecular formula: CpH,As02
Molecular weight: 138.01
CAS Registry Number: 75-60-5
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Cacodyllc acid Is a colorless and odorless solid at ambient temperature;
1t Is soluble in water and ethanol, but Insoluble In ethyl ether (Worthing,
1983; Woolson, 1976). Some of the relevant physical properties of this
chemical are listed below:
Melting point:
Boiling point:
\.
Density:
Water solubility:
Vapor pressure: .
Log Kow: >
pKa at 25°C:
200°C
not available
not available
667,000 mg/a at 20-25°C
not available
-1.78 (estimated from
regression equation)
6.29
Woolson, 1976
Woolson, 1976
Lyman et al., 1982
Wauchope, 1976
0128d
-1-
03/13/89
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As Indicated by Us pKa value, this compound 1s an add and forms the
sodium salt with NaOH at about neutral pH (Worthing, 1983). Since cacodyllc
acid is amphoterU {Lemmo et al., 1983), 1t can form both catlonlc and
anlonlc compounds. Cacodyllc add undergoes two main kinds of reactions,
one with adds and the other with metal salts; for example, 1t reacts with
HI to form dimethyl arsenic Iodide. Details of these reactions are
available 1n a review article by Lemmo et al. (1983). It Is quite stable
towards oxidation/reduction, and only strong oxidizing and reducing agents
are required for Its decomposition (Worthing, 1983; Braman and Foreback,
1973).
1.3. PRODUCTION DATA
Cacodyllc add Is made commercially by the reaction of monosodlum
methylarsonlc add wHh methyl chloride and sulfur dioxide at 80°C and 5 psl
pressure (Woolson, 1976). It can also be made by the alkylatlon of dlsodlum
methanearsonate with methyl chloride, followed by hydrolysis of the product
with HC1 (HSDB, 1988). According to the Directory of Chemical Producers
(SRI, 1987), Orexel Chemical Co, Tunica, MS, and Vlneland Chemical Co.,
Vlneland, NJ, are the current producers of cacodyllc acid In the United
States. USITC (1987) lists only the former company as a manufacturer of
this chemical 1n the United States In 1986. It was reported that 2 million
pounds of cacodyllc add was produced In the United States 1n 1971 (Lewis
and Lee, 1976). The current U.S. production volume of cacodyllc add Is not
available. The total consumption of arsenic and compounds In 1987 was 50.7
million pounds (expressed as arsenic); 19% of the total consumption was used
for agricultural chemicals (USDI, 1988). If H Is assumed that a maximum of
50% of the total agricultural usage was In the form of cacodyllc add
(Woolson, 1976), a maximum of 4.8 million pounds of this chemical was
0128d -2- 03/13/89
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consumed In 'the United States In 1987. Technical grade cacodyllc add Is
65% pure and contains NaCl as one of the Impurities (Worthing, 1983).
1.4. USE DATA
Cacodyllc acid Is used as a nonselectlve postemergent herbicide for weed
control, for 'lawn renovation, as a deslccant and defoliant for cotton, for
killing unwanted trees by Injection, for thinning forests, and for controll-
ing Insects and fungi that attack trees {Woolson, 1976, 1986; Worthing,
1983).
1.5. SUMMARY
Cacpdyllc acid 1s a colorless and odorless solid at ambient tempera-
tures. It Is soluble In water and ethanol, but Insoluble In ethyl ether
i
(Woo.lson, 1976; Worthing, 1983). Cacodyllc acid Is an acid and forms both
catlonlc and anlonlc compounds. 'The chemical Is produced commercially by
the reaction ;of monosodlum methylarsonlc acid with methyl chloride and
*f
sulfur dioxide at 80°C and 5 psl pressure (Woolson, 1976). It Is manufac-
tured In the , United States by Vlneland Chemical Co., Vlneland, NJ, and
Drexel Chemical Co., Tunica, MS (SRI, 1987). Data regarding U.S. production
volume are not available. It 1s estimated that a maximum of 4.8 million
pounds of cacodyllc add was consumed In the United States In 1987.
Cacodyllc add Is used as a herbicide, as a deslccant and defoliant for
cotton, for killing unwanted trees and thinning forest, and for controlling
Insects and fungi that attack trees (Woolson, 1976, 1986; Worthing, 1983).
0128d
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
The fate of cacodyllc add 1n the atmosphere Is not well understood.
Because cacodyllc acid Is an Ionic compound, H 1s not expected to
volatilize significantly from aquatic or terrestrial media. As a result of
Its use In agricultural and forest lands, however, It Is likely to be trans-
ported as aerosols to the atmosphere. A second process that may transport
aquatic and terrestrial arsenic from cacodyllc add to the atmosphere 1s Its
conversion to volatile dimethyl and trlmethyl arslnes by both bacteria and
fungi that may be present In the natural ecosystem (Cox and Alexander, 1973;
Wong et al., 1977). Methyl arslnes at concentrations >0.05-0.10 ppm are
very unstable In air and are oxidized rapidly. At low concentrations,
methyl arslnes are more stable and may be transported from the source before
being oxidized In air (Lemmo et al., 1983). The oxidation products of
trlmethyl arslnes 1n air have been Identified as trlmethylarslne oxide and
cacodyllc add (Parrls and Brlnckman, 1976). The oxidation of partlculate
cacodyllc add by HO- 1n air Is likely. This 1s supported by the fact
that a very slow oxidation of this compound to arsenate has been observed In
model aquatic systems (Holm et al., 1980). Rate constants for reactions of
cacodyllc add with the oxldants present In the atmosphere are not available.
The fate of atmospheric cacodyllc add may be partially assessed from
the monitoring data. An abstract of a Japanese publication (Tanaka et al.,
1984) reported that cacodyllc add was found In the partlculate phase but
not In the gas phase. All the organic arsenic was present In particles of
aerodynamic diameter <4 ym, with a concentration maximum at 0.5 »m.
Therefore, cacodyllc acid 1n the atmosphere 1s expected to be present as
Inhalable particles. Besides oxidation, some of the partlculate cacodyllc
add may be removed from the atmosphere by dry and wet deposition.
0128d
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2.2. WATER i
The fate of cacodylk acid In water at environmental concentration
levels with respect to abiotic reactions, such as hydrolysis, oxidation and
reduction, and photolysis has not been well studied. It 1s known that this
compound will not oxidize chemically under mild oxidation conditions (Braman
and Foreback, 1973), nor does 1t contain any functional group that Is amen-
able to hydrolysis. Therefore, 1t could be resistant to abiotic reactions
1n water. The blotlc oxidation, reduction and mineralization of cacodyllc
add 1n water was reported by a few authors. In a model aquatic ecosystem
study, cacodyllc add formed arsenate, arsenite, C00 and probably alkyl-
c. \
arslne. Arsenate was the predominant form after 59 days (Lemmo et a!.,
1983); however, the conversion rates of cacodyllc add to arsenate 1n model
aquatic systems was estimated at 0.067-0.404% per day! If first-order •
kinetics 1s assumed, the half-life of the oxidation process Is 6-35 months
(Holm et al., ;1980). In a sediment Incubation experiment, the blodegrada-
tlon of cacodyllc add proceeded with the formation of Inorganic arsenic.
The rate of cacodyllc add degradation could be explained almost exclusively
on the basis of arsenate formation (Holm et al., 1980). The degradation
half-life was -30 days. According to Andreae (1979), the uptake of arsenate
from the photic region of the ocean by plankton 1s followed by conversion of
Inorganic arsenate to methylated spedes by an unknown mechanlsm(s).
Biological demethylatlon of methylarsenlcals to Inorganic arsenate also
occurs by unknown mechanisms. The concentrations of arsenic species In
water are controlled primarily by the relative rates of biological
reactions, superimposed on physical transport processes. Blomethylatlon of
arsenic does not occur In the Interstitial waters of aerobic and anaerobic
:u \.
sediments (Andreae, 1979).
0128d -5- 02/01/89
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I
The loss of cacodylVc acid from direct volatilization will be Insignifi-
cant because the compound Is Ionic. (The loss of small amounts of the
compound from volatilization of methyl arslnes formed as a result of
blotransformatlon will occur.) Some loss of cacodyllc add from sorptlon
onto sediments will occur. Based on a water solubility value given In
Section 1.2. and the regression equation, log K = -0.55 log S + 3.64
(Lyman et al., 1982), a K value of 3 can be estimated. This would
predict a negligible sorptlon of cacodyllc add on sediments; however, the
sorptlon equation 1s not valid for cacodyllc acid where the sorptlon is due
primarily to 1on1c Interaction. The sorptlon behavior of cacodyllc add on
soils and sediments was found to depend on the clay content, more specific-
ally, the aluminum and Iron content of the clay, and on the pH of the
medium. The dependence on pH 1s probably due to the dependence of the
dissociation equilibrium of cacodyllc add on the pH (Mauchope and McDowell,
1984). Sorptlon of arsenlcals on sediments follows a Langmulr Isotherm
pattern. Among the arsenlcals, arsenate Is sorbed most strongly, followed
by monomethyl arsonlc add, arsenlte and cacodyllc acid. Therefore, the
sorptlon of cacodyllc add on sediments Is weakest of all the arsenlcals
(Holm et al., 1980; Lemmo et al., 1983).
The bloaccumulatlon of alkyl arsenlcals was studied In a model ecosystem
(Isensee et al., 1973). The BCFs 1n dried tissues were 1635 for algae,
Oedogonlum cardlacum; 1658 for daphnla, Daphnla magna; and 21 for fish,
Gambusla affinis. Indicating that lower food chain organisms bloconcentrated
more cacodyllc add than did higher food chain organisms.
2.3. SOIL
The fate of cacodyllc add 1n soil has been studied more extensively
than Us fate In air and water. Under aerobic conditions, cacodyllc add
0128d -6- 03/13/89
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primarily degrades by two mechanisms, one leading to the formation of
arsenate and the other to volatile organic arsenlcals, probably dlmethyl-
arslne or an oxide. A small amount of cacodyllc acid may be lost as a
result of complete mineralization to C0_ and arsenate (Woolson, 1976).
Odanaka et al. (1985a), however, reported almost exclusive detection of
Inorganic arsenic (species not identified) from aerobic degradation of two
soils. Evolution of volatile arsenic compounds was found to be a relatively
minor route. The rate of aerobic degradation was also found to depend on
soil type. For example, the aerobic degradation of cacodyllc acid was -90%
i
In 6 weeks In two soils, but was <5% In another soil (Odanaka et al.,
1985a). Whether the difference In the degradation rate 1s due to the
difference In some physical characteristics of the soil or to the presence
of a higher number of degrader/accllmatlzed microorganisms Is not clear.
Under anaerobic conditions, one group of authors reported volatile organo-
arsenlcals as the primary degradation product 1n soil (Woolson and Kearney,
1973; Woolson,. 1976), while another group (Odanaka et al., 1985b) reported
Inorganic arsenic as the primary product. In the experiments of Woolson and
Kearney (1973)1 the anaerobic degradation of cacodyllc acid 1n three soils
produced on the average 61% volatile organlc-arsenlcals In 24 weeks.
Odanaka et al. (1985b), however, reported almost 90% degradation of
cacodyllc acid1 to Inorganic arsenic in two flooded soils and almost no
degradation 1n; a third soil after 6 weeks of Incubation. Neither group
reported detection of arslne gas from the degradation of cacodyllc acid In
soils.
The sorptlon of cacodyllc add by soil was found to depend on the clay
and Iron oxide content of the soil; however, the sorptlon capacity of
cacodylate 1s lower than both arsenate and methylarsonate (Wauchope, 1975).
0128d -7- 02/01/89
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Cacodyllc acid can form Insoluble compounds with aluminum 1n soil and a
certain part of sorbed cacodyllc add may remain fixed In soil 1n an
occluded form (Woolson, 1976). Leaching of this compound from field soils,
particularly from sandy soils, may be more prevalent than the leaching of
arsenate and methylarsonate.
The level of cacodyllc add In cotton seeds collected between the second
day and harvesting time following application of the herbicide was nearly at
the preappHcatlon level. It was concluded that there was no detectable
transport or translocatlon of the herbicide within the plant as a result of
application (Hastradone and Woolson, 1983).
2.4. SUMMARY
The fate of cacodyllc add in the atmosphere Is not well understood. It
Is likely to be present In the participate phase of aerodynamic diameter of
<4 jim, with a concentration maximum at aerodynamic diameter of 0.5 van
(Tanaka et al., 1984). The oxidation of partlculate cacodyllc add by H0»
In the atmosphere Is likely, but the kinetic data that will allow the
estimation of Us residence time In air for this reaction are not
available. Some of the partlculate cacodyllc add may be removed by dry and
wet deposition. Since this compound Is quite stable towards oxidation/
reduction (Braman and Foreback, 1973), 1t may have a long residence time 1n
the air, which will allow H to transport long distances. No data were
found In the literature to Indicate that cacodyllc acid will undergo
significant abiotic reaction 1n water. Blodegradatlon of cacodyllc add In
water and sediment has been reported, and arsenate 1s the primary product,
although small amounts of arsenlte, C02 and probably alkylarslnes are also
formed. The half-life of this compound In water 1s >1 month (Lemmo et al.,
1983; Holm et al., 1980). Significant volatilization of this compound from
0128d -8- 03/13/89
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water Is not expected. Sorptlon onto sediments will cause some cacodyllc
acid In water to be lost, and the sorptlon will Increase with Increase of pH
and aluminum arid Iron content of the sediment; however, the sorptlon of this
compound on sediments Is weakest of all the arsenlcals (Holm et al., 1980;
Lemmo et al., 1983). B1oconcentrat1on of this compound 1n lower food chain
organisms will ,be significantly higher than In higher food chain organisms.
Therefore, significant bloconcentratlon In edible fish may not occur
(Isensee et ai., 1973). In aerobic soils, cacodyllc acid will undergo
blodegradatlon with the formation of primarily arsenate. The blodegradatlon
rate may depend on the nature of soil, with 90% degradation observed In two
soils compared :w1th <55t degradation 1n another soil (Woolson, 1976; Odanaka
et al., 1985ah Conflicting data are available on the degradation products
In soils under anaerobic conditions. While one group of researchers
{Woolson and Kearney, 1973; Woolson, 1976) reported organoarsenlcals as the
primary product, another group (Odanaka et al., 1985b) reported Inorganic
arsenic as the primary product. The sorptlon of this compound In soil will
depend on clay .and Iron oxide content of the soil, but the sorptlon capacity
may be lower than both arsenate and methylarsonate. Therefore, leaching of
this compound particularly from sandy soils may be more prevalent (Uauchope,
1975; Woolson, 1976). No detectable transport or translocatlon of the
herbicide within cotton seeds was observed as a result of application In a
cotton field (Mastradone and Woolson, 1983).
0128d -9- 03/13/89
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3. EXPOSURE
Limited monitoring data on the ambient levels of cacodyllc add 1n any
environmental medium are available. More than 99% of the arsenlcals 1n the
atmosphere over various sites In Japan was reported to be present as
Inorganic arsenic. The concentration of organic arsenlcals In air partlcu-
late matter at these sites was 30-270 pg/m3. Most of the organic arsenic
was In the form of cacodyllc acid, and no gaseous organic arsenic was found
In the atmosphere. Organic arsenlcals were present as fine particles, with
a concentration peak at an aerodynamic diameter of 0.5 ^m {Tanaka et al.,
1984). The levels of cacodyllc acid In the air over an unpolluted Island
and over a rural Inland area In Japan were \n the range of 7 and 71 pg
arsenlc/m3. A seasonal variation 1n airborne cacodyllc acid was also
observed, with maximum levels during summer when the biological activity on
aquatic and terrestrial media were maximum, and minimum levels during the
winter (Mukal et al., 1986).
The concentrations of cacodyllc acid In a wide range of fresh natural
waters Including lakes, rivers and ponds In and around Tampa, FL, were In
the range <0.02-0.62 yg/l. Saline waters at several locations along the
shores of Tampa Bay contained 0.2-1.0 yg/i of cacodyllc acid. The
concentration of this chemical 1n well water at a remote camping site near
Wlthlacocochee River 1n Florida was 0.? pg/i. No cacodyllc add was
detected (detection limit of 0.02 wg/i) in lampa tap waters (Braman and
Foreback, 1973). Lake, river and pond waters from the Molra River area In
Ontario, Canada, which flows through an abandoned smelter (still emitting
high levels of arsenic from Its watershed), contained 2.3-3.3 ug/8. of
cacodyllc add (Hong et al., 1977). \
0128d -10- 02/01/89
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Cacodyllc add levels In other media have been reported. Samples of
seashells, bir.d eggshells and a sedimentary rock contained unreported
amounts of the compound (Braman and Foreback, 1973). Urine samples of
(presumably unexposed) humans contained an average 15 vq/i of cacodyllc
acid, constituting an average of 6654 of the total urinary arsenic excretion
(Braman and Foreback, 1973). In forestry workers, the urinary cacodyllc
add level In 11 weeks ranged from 24-172 »ig/24 hours compared with a
i
range of 26-73 yg/24 hours during the same period for nonexposed workers.
Based on this analysis, It was concluded that urinary excretion of arsenic
correlates well with and constitutes an Index of exposure; blood arsenic
levels, however, correlated poorly with exposure (Wagner and Heswlg, 1974).
The same conclusion was reached by Morris (1985), who detected levels of
arsenic as high as 1.8 mg/8. 1n urine of exposed forestry workers,
corresponding to an exposure of >0.036 mg arsenic/kg bw/24-hour day In
applicators of monosodlum methanearsonate and cacodyllc acid.
3.1. SUMMARY
Limited monitoring data on the ambient levels of cacodyllc acid 1n any
environmental medium are available. The concentration of this compound In
air sampled at sites In Japan ranged from 7-270 pg/m3. A seasonal varia-
tion 1n airborne cacodyllc add levels was observed, with maximum levels
during summer when the biological activities In aquatic and terrestrial
media were maximum (Tanaka et al., 1984; Mukal et al., 1986). The concen-
trations of this chemical In a few surface waters sampled In the United
States were <0.02-1 tig/I, but 1t was not detected In Tampa tap waters
{Braman and Foreback, 1973). Urine samples of presumably unexposed people
01280
-11-
03/13/89
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averaged 15 pg/a, with values as high as 1.8 mg arsenlc/i 1n appli-
cators using monosodlum methanearsonate and cacodylic add. The later level
corresponds to an exposure of >0.036 mg arsenic/kg bw/24-hour day (Braman
and Foreback, 1973; Norrls, 1985).
0128d -12- 02/01/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC; TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Oliver et al. (1966) assessed the
toxiclty of cacodyllc add to mosquito fish, Gambusla aff1n1s. and southern
toad tadpoles, Bufo terrestrls. Tests were conducted In 6 a Erlenmeyer
flasks each containing 4 a of test solution with 30 fish and 50 tadpoles
1n each flask.. Treatments were not replicated. No mortality was reported
among fish and; tadpoles exposed to 100 ppm cacodyllc add after 48-72 hours,
and 100% mortality was reported among fish and tadpoles exposed to 1000 ppm
cacodyllc acid after 48 hours.
Mayer and Ellersieck (1986) reported the results of studies assessing
the acute toxiclty of cacodyllc add to one spedes of fish and two crusta-
cean spedes. Blueglll sunflsh, Lepomls macrochlrus. were exposed to 10054
technical material of cacodyllc acid In soft water (44 mg/a as CaCO-) at
18°C under static conditions. Under these conditions, the 24- and 96-hour
LC5Qs (and 95% confidence limits) for bluegllls were 21 (19-23) and 17
mg/a (15-19),: respectively. Studies with the amphlpod, Gamma r us
fasdatus. were conducted under static conditions at 15°C 1n both soft (44
mg/a as .CaCOj) and hard water (272 mg/a as CaC03). The 96-hour
LC,.gS (with 95% confidence limits) for amphlpods under these conditions
were 140 (40-486) and 135 mg/Sl (80-227), respectively. The 96-hour LC™
(with 95% confidence limits) for shrimp, Palaemonetes kadlakensls. exposed
to cacodyllc add at 21°C In hard water (272 mg/i as CaC07) under static
O
conditions was 28 mg/a (14-58).
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY ~ Cockell and Hilton (1985) reported that
cacodyllc add did not produce sublethal responses In rainbow trout. Sal mo
0128d -13- 02/01/89
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qalrdneM. fed 1600 ppm 1n the diet over an 8-week period, Sublethal
endpolnts monitored Included feed refusal, growth depression and Impaired
feeding efficiency. Cockell and Hilton (1988) reported a dose-response
relationship between the cacodyllc acid exposure rate and the levels of
carcass arsenic residues. Residue levels rose from 3.0-11.4 yg As/g
carcass as the level of arsenic 1n the diet Increased from 163-1497 \ig
As/g diet. The Investigators also reported that the NOEC for cacodyllc add
1n juvenile rainbow trout was >1497 ^g As/g diet.
4.1.2.2. BIOACCUMUWTION/BIOCONCENTRATION -- Isensee et al. (1973)
monitored the uptake of cacodyllc acid by a variety of species 1n a static
laboratory aquatic ecosystem. Experiments were conducted In 4 a of test
solution In all glass aquariums at 22il°C. Test organisms Included a
filamentous algae, Oedogonlum cardiac urn, daphnlds, Daphnla maqna. snails,
*
Physa sp., mosqultoflsh, Gambusla afflnls. and a variety of diatoms,
protozoa and rotifers. Organisms other than fish were allowed to adjust to
tank conditions for 5 days before Introducing the test material. F1sh were
added 29 days after the addition of test material. The study duration was
32 days. B1oaccumulat1on ratios were based on the levels of 14C In
environmental samples and calculated from the ratio of cpm/mg tissue to
cpm/mg of solution. Bloconcentratlon ratios for algae, daphnlds, snails,
and fish were 1635, 1658, 110-419 and 21, respectively.
Schuth et al. (1974) monitored the uptake of cacodyllc acid by a variety
of species 1n static laboratory aquatic mlcroecosystems for 20 days. Three
different soils were treated with 15 ml of an aqueous solution containing
19 yC1 of [14C]cacodyl1c add and 244 mg of unlabeled cacodyllc acid and
mixed with an additional 10.9 kg of the same soil. After treatment, 11.4 kg
of soil was layered on the bottom of separate 110-1 all-glass aquarium
0128d -14- 03/13/89
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tanks, flooded' with 80 j. of distilled water and allowed to equilibrate for
1 week. Aeration was Initiated when organisms -were added to the tanks.
Organisms Included catfish, Ictalurus punctatus. crayfish, Procambarus
clarkl. daphnids, D. magna. snails, Physa sp., filamentous algae, 0.
cardlacum, and duckweed, Lemna minor. Concentrations of cacodyllc add In
organisms and environmental samples were determined by analysis for 14C
and arsenic by a variety of methods.
The Investigators reported bloconcentratlon ratios of cacodyllc add
based on 14C (concentration In tissues/concentration in water) ranging
from 80-298, 52-88, 51-147, 22-26, 0.8-2.8 and 0.5-2.0 for algae, duckweed,
daphnids, snails, catfish and crayfish soft tissue, respectively. Estimates
of bloconcentratlon ratios based on levels of arsenic In tissues and water
samples were comparable with those determined by 14C. Bloconcentratlon
ratios calculated for these organisms In a second experiment were much
higher than previously observed. Investigators reported bloconcentratlon
ratios of cacodyllc add based on 14C for the second 20-day study ranging
from 163-27,000, 174-1301, 4.3-1050, - 2.1-275 and 3.0-13.6 for algae,
duckweed, snails, catfish and crayfish soft tissue, respectively. Estimates
of bloconcentratlon ratios based on levels of arsenic In tissues and water
samples In the second study were much lower than those estimated from 14C,
but comparable with those estimated in the first study. The Investigators
speculated that the 14C of cacodyllc add was Incorporated into a variety
of degradation products.
Stary et al. (1982) assessed the accumulation of cacodyllc acid by
gupples, Poedlla retlculata. from both water and food. F1sh kept in
solutions of radlolabeled 74As-cacodyl1c add (10~s mol/fc) for several
days showed only negligible levels of radioactivity. 74As-cacodyl1c
0128d -15- 03/13/89
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acid-contaminated fish food was given to fish for 1-2 hours before fish were
washed with distilled water and transferred to clean containers and fed
uncontaralnated food for the duration of the study (Stary et a!., 1980).
Radlolabeled cacodyUc add consumed by fish through the diet was lost 1n a
blphaslc manner. The Initial 95K of activity had a half-life of 0.3^0.1
days, with the remaining activity decreasing by SOX each 35^5 days.
j
The calculated BCF for cacodyllc acid based on the log K value of
-1.78 (see Section 1.2.) and the regression equation, log BCF = 0.76 log
K -0.23 (Lyman et al.t 1982), Is estimated to be 0.03. This value does
not agree with experimental BCF values of 100-1000 generated 1n the studies
cited above, although the experimental values were based on 14C levels.
The calculated BCF supports the speculation that cacodyllc acid degrades
rapidly and should not bloaccumulate significantly 1n aquatic organisms. A
calculated BCF based on a water solubility of 667,'000 mg/4 for cacodyllc
acid (see Section 1.2.) and the regression equation, log BCF = 2.791-0.564
log S (Lyman et al., 1982) 1s estimated to be 0.32. This value also
supports the conclusion that cacodyllc acid Is not likely to accumulate 1n
tissues of aquatic organisms, although the bloaccumulatlon of arsenic from
the In vivo degradation of cacodyllc acid 1s possible.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY ~ Oliver et al. (1966) assessed the effect of
cacodyllc add on productivity of pond algae. Six 300 ml samples of pond
water laden with algae and treated with concentrations of cacodyllc acid
ranging from 5.53 (equivalent to 2 Ibs/acre) to 162 ppm. Productivity was
assessed by the presence of chlorophyll, as determined by spectrophotometrlc
methods. Concentrations of cacodyllc add >55.3 ppm (equivalent to 15
Ibs/acre) resulted 1n a 50% reduction In productivity after 48 hours.
0128d -16- 02/01/89
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Roederer (1986) demonstrated that exposure of the freshwater golden
brown alga, Pj t er ijj oc h r omo n a s malhamensjs. to 35 mM of the sodium salt of
cacodylic acid blocked cytokinesis in these algae thereby Inhibiting
reproduction.
4.1.3.2. BIOCONCENTRATION — Stary and Kratzer ('1982) assessed the
uptake of cacodylic acid by the alga, Chlorella kessleri. Accumulation was
i
expressed by the cumulation factor F calculated from the equation F = A /
(A N V ), where A = radioactivity of the algae, A = radio-
Ml u a a IU
activity of the medium, N = number of algal cells (cm3) and V - mean
a a
geometric volume of one cell (cm3). Experiments were conducted for 3
hours at 22°C. The investigators reported that equilibrium was achieved
after 1 hour and was pfi Independent. The log F value for cacodylic acid was
reported as ~1,25; the log F values for arsenic acid and methylarsonlc acid
were -2.5 and 2, respectively.
4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to cacodylic acid could not be located in the
available literature as cited in Appendix A.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Del Rlvero (1981) Investigated the potential of
cacodylic acid as a mollusdclde for snails, Helix aspersa and Theba pisana.
Baits were prepared from the commercial product Phytar 560 (29.8% active
Ingredient of cacodylic acid) with medium size wheat bran and water but
without attractants. H. aspersa were given baits at 28"C with percentages
of active ingredients of 1.5, 1.9 and 2.4. Respective mortality levels were
42.5, 32.5 and 67.5%. Experiments with T. pisana were conducted at 28°, 20°
and 23°C and three levels of active Ingredient, 1.5, 1.9 and 2.4%.
Mortality levels In all experiments ranged from 67.5-97.5%.
0128d -17- 02/01/89
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4.2.2. Effects on Flora. Pertinent data regarding the effects of
cacodyllc acid on flora could not be located In the available literature as
cited In Appendix A.
4.3. FIELD STUDIES
Oliver et al. (1966) assessed the effects of cacodyllc acid on sandhill,
hammock and grassland communities. Cacodyllc add was applied to plots
along a survey line passing through a sandhill community at rates of 2, 6
and 30 Ibs/acre. Effects on vegetation were noted after 1 month. An uneven
distribution of vegetation In the hammock community required that cacodyllc
acid be sprayed on Individual plants at rates corresponding to 2 and 30
Ibs/acre. Effects on treated plants were assessed after 2 weeks. Three 1
rod square plots and 2-10 foot square plots of grassland were treated with
cacodyllc acid application rates of 2, 15 and 30 Ibs/acre and 6 and 6 Ibs/
acre, respectively. Effects on grasses were assessed after 2 and 4 weeks.
The Investigators reported that an application of 2 Ibs/acre to the
sandhill community did not result 1n a modification of the community, but
that repeated applications of cacodyllc add at this rate would modify the
plant community structure. An application of 30 Ibs/acre resulted In a
complete kill among sandhill flora. It did not appear likely that sandhill
fauna would be affected directly by field concentrations of cacodyllc add,
but that changes In the structure of the plant community would Indirectly
affect the faunal community. The Investigators speculated that a completely
denuded sandhill community would require 20-30 years to recover. Heavy
rains minimized the effects of cacodyllc add on flora of the hammock
community, but the Investigators reported that plants treated with 30
Ibs/acre exhibited brown leaves or were defoliated within 2 weeks.
Application of cacodyllc add to grassland plots at concentrations of 2, 15
and 30 Ibs/acre resulted In 50, 75-90 and 100% kill of grasses. Recovery
0128d -18- 03/13/89
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of treated plots was Inversely related to the application of cacodyllc
acid. Recovery of 2 Ibs/acre-treated plots was nearly complete, while
little recovery was observed In 30 Ibs/acre-treated plots 1 month after
treatment.
4.4. AQUATIC RISK ASSESSMENT
Insufficient data prevented the development of a criterion for the
protection of' freshwater life exposed to cacodyllc acid (Figure 4-1).
Development offa freshwater criterion requires the results of acute assays
with a salmon1d fish species, a chordate other than blueglll sunflsh, an
Insect, a non-'Athropod/Chordate and a new Insect or phylum representative.
Results from chronic assays required for the development of a freshwater
criterion Include assays with two species of fauna and at least one flow-
through bloconcentratlon study. There were no data available regarding the
effects of exposure of marine fauna or flora to cacodyllc acid, precluding
the development of a saltwater criterion.
4.5. SUMMARY
The 96-hour LC5ns for mosqultoflsh and southern toad tadpoles were
estimated to be between 100 and 1000 mg/i (Oliver et al,, 1966). The
96-hour LC5Qs for bluegllls, amphlpods and shrimp were 17, 140 and 135 and
28 mg/l, respectively (Mayer and Ellersleck, 1986). Cockell and Hilton
(1988) reported that the NOEC for cacodyllc acid In juvenile rainbow trout
was >1497 Pg As/g diet. Mortality was 42.S-97.5X In terrestrial snails
given baits containing 1.5-2.4X cacodyllc add.
Uptake of cacodyllc add by organisms In laboratory aquatic ecosystems
was greatest In, algae, aquatic plants and daphnids, followed by snails, fish
and crayfish. Bloconcentratlon ratios In these organisms ranged from a high
of -1650 for algae and daphnlds to ~1-15 for fish and crayfish (Isensee et
0128d -19- 03/31/89
-------
1
Farm iy . . - " '
i nordate
-------
al., 1973; Schuth et al.. 1974). Stary et al. (1982) demonstrated that
uptake of cacodyllc acid by gupples from water was negllble after a few days
of exposure and that 95% of the tissue residues from Ingested cacodyllc acid
was depurated, within hours. Calculated BCFs estimated from log K and
. ow
water solubility were <1, suggesting that cacodyllc acid was not Hkely to
accumulate In the tissues of aquatic organisms.
Algal productivity was reduced by 50% 1n the presence of 55.3 ppm
cacodyllc acid, for 48 hours (Oliver et al., 1966). Reproduction 1n brown
algae was Inhibited by 35 mM of the sodium salt of cacodyllc acid (Roecierer,
1986).
Field studies revealed low to moderate effects on vegetation from three
terrestrial communities exposed to 2 Ibs/acre of cacodyllc acid. Treatment
levels of 30 Ibs/acre were highly detrimental to the survival of vegetation
In those communities (Oliver et al., 1966).
0128d
-21-
03/31/89
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5. PHARMACOKINETICS
5.1. ABSORPTION
Stevens et al. (1977) compared the absorption of cacodyllc add follow-
ing Intravenous, Intratracheal and oral administration of the compound.
Intravenous absorption was assumed to represent 100%. Lung absorption was
determined by administering a single 78 mg/kg dose of 14C-labeled
cacodyllc acid In 100 yH of aqueous solution to young adult male Sherman
strain rats Intratracheally by a cannula Inserted between the 4th and 5th
trachea! rings. Following dosing, lungs and trachea were excised at 0, 5,
10 and 20 minutes and assayed for 14C-cacodyl1c add equivalent.1 The
amount absorbed was estimated as the difference between the amount admin-
istered and the amount remaining In the excised organs. Results showed that
lung absorption was rapid and almost complete; 5% remained 1n the lung 15'
minutes posttreatment, and the half-time for absorption was estimated at 2.2
minutes. The plasma 14C-concentrat1on vs. time curve resulting "from
Intratracheal administration of 33 jig 14C-cacodyHc acid was similar to
that generated following Intravenous Injection, with maximal concentration
observed at 5 and 10 minutes, providing further evidence of the rapid
absorption rate characteristic of this route. These data were derived from
sequential samples of blood collected from the Interorbltal sinus (number of
animals used was not reported). Percent absorption from the lungs 24 hours
after an Intratracheal dose of 33 yg 14C- and 13.8 wg 74As-labeled
cacodyllc acid was 92%, which was determined by combining amounts retained
In body tissues {-24% of dose), excreted In urine (~60%), and 1n feces
(-8%). In a separate part of this study, cumulative 14C02 expiration
was measured over 24 hours following a single Intratracheal dose of
14C-cacodyl1c acid. Expired 14C02 accounted for only 0.0069% of the
0128d -22- 03/31/89
-------
dose, Indicating that failure to recover and measure 14CO_ 1n the
estimation of .lung absorption described above had no discernible effect on
the result.
In another part of the same study using male Sherman rats, GI absorption
of a single 0.5 ma gavage dose of 33 yg 14C- and 6.9 yg 74As-
cacodyllc acid dissolved In water was estimated by sacrificing the rats at 4
hours posttreatment and assaying the digestive tract for equivalent percent
of administered dose remaining. A 61 absorption half-time of 248 minutes
was estimated. Plasma levels following absorption from the GI tract peaked
at -1 hour. From other similarly treated rats the Investigators estimated
that 66% of the dose was absorbed at 24 hours, with -32% retained In body
tissues and -25% excreted In urine. About 31% was eliminated In the feces,
of which only a minute fraction appears be of biliary origin (biliary
secretion at 2 hours was 0.226% of dose). Since the amount of cacodyllc
add eliminated by the lungs as 14CO_ was very minor (equivalent to
0.13% of a 200i mg/kg oral dose of 14C-cacodyUc acid 1n 24 hours), 1t had
little effect upon absorption estimations.
Excretion data on hamsters and mice support the estimates of GI absorp-
tion determined In rats. Yamauchl and Yamamura (1984) administered
cacodyllc acid at 40 or 50 mg/kg by gavage to male Syrian golden hamsters
and measured total arsenic excretion In urine and feces over a 5-day collec-
tion period. When corrected for pretreatment values, total urinary excre-
tion accounted ;for 48.9% of the dose, with 92% of that recovered within the
first 24 hoursi Fecal excretion accounted for 36% of the dose. Marafante
et al. (1987) administered 74As-cacodyl1c add by gavage to male NHRI mice
and male hamsters at 40 mg As/kg and measured radioactivity In urine and
feces over a 48-hour collection period. From hamsters, 41.2% of the dose of
0128d -23- 03/31/89
-------
radioactivity was recovered from the feces and 56.3% from the urine (total
recovery = 97.5%), while 29.2% was recovered from the feces and 67.6% from
the urine In mice (total recovery = 96.8%).
In one male volunteer given a single oral dose of cacodyllc add of 0.1
mg As/kg, urinary excretion of cacodyllc acid and a metabolite accounted for
-84% of the dose In 3 days (Harafante et al.f 1987). These data suggest
that cacodyllc add Is well absorbed by the human GI tract. Urinary excre-
tion of 75% of the arsenic of an oral dose (500 jig As) of sodium dlmethyl-
arslnate In 4 days In four volunteers (Buchet et al., 1981) Is further
support for a GI absorption factor for humans of at least 80%.
Hwang and Schanker (1973) studied the J_n vivo rate and mechanism of
Intestinal absorption of cacodyllc add In Charles River-derived male rats.
One ma of a 5 mM solution of cacodyllc add In modified Krebs-Rlnger
phosphate solution (pH 6.7) was Injected Into the Intestinal lumen following
surgical placement of ligatures that blocked conduction by the lumen, but
did not occlude major blood vessels. Intestinal cacodyllc acid content was
assayed over a 4- to 5-hour absorption period. Absorption data over this
time fit a first-order process, with a rate constant of 0.207 hour"1 and a
half-time of 201 minutes, a value not appreciably different from that 1n the
Stevens et al. (1977) study discussed previously.
The mechanism of absorption was determined by Hwang and Schanker (1973)
to be by a nonsaturable transfer process, probably passive diffusion.
Increasing the concentration of administered compound by 100-fold did not
yield evidence of saturation. By comparing absorption rate coefficients
with molecular weights of two other organic arsenlcals, 1t was shown that
molecular size does not Influence absorption rate, thereby Indicating that
movement by aqueous channels (membrane pores) was an unlikely pathway.
0128d -24- 03/31/89
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5.2. DISTRIBUTION
Stevens et al. (1977) studied the tissue distribution following both
high and low doses of cacodyllc add. High-dose distribution of radio-
activity was studied In young adult male Sherman rats sacrificed at 0.117,
0.25, 1, 24, 72 and 168 hours after -Intravenous dosing with 14C-cacodyHc
acid 1n aqueous solution at 200 mg/kg (0.5 ml/150 g bw). Blood, lung,
liver, brain,t spleen and kidney concentrations, 1n terms of the
14C-cacodyl1c acid-equivalent, were measured and reported as a percent of
the dose recovered. Additional rats were dosed similarly, and whole blood
was collected at selected Intervals from the IntraorbHal sinus and assayed
for blood clearance by separating plasma and erythrocytes, then counting the
radioactivity of each. The plasma concentration vs. time plot showed
trlphaslc elimination with half-times of 0.014 and 3.42 hours, and permitted
estimation of an apparent, volume of distribution of 15,3 mi. At 15
minutes, the highest tissue concentrations from this high-dose Intravenous
test were In whole blood (12.5%) and liver (9.81%), followed by kidney
(2.98%), lung (0.61%), spleen (0.20%) and brain (0.08%). Concentrations
were reduced 1n all tissues except blood (14.8%) at >1 hour postdosing.
Low-dose distribution In adult male Sherman rats was measured by giving
a fixed volume of 0.5 aqueous solution containing 33 yg of 14C-cacodyl1c
acid and a varied amount ranging from 3.47-13.99 |ig 74As-cacodyl1c acid
(adjustment of amount was required because of Its short half-life). The
dose was given Intravenously, Intratracheally or orally. A comparison of
whole blood radioactivity concentration-time curves revealed higher concen-
trations ~8 hours after oral dosing than by the other two routes. Whole
body retention at 24 hours was slightly greater after oral administration
0128d -25- 03/31/89
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(31.8% dose) than after Intratracheal (24.3%) or Intravenous {20.5%) admin-
istration. Contrast between whole blood and plasma levels showed that
cacodyllc acid was cleared rapidly from the plasma, but became bound to
erythrocytes. . The Investigators suggested that the rat RBC has a high
affinity for cacodyllc acid, but that there Is considerable Intraspecles
variation with regard to the affinity of the RBC for cacodyllc add.
Half-times for whole blood clearance were 90 days after Intravenous, 76 days
following Intratracheal and 90 days after oral dosing.
No significant differences In the percent dose recovered from tissues
were found following Intravenous administration of high- and low-dose
levels, except for proportionally lower levels In the liver and higher
levels In the kidney 15 minutes after dosing at the lower dosage level.
This Indicates Uttle or no dose dependency on tissue distribution of •
cacodyllc add over the dose range tested. Table 5-1 shows comparative
low-dose tissue levels for the three routes at 105 days posttreatment.
Residues, although slight In some cases, remain In all tissues. Significant
route-dependent differences In tissue levels noted at this time were few:
tissue levels 1n the spleen and kidney were higher after Intratracheal
administration than after Intravenous administration, and oral dosing led to
higher levels In the liver than did Intravenous Injection.
Pregnant CO rats were treated with a single 33 ug dose of
1AC-cacodyl1c add to study placenta! transfer (Stevens et a!., 1977).
Levels of radioactivity were measured at 24 hours after treatment on day 21
i
of gestation 1n maternal and fetal whole blood, brain, kidney and liver.
The results Indicated that cacodyllc add crosses the placenta readily and
/•
distributes to fetal tissues at concentrations similar to those of the dam.
Exceptions to this were the brain (lower levels) and kidney (higher levels)
In the fetus (p>0.05).
0128d -26- 03/31/89
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TABLE 5-1
Tissue Distribution of 14C 105 Days After Administration of
14C-CacodyHc Add to Adult Male Sherman Rats by Various Routesa»b
ng/g Fresh Tissue
Tissue
Intravenous
Intratracheal
Oral
Heart
Lung
Spleen
Liver
Kidney
Brain
Testes
Muscle
4.86
16.8
15.8
r
5.86
5.75
1.66
1.22
0.88
± 1.55
+ 1.22
± 2.87
± 0.66
* 0.33
± 0.22
± 0.22
± 0.22
(0
(0
(0
(0
(0
(0
(0
(0
.02)c
.09)
.03)
.19)
.04)
.01)
.02)
.47)
7.39
20.2
41.2
5.58
13.9
2.84
1.28
0.85
± 1.70
± 5.40
i 7.81d
± 2-56
± 2.70d
1 1.28
i 0.14
± 0.28
(0
(0
(0
(0
(0
(0
(0
(0
.02)
.07)
.07)
.29)
.08)
.01)
.01)
.33)
8.47
24.8
31.5
15.7
9.68
1.82
1.69
0.85
± 1.33
± 5.93
± 7.87
i 5.69
1 1.82
i 0.48
i 0.12
* 0.36
(0.05)
(0.11)
(0.06)
(0.54)
(0.07)
(0.01)
(0.02)
(0.45)
aSource: Stevens et al., 1977
bAll rats were given a single 33 yg dose of "C-cacodyllc acid by
either of three routes 1n addition to 3.5 vg Intravenously, 13.8 v>9
Intratracheally and 6.9 yg orally of 74As-cacodylU add.
cMean percent of total dose per tissue In parentheses (n=4).
^Difference from Intravenous dose at p<0.05.
0128d
-27-
03/31/89
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\
Yamauchl and Yamamura (1984) administered a single oral (gavage) dose of
50 rag/kg cacodyllc add to male Syrian golden hamsters (Section 5.3.), and
measured levels In blood, brain, hair, kidney, liver, lung, muscle, skin and
spleen at several time points up to 120 hours after treatment. The compound
was found In all tissues, reaching a peak 1n concentration 6 hours post-
^
treatment 1n all tissues except hair. Highest levels at 1 hour were found
1n lung > spleen > kidney > liver > skin > muscle - brain. Concentrations
of cacodyllc add decreased to amounts equivalent to controls within 72
hours posttreatment 1n all tissues except the hair and lung. This differs
somewhat from findings 1n the rat {Stevens et al., 1977), suggesting to the
authors of the current study that U) vivo retention varies between species.
5.3. METABOLISM
Yamauchl and Yamamura (1984) studied the metabolism of cacodyllc add In
male Syrian golden hamsters. A single gavage dose of 40 or 50 mg/kg bw
(vehicle unspecified) was administered by stomach tube, and the metabolites
were measured 1n tissues and excrement. Methylarsonlc add values slightly
above pretreatment levels were observed 1n the brain, kidneys, lung and
urine. Inorganic arsenic was slightly, but significantly, Increased over
control values 1n the blood, kidneys and lungs. Also, the excreted amounts
of Inorganic arsenic In urine and feces were 11.9 tig greater than the sum
of pretreatment values plus Inorganic arsenic present as a contaminant In
the test sample of cacodyllc add. This suggested the possibility that a
small amount of In vivo demethylatlon occurs 1n hamsters.
Marked elevations In the levels of a form of TMA compound were found In
the liver, kidneys, lungs, muscle and brain, from 1 hour posttreatment (24
0128d -28- 03/31/89
-------
hours In urine, which was the first sample time for this body fluid) to the
end of the observation period, 120 hours. TMA concentration was highest In
the liver. These observations suggest that substantial methylatlon of
cacodyHc add'occurs In. vivo In the hamster, and that the liver 1s the site
>
of this metabolic pathway. The TMA blosyntheslzed by hamsters was believed
to be In a form such as arsenobetalne rather than as the highly toxic TMA,
but the exact chemical structure of this TMA-lIke product has not yet been
elucidated.
In the Stevens et al. (1977) rat study with 14C- and '"As-labeled
cacodyllc acid1 (see Section 5.2.), no differences were reported In the
tissue distribution of the 74As- and 14C-labels. The authors concluded
that substantial conversion in vivo from organic to Inorganic arsenic did
not appear to occur In the rat; however, they did not rule out the possibil-
ity of valence.state changes. The recovery of only minor amounts (<0.13% of
dose) of l4C-cacody!1c acid as expired 14COp Is further evidence that
demethylatlon to Inorganic arsenic Is a minor pathway (Stevens et al.,
1977). Marafante et al. (1987) did not detect any Inorganic arsenic In the
excrement of mt1ce or hamsters treated orally with 74As-cacodyl1c acid (40
mg As/kg bw), or In the urine of a male volunteer who Ingested cacodyllc
acid corresponding to 0.1 mg As/kg bw. No additional metabolic breakdown
products .were found by Marafante et al. (1987). Oral administration of
cacodyllc add: to mice, hamsters and a human resulted In the excretion of
unmetabollzed cacodyllc add, cacodyllc add complex and TMAO In the urine
and feces (Tables 5-2 and 5-3). These results are at variance with the
generally accepted assumption that cacodyllc add Is the endpolnt In the
detoxification of Inorganic arsenics. Marafante et al. (1987) suggested
0128d -29- 03/31/89
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TABLE 5-2
Excretion of Metabolites of Cacodyllc Add 1n the Urine
Following Oral Administration3
Species
Hamsterb
Mouseb
Human0
Cacodyllc Add
38.7
56.4
80
% of Dose
Cacodyllc Add
Complex
11.2
7.7
NR
TMAO
6.4
3.5
3.6
aSource: Marafante et al., 1987
bS1ngle dose of 74As-cacodyl1c acid by gavage at 40 mg As/kg; excreta
collected for 48 hours; n=5.
cSingle dose of 74As-cacodyl1c add at 0.1 mg As/kg; urine collected for
3 days
NR = Not reported; TMAO = trlmethyl arslne oxide
0128d -30- 03/31/89
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TABLE 5-3
Excretion of Metabolites of Cacodyllc Add In the Feces
Following Oral Administration3
Species
Hamster5 :
Mouse5
Human
Cacodyllc Acid
37.3
24.3
NR
% of Dose
Cacodyllc Add
Complex
3.9
4.9
NR
TMAO
ND
ND
NR
aSource: Marafante et al., 1987
bS1ngle dose of 74As-cacodyl1c add by gavage at 40 mg As/kg;. excreta
collected for 48 hours; n=5.
ND = Not detected; NR = not reported; TMAO = trlmethyl arslne oxide
0128d
-31-
03/31/89
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that cacodyllc acid may react with SH-contalnlng compounds such as
2-mercaptoethanol, cystelne, glutathlone and llpolc add In a reducing step,
which Is followed by oxldatlve methylatlon by S-adenosylmethlonlne to form
THAO. Thus, the cacodyllc acid complex Is believed to be an Intermediary
step 1n the further methylatlon to TMAO, probably occurring In the liver.
5.4. EXCRETION
Elimination of cacodyllc add is believed to be faster than that of
Inorganic arsenic (Vahter, 1983). Inorganic arsenic Is methylated In the
body, a detoxification process that renders the arsenic less reactive and
facilitates Its excretion by the kidney.
Stevens et al. (1977) found the rate of excretion of cacodyllc add to
be very rapid 1n rats. With peroral dosing (33 yg 14C-cacodyl1c acid),
the primary route of excretion was fecal (3154 of the dose) with 25% 1n
urine. Urinary excretion after Intratracheal and Intravenous treatment at a
similar dosage was >60%. The minor amounts excreted In feces after Intra-
venous treatment (1.18% of the dose) are believed to be a result of'biliary
secretion. Minor amounts of radlolabel were eliminated as C0?, <0.01% of
the dose 24 hours following Intravenous or Intratracheal administration and
"10-fold higher after oral administration.
Yamauchl and Yamamura (1984), In their study with the golden hamster,
found that 24 hours after administration of 40 mg/kg bw of cacodyllc acid by
gavage, 45% was excreted 1n urine and 34.7% 1n feces. At 5 days posttreat-
ment, 84.9% of the total dose administered was excreted In urine and feces,
suggesting that some accumulation may occur In hamsters. No data regarding
* _
excretion by lungs were reported.
Excretion of cacodyllc add In mice, hamsters and humans was studied by
Marafante et al. (1987) (see Tables 5-2 and 5-3). More than 96% of the dose
0128d -32- 03/31/89
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was excreted by mice and hamsters after 2 days. Fecal excretion was 41.2%,
In the hamster and 29.2% 1n the mouse. Urinary excretion 1n the hamster was
56.3%, and In the mouse, 67.6%. In the human study, -84% of the dose 3 days
postingestlon was excreted In urine. Buchet et al. (1981) recovered 75% of
the arsenic from an oral dose of sodium dlmethylarslnate (500 mg As) In the
urine of four male volunteers In 4 days.
5.5. SUMMARY
Cacodyllc acid appears to be asorbed rapidly and virtually completely
from the respiratory tract of Intratracheally treated rats, with a half-time
of 2.2 minutes (Stevens et al., 1977). Gastrointestinal absorption In rats
1s considerably slower, with an estimated half-time of 248 minutes (Stevens
et al., 1977)i Excretion data 1n rats (Stevens et al., 1977), hamsters
(Yamauch! and Yamamura, 1984; Marafante et al., 1987) and mice (Harafante et
al., 1987) indicate that GI absorption ranges from ~60-70% In these species.
Urinary excretion data In humans (Marafante et al., 1987; Buchet et al.,
j
1981) suggest a GI absorption factor for humans of ~80%.
Distribution data obtained from rats treated Intravenously with high
(200 mg/kg) and low (33 yg) doses Indicate that the rat RBC has an
affinity for cacodyllc add (Stevens et al., 1977). Among other tissues,
highest concentrations were found In the liver > kidney > lung > spleen >
brain. The magnitude of the dose had no effect on tissue distribution.
t
Plasma elimination was trlphaslc, with a terminal half-life of 3.42 hours.
Tissue distribution appeared to be similar 1n hamsters, except that the
t
hamster RBC did not appear to have a particular affinity for cacodyllc acid
(Yamauchl and Yamamura, 1984).
The metabolism of cacodylic add has been studied by quantifying Its
metabolites In tissue, expired air and excreta of treated rats, mice,
hamsters and humans (Stevens et al., 1977; Yamauchl and Yamamura, 1984;
0128d -33- 03/31/89
-------
Marafante et al., 1987). Excretion data In hamsters, mice and humans
suggest that metabolism Is not nearly as Important as excretion In the
elimination of cacodyllc acid (Marafante et a!., 1987). Demethylatlon to
methylarsonlc add, Inorganic arsenic and carbon dioxide appears to be a
minor metabolic pathway (Yamauchl and Yamamura, 1984; Stevens et al., 1977).
The most Important blotransformatlon pathway appears to be methylatlon to a
trlmethyl compound, probably to a trlmethylarslne oxide conjugate (Yamauchl
and Yamamura, 1984; Marafante et al., 1987). Complexatlon with thlo-
contalnlng compounds may be an Intermediate step In the formation of
trlmethylarslne oxide.
Excretion of a parenteral dose Is primarily through the kidney, with
minor amounts expired as CO- and excreted through the bile (Stevens et
al., 1977; Marafante et al., 1987). Fecal excretion of an oral dose'
probably represents largely unabsorbed compound. A plasma half-life 1n rats
of 3.42 hours was estimated for the terminal phase of a trlphaslc decay
function (Stevens et al., 1977). In hamsters and mice, urinary and fecal
excretion together accounted for 97.5 and 96.8% of an oral dose after 48
hours, suggesting that excretion 1n these species Is fairly rapid (Marafante
et al., 1977). In humans, -80% of an oral dose was recovered from the urine
within 3 days of treatment (Marafante et al., 1987; Buchet et al., 1981).
0128d -34- 03/31/89
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. Pertinent data regarding Inhalation
exposure to cacodyllc acid could not be located In the available literature
as cited 1n Appendix A.
6.1.2. Oral Exposures.
.6.1.2.1. SUBCHRONIC -- In a study by Nees (1968) with weanling
Sprague-Dawley rats, dietary levels of 0, 3, 15, 30 and 100 ppm cacodyllc
acid were administered for 30-90-days. Data 1n the CBI files Indicated that
these dietary levels actually represented arsenic, and the equivalent corre-
sponding dietary concentrations of cacodyllc add were calculated as 0, 5.5,
27.6, 55.3 and, 184 ppm,. respectively. Because the original study was not
available, exact details were lacking. Urlnalysls, hematologlcal studies
and,gross pathology examinations were performed. No significant effects on
body weight, food consumption, hematology, organ weight or histology could
be attributed :to the test substance. It Is not clear 1f the testls was
among the organs examined.
In a 20-day study by Nees (1960), weanling Sprague-Dawley rats were fed
diets that provided cacodyllc add at dosages of 0, 70, 140 or 280 mg/kg.
At a dose of 280 mg/kg, hlstologlcal examination showed reduced activity of
spermatogonla cells, along with atrophtc changes In seminiferous tubules,
but no adverse effects were noted In the cerebrum, cerebellum, heart, lungs,
liver, spleen, kidney, pancreas, adrenals, stomach Intestines, urinary
bladder or bone. A NOAEL of 140 mg/kg was reported.
Derse (1968) conducted a 90-day feeding study using 32 beagle puppies.
Three groups of four males and four females each received dietary levels of
cacodyllc acid, of 0, 3, 15 or 30 ppm. Body weights were recorded weekly.
0128d -35- 03/31/89
-------
f
At 90 days, endpolnts examined were kidney and liver function, urlnalysls
and hlstopathology of major organs and tissues. No significant differences
were found between test groups and controls, and no mortality was noted In
any test group. Lesions 1n the brain, heart, liver, kidney, spleen,
Intestine and other organs occurred randomly among both experimental and
control groups and were therefore not attributed to cacodyllc add. It 1s
unclear whether the testls was examined hlstologlcally.
The Weed Science Society of America (1983) reported briefly on a study
obtained from Vlneland and Crystal Chemical Company. Groups of 10 rats
(strain not reported) were fed doses of 226, 118, 54 or 0 mg/kg for 3 weeks.
A LOAEL was determined at 226 mg/kg, associated with atrophlc changes In
seminiferous tubules and decreased activity of spermatogonla cells. The 118
mg/kg group did not differ from the controls; therefore, 118 mg/kg'
represents a NOAEL. No other details of this study were given.
6.1.2.2. CHRONIC -- Pertinent data regarding chronic oral exposure to
cacodyllc acid could not be located In the available literature as cited In
Appendix A. The Office of Pesticide Programs (OPP, 1987) reports that
chronic data are being generated.
6.1.3. Other Relevant Information. Data regarding the acute toxlclty of
cacodyllc acid are presented In Table 6-1. Oral LD5Q values for rats
ranged from 644-1433 mg/kg. No marked age or gender related effects on the
acute toxlclty of cacodyllc add were apparent In rats. Data for rats and
mice are similar for the Inhalation and Intraperltoneal routes of exposure.
No Information regarding toxldty of cacodyllc add to humans by oral or
Inhalation routes was found; however, workers using arsenic-containing
sllvlcldes for tree-thinning purposes had higher urinary concentrations of
0128d -36- 03/31/89
-------
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arsenic compounds (>0.3 mg/a.), Including cacodyllc acid, than did the
unexposed control group (0.03-0.14 mg/j.) (Tarrant and Allard, 1972).
Concentrations 1n workers were generally near normal on Monday and high on
Friday. No evidence of arsenic poisoning was observed, and urinary levels
did not appear to Increase over time. Personnel took protective measures,
Including use of protective clothing and skin creams, and thorough post-
exposure washing.
In another study (Wagner and Weswlg, 1974) that tested urinary excretion
and blood levels of arsenic In five workers exposed to cacodyllc add for 2
months, urinary arsenic correlated more closely with exposure levels than
did blood levels, and there was an Immediate Increase 1n the dally excretion
rates. Levels dropped back to normal when exposure was discontinued.
Workers reported a strong odor of garlic In the work area. Arslne gas Is
characterized by such an odor, suggesting that perhaps the cacodyllc acid
was being converted to this toxic gas.
6.2. CARCINOSENICITY
6.2.1. Inhalation. Pertinent data regarding the Inhalation cardnogen-
Iclty of cacodyllc acid could not be located In the available literature as
cHed 1n Appendix A.
6.2.2. Oral. Oral cancer studies were limited to one long-term carclno-
genldty study by BRL (1968) and Innes et al. (1969). In the study, two
strains of mice were tested [(C57BL/6 x C3H/Anf)Fl (86C3F1) and (C57BL6 x
AKR)F1 (B6AKF1)]. Dose levels chosen were maximum tolerance levels. Groups
of 18 males and 18 females of each strain were administered 46.4 mg/kg
bw/day In distilled water by gavage from 7-28 days of age. On day 28,
adjustments were made for body weight changes, and a concentration (121 ppm)
0128d -38- 08/30/89
-------
calculated to deliver an equivalent dally dose was added to the diet for the
remainder of the 80-week test period. Eleven male and 18 female BC6C3F1
mice and 17 male and 16 female B6AKF1 lived until the end of the test.
Although pulmonary adenoma, uterine lelomyoma and Incidental lesions
occurred 1n a ,few animals, the Incidence was not significantly different
from that of untreated and pooled controls.
Cacodyllc add has not been scheduled for cardnogenlclty testing by the
NTP (1988).
6.2.3. Other Relevant Information. In another BRL (1968) study, which
used the same .strains of mice reported above, a single subcutaneous Injec-
tion of cacodyllc acid at 464 rug/kg bw In distilled water was administered
In the nape of the neck to 28-day weanlings to screen for "strong" carclno-
genlclty. Results were negative, with tumor Incidences not significantly
Increased over controls.
Johansen et al. (1984) studied the promoting effect of cacodyllc acid on
tumors Induced In male Hlstar rats by DENA. Partially hepatectomlzed rats
were Injected Intraperltoneally with saline (controls) or 30 mg/kg of DENA.
On postsurgery day 7, 80 ppm (MTD) cacodylU add was administered In drink-
Ing water to both groups. The Investigators estimated an average dose of
~3.8 mg/rat/day. Body weight was monitored weekly, and rats were sacrificed
and necropsled after 6 months. Hlstopathologlcal examinations were limited
to the liver and kidney. Renal tumors developed In 2/11 DENA control rats
and 3/7 rats receiving both compounds (statistically Insignificant);
cacodyllc add-treatment alone produced no tumors (0/8). A nonsignificant
Increase 1n liver lesions, basophlUc fod and neoplastlc nodules occurred
among rats receiving DENA and cacodyllc add, but not among the controls.
0128d . -39- 03/31/89
-------
The authors concluded that these results suggest a tumor promoting effect of
cacodyllc add despite the lack of statistical significance, which might be
shown 1f an Increased number of animals had been studied and If the dose of
DENA had been reduced.
6.3. MUTAGENICITY
Cacodyllc add has been tested for mutagenldty and genotoxldty 1n
bacteria, yeast, DrosophUa and mammalian cell cultures with mixed results
(Table 6-2). Consistently positive test results were obtained 1n Saccharo-
myces cerevlslae (Simmon et al., 1977; Jones et al., 1984; R1cc1o et al.,
1981).
Differential toxlclty tests with Escherlchla coll were reported to be
negative by Simmon et al. (1977); however, Jones et al. (1984) re-examined
data from Simmon et al. (1977) and suggested that their test should be
regarded as Inconclusive (reason not given). A reverse mutation test also
conducted by Simmon et al. (1977) and using E^ coll appears to be unequivoc-
ally negative. Tests 1n Salmonella typhlmuMum were consistently negative
(Simmon et al., 1977; Andersen et al., 1972).
Tests using DrosophUa also produced negative or equivocal results. The
nondlsjunctlon test was clearly negative (Ramel and Magnusson, 1979).
Although the sex-linked recessive lethal test (Valencia, 1981) was judged to
be negative, there were some, problems with maintaining replicates In both
experimental* and controls, which was considered to weaken this data point.
Results from mammalian cell tests Mere mixed. The co-mutagenldty
(Taylor et al., 1984) and sister chromaUd exchange (Jones et al., 1984)
tests using Chinese hamster ovary cells were negative, as was the unsched-
uled DNA repair synthesis test (Simmon et al., 1977). Both the forward
mutation test and mlcronucleus test (Jones et al., 1984) showed positive
mouse tissue sensitivity to cacodyllc add as a mutagen.
0128d -40- 03/31/89
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It Is clear that cacodyllc add Is mutagenlc In certain systems and
under certain conditions. In an analysis of mutagenesls methodology for
pesticides. Waters et al. (1981) classified cacodyllc acid as having medium
priority status for further evaluation as a mutagen or carcinogen. Using a
computerized data management system, Garrett et al. (1986) analyzed the
qualitative results of the work by Waters et al. (1981). Their comparison
showed that, although cacodyllc add yielded positive results In eukaryotlc
systems (gene mutation, DNA damage and chromosomal effects), evidence for
Us mutagenldty 1s weak when compared with other pesticides.
6.4. TERATOGENICITY
Rogers et al. (1981) administered cacodyllc acid (99% pure) In distilled
water by gastric Intubation to time-pregnant random-bred albino CO rats and
CD-I mice on days 7-16 of gestation. Day 1 was defined by demonstration of
a sperm plug 1n mice, and presence of sperm 1n the vaginal smear of rats.
Dams were sacrificed on day 21, and fetuses were weighed, fixed and examined
for visceral and skeletal effects. For data analysis the Utter was used as
the experimental unit. In the rat study, between 21 and 40 rats/group were
given 0 (distilled water), 7.5, 15, 30, 40, 50 or 60 mg/kg/day doses In 0.2
ml/day Intubation volumes. Both maternal (significantly reduced body
weight gain) and fetal toxldty (reduced body weight and retarded sternal
and caudal ossification) were significant at 40 mg/kg/day. Maternal
mortality (67%) occurred at the highest dose tested, and fetal mortality was
significantly elevated at 50 mg/kg/day. Irregular palatine rugae (ridges
that were discontinuous and/or not lying In apposition at the palatal raphe)
occurred In a dose-related manner and were significantly different from
controls at >30 mg/kg/day. No significant effect was observed at 15
mg/kg/day.
0128d -44- 08/30/89
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In the same study, 30-32 mice/group were administered 0. 200, 400 or 600
mg/kg/day 1n 0.1 ma/day Intubation volumes. Maternal toxldty as
evidenced by reduced body weight gain was significant at 200 mg/kg/day.
Doses >20Q mg/kg/day caused significant decreases In fetal weight and
retardation of caudal ossification. Cleft palates resulted from doses of
400 (1n 51% of litters) and 600 mg/kg/day (In 70% of litters). Fetal
mortality was significantly higher at 600 mg/kg/day.
Kavlock et al. (1985) treated random-bred CO-1 mice by Intubation (0.5
ml/mouse) on day 8 of gestation with doses of cacodyllc acid (99.5%
purity) expected to-Induce a low degree of maternal lethality (20 mice/1600
mg/kg each) or a moderate dose for maternal lethality (40 mice/2400 mg/kg
each). Twenty controls received only the distilled water vehicle. On day
18 of gestation, dams were sacrificed and examined for weight gain, while
fetuses were examined to determine presence of malformations and rate of
development. The Utter was considered the experimental unit. Maternal
toxlclty occurred at 1600 mg/kg (26% maternal death; reduced weight gain).
A significantly high percentage of prenatal mortality occurred at 1600
mg/kg, along with reduced fetal weight. At 1600 mg/kg, delays In sternal
and caudal ossification and major delays In renal papilla development
occurred. The .Incidence of supernumerary ribs and other skeletal and soft
tissue abnormalities was markedly elevated over controls at both dosages.
In a prior 'screening study, Chernoff and Kavlock (1982) administered a
minimum toxic dose of 0 or 600 mg/kg of cacodyllc add (purity not reported)
by gavage In water on days 8-12 gestation to 24 CD-I mouse dams to assess
effects on offspring. Parameters of toxlclty evaluated Included maternal
survival and weight change and offspring survival and body weight at post-
partum days 1 and 3. Increased maternal death (7/24) reduced the sample
0128d -45- 08/30/89
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size such that relatively large inter size reductions were not signifi-
cantly different from controls; however, significantly reduced maternal and
fetal weights resulted. This test was later repeated with 40 vehicle
control and 30 treated mice treated at doses of 0 and 600 mg/kg of cacodyllc
acid as previously described (Kavlock et al., 1987). Treatment resulted In
tfie death of four dams and a significant reduction In maternal body weight
gain. Reduced fetal body weights were observed on postpartum day 3.
Outbred Lak:LVG (SYR) strain Golden hamsters were mated, and >10 preg-
nant females per group were Injected Intraperltoneally with a single dose of
900 or 1000 mg/kg sodium cacodylate (purity not reported) (judged by a pilot
study to be In the range of the minimum lethal dose for pregnant females) In
deIonized distilled water (Hood et a!., 1982). Treatments were administered
on 1 of gestation days 8-12. Mice were sacrificed on gestation day 15, and
dams were examined for weight gain and liver-to-body weight ratios; uterine
contents of dams were also examined. Fetuses were weighed and examined for
visceral and skeletal anomalies. Significantly greater numbers of maternal
deaths occurred 1n treated mice, suggesting that 900 mg/kg 1s greater than
the minimum lethal dose. Fetal deaths from treatment occurred at all times
of administration, with the greatest effects observed on days 8 and 9 of
gestation. Significantly greater gross malformations were Induced In
fetuses from all treatment groups over their untreated counterparts. Cleft
Up, cleft palate, syndactyly, exencephaly, talipes and mlcromella were
commonly observed. Similar results were reported from a pilot study at 1000
mg/kg, but control data for the pilot study were not reported.
WHlhUe (1981) Intravenously Injected groups of five pregnant "Golden
hamsters on day 8 of gestation with 20, 50 or 100 mg/kg of the sodium salt
of cacodyllc add. A group of seven pregnant hamsters Injected - with
*.
0128d -46- 08/30/89
-------
distilled water served as a control. The 50 and 100 mg/kg doses Induced
some cranloschlsls and abnormalities of ribs and kidneys, although the
response did ,not occur 1n a dose-related fashion and statistical analysis
was not performed.
6.5. OTHER REPRODUCTIVE EFFECTS
The Weed Science Society of America (1983) reported damage to spermato-
gonla cells In rats fed a diet that provided cacodyllc acid at 226 mg/kg.
No effects were observed at 118 mg/kg/day (see Section 6.1.2.1.). In the
Nees (1960) study (see Section 6.1.2.1.), testlcular pathological changes
resulted when weanling rats were fed 280 mg/kg/day, but not 140 mg/kg/day
for 20 days.
6.6. SUMMARY
Oral LD5Q; values 1n rats range from 644-1433 mg/kg, with little
apparent age or gender difference 1n magnitude (see Table 6-1). Inhalation
and Intraperltoneal single exposure data Indicate little difference 1n the
sensitivity of rats compared with mice. Intraperltoneal LDj0 values In
both species ranged from 500-1000 mg/kg. In a 20-day dietary study In rats,
testlcular effects were observed at 180 mg/kg bw/day, but not at 140 mg/kg
bw/day (Nees, 1960). A dietary concentration of 184 ppm was a NOEL In rats
1n a 30- to 90-day dietary study (Nees, 1968) and 30 ppm was a NOEL 1n a
90-day study 1n dogs (Derse, 1968). It Is not clear whether the testls was
examined 1n these longer-term studies.
Data regarding the toxlclty of cacodyllc acid In humans were not
located; however, workers applying arsenic-containing sllvlddes had higher
urinary concentrations of arsenic compounds, Including cacodyllc add, than
did nonexposed controls. The levels of cacodyllc add In the urine did not
appear to rise with Increased duration of exposure. Near normal levels were
observed on Monday mornings.
012Bd -47- 08/30/89
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Cacodyllc acid did not yield evidence of carclnogenldty In an 18-month
gavage/dletary exposure study, where mice were fed 46.4 mg/kg/day by gavage
at days 7-28 of age and 121 ppm In the diet after day 28 of age (BRL, 1968;
Innes et al., 1969). In a different BRL {1968} experiment with mice, a
.single subcutaneous Injection at 464 mg/kg of cacodyllc add 1n distilled
water did not produce a significant Increase 1n tumor Incidence compared
with controls. A drinking water study produced equivocal evidence that
cacodyllc add may promote liver tumors In partially hepatectomlzed rats
Initiated with DENA (Johansen et al., 1984). Results of mutagenldty
testing were mixed. Tests In prokaryotes {Simmon et al., 1977; Jones et
al., 1984;. Andersen et al., 1972) and Drosophllla (Ramel and Hagnusson,
1979; Valencia, 1981) were negative, but tests 1n Saccharomyces were
positive (Simmon et al., 1977; Jones et al., 1984). Mixed results were'
obtained In various mammalian test systems {Simmon et al., 1977; Jones et
al., 1984; Taylor et al., 1984). The compound Is not scheduled for testing
by the NTP (1988).
Developmental toxlclty studies (Rogers et al., 1981; Kavlock et al.,
1985; Chernoff and Kavlock, 1982) suggest that rats are more sensitive than
mice. In a gavage study using rats, 40 mg/kg/day was associated with
retarded maternal weight gain, reduced fetal body weights and retarded
ossification (Rogers et al., 1981). An Increased Incidence of Irregular
palatine rugae was observed at 30 mg/kg/day. There were no significant
effects at 15 mg/kg/day. In mice treated by gavage, 200 mg/kg/day resulted
In adverse body weight effects on both the dam and the fetus; 400 mg/kg/day
resulted In an Increased Incidence of cleft palate (Rogers et al., 1981).
Q128d
-48-
08/30/89
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1987) recommended a TLV for arsenic and Us soluble compounds of
0.2 mg As/m3, based primarily on the toxkUy of As^O- (ACGIH, 1986).
OSHA (1985) has established a PEL for arsenic In air of 0.5 mg As/m3 TWA.
7.2. AQUATIC!
Guidelines and standards for the protection of aquatic life from
exposure to cacodyllc acid could not be located In the available literature
as cited In Appendix-A.
0128d
-49-
03/31/89
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8. RISK ASSESSMENT
Statements concerning available literature In this document refer to
published, quotable sources and are In no way meant to Imply that
confidential business Information (CBI), which this document could not
address, are not In existence. From examination of the bibliographies of
the CBI data, however, It was determined that CBI data that would alter the
approach to risk assessment or the risk assessment values presented herein
do not exist.
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the Inhalation carcinogen-
Idty of cacodyllc acid could not be located In the available literature as
cited 1n Appendix A.
8.1.2. Oral. In an 18-month study using (C57BL/6 x C3H/Anf)Fl (B6C3F1)
and (C57BL6 x AKR)F1 (B6AKF1) strain mice, groups of 18 males and'18 females
of each strain were administered gavage doses of 46.4 mg/kg bw/day 1n
distilled water (an amount determined 1n a previous test to be a maximum
tolerance level) from days 7-28. At day 28, adjustments were made for body
weight changes, and a concentration of 121 ppm, which was calculated to
deliver an equivalent dally dose, was added to the diet for the remainder of
the 80-week test period. Eleven male and 18 female 8C6C3F1 mice and 17 male
and 16 female B6AKF1 mice lived until the end of the test. Although
pulmonary adenoma, uterine lelomyoma and incidental lesions occurred In a
few mice, no significant differences In incidence from those of untreated
and pooled controls were noted.
8.1.3. Other Routes. Results were negative In another study (BRL, 1968)
using the same strains of mice as above and In which single subcutaneous
0128d -50- 03/31/89
-------
Injection of 464 mg/kg bw cacodyllc add In distilled water was administered
In the nape of the neck to 28-day weanlings.
8.1.4. Weight of Evidence. Although only few animals of one species and
one dose group were used In the above cardnogenldty studies, these studies
are the best available data to date. The pre-determlned MTDs of cacodyllc
add were administered. The only additional pertinent Information located
1n the literature was a possible tumor promoting effect of. cacodyllc acid
when administered with DENA (Johansen et al., 1964). IARC (1980) concluded
that there 1s Inadequate support In the literature for the carclnogenldty
of arsenic compounds In animals, and that evidence for such In humans Is
restricted to Inorganic forms of arsenic. The lack of data regarding the
carclnogenldty of cacodyllc add In humans and the Inadequate studies In
animals are the basis for assigning cacodyllc add to EPA Group D, not'
classifiable as to human carclnogenldty, using the U.S. EPA (1986a) classi-
fication scheme.
8.1.5. Quantitative Risk Estimates. The Tack of positive data precludes
estimation of Carcinogenic potencies for cacodyllc add for either Inhala-
tion or oral exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding Inhalation exposure
to cacodyllc add could not be located In the available literature as cited
In Appendix A.
/•
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Toxldty
studies of cacodyllc add are limited. A study by Nees (1960) regarding
weanling rats and one reported In the Weed Science Society of America (1983)
\
were both of Inadequate duration for RfD determination (20 days and 3 weeks,
respectively). A 90-day study of beagle pups (Derse, 1968) gave negative
0128d -51- 08/30/89
-------
results at the highest dose tested, 30 ppm, thus falling to establish a
LOAEL or highest NOAEL.
The Nees (1968) 90-day study 1s marginally adequate for deriving an RfD.
Weanling rats were fed cacodyllc acid at dietary exposures of 0, 3, 15, 30
and 100 ppm for 30 or 90 days. There were no significant effects on body
weight, food consumption, hematology, histology or organ weight at the
highest concentration tested, therefore Identifying a NOAEL of at least 100
ppm 1n the diet, equivalent to 5 mg/kg/day.
Additional data regarding the Nees (1968) study from the OPP CBI files
Indicated that the dietary concentrations presented actually refer to the
arsenic equivalent rather than to cacodyllc acid per se. Corresponding
dietary concentrations of cacodyllc acid are 0, 5.5, 27.6, 55.3 and 184
mg/kg. The highest dietary concentration , corresponds to a dosage of 9.2
mg/kg/day, assuming that a rat consumes food equivalent to 5% of Us body
weight/day (U.S. EPA, 1980).
Application of an uncertainty factor of 300, 10 for Interspecles
extrapolation, 10 for variations within the human species and 3 to reflect
limitations In the data base, results In an RfD for subchronlc oral exposure
of 0.03 mg/kg/day. Confidence 1n the study, data base and RfD are low.
8.2.2.2. CHRONIC EXPOSURES — Pertinent data regarding chronic oral
exposure to cacodyllc add could not be located In the available literature
as cited 1n Appendix A. The OPP (1987) reports that chronic data are being
generated. A provisional chronic oral RfD can be generated from the sub-
chronic oral RfD of 0.03 mg/kg/day based on the NOEL of 9.2 mg/kg/day In the
90-day rat study by Nees (1968). Application of an uncertainty factor of 10
to the subchronlc RfD of 0.03 mg/kg/day results 1n an RfD for chronic oral
exposure of 0.003 mg/kg/day. A chronic oral RfD for cacodyllc add Is
currently under review by the U.S. EPA.
0128d -52- 08/30/89
-------
The boundaries for adverse effects and no effects are relatively
t
unequivocal, enclosing a relatively small area of contradiction. The two
LOAEL data points located on or wHhln the area of contradiction are from
the teratology rat study by Rogers et al. (1981). The point on the adverse
effects line represents a slight teratologlcal effect (Irregular palatine
rugae) In rats resulting from oral exposure to 30 mg/kg/day of cacodyllc
add; the other (located above It) represents maternal toxlclty (reduced
weight gain) In the mouse that resulted from oral exposure to 200 mg/kg/day
of cacodyllc add. These effect levels are clearly above the NOEL from Nees
(1968) of 9.2 mg/kg/day, which has been chosen as a basis for subchronlc and
chronic oral RfO determination and to which uncertainty factors of 300 and
3000 have been applied, respectively (see above). The resulting subchronlc
and chronic RfO values (0.03 and 0.003 mg/kg/day, respectively) are well
below the boundary for adverse effects.
0128d -53- 03/31/89
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of cacodyllc add was discussed In Chapter 6 and dose-
response data considered for CS derivation are summarized 1n Table 9-1.
Since no chronic toxldty data were available, subchrontc data were
considered. Data suitable for RQ determination were provided by the staff
of Rogers et al. (1981), who found teratogenlc effects (cleft palates) 1n
mice at an equivalent human dose of 30.2 mg/kg/day and teratogenldty In
rats at an equivalent human dose of 5.1 mg/kg/day. The Weed Science Society
of America (1983) reported atrophk changes In seminiferous tubules and
decreased activity of spermatogonla In rats at an equivalent human dose of
38.6 mg/kg/day. CSs for these effects are presented In Table 9-2.
The effect chosen for RQ determination for cacodyllc acid was terato-
genlclty In rats from the Rogers et al. (1981) study, which was the most
sensitive yet reported. This effect yielded the highest CS (15.3), which
corresponds to an RQ of 1000 (Table 9-3).
In another recent analysis, U.S. EPA (1987) derived candidate CSs for
the teratogenlc effects In rats and mice and also for the effects of
maternal toxlclty (reduced maternal body weight gain) 1n the dams treated
for 10 days during gestation (Rogers et al., 1981). In recognition of the
fact that the maternal effects observed were a manifestation of acute rather
than chronic toxlclty, an uncertainty factor of 100 was applied In the esti-
mation of an equivalent human dose. This methodology appears to contradict
that established by the Agency for the ranking of chemicals based on chronic
toxlclty data (U.S. EPA, 1984), 1n which It Is stated that only subchronlc
and chronic data will be considered for derivation of CSs. Therefore, since
In this analysis the acute manifestations of maternal toxlclty observed
0128d -54- 03/31/89
-------
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TABLE 9-3
Cacodyllc Acid
Minimum Effect Dose (MED) and Reportable Quantity {RQ}
Route:
Species/Sex:
Dose*:
Duration:
Effect: !
RVd
RVe
Composite Score:
RQ:
Reference:
oral/gavage
Rat/female
357 mg/day
gestation days 7-16
Developmental tox1c1ty:
1.7
9
15.3
1000
Rogers et al., 1981
Irregular palatine rugae
'Equivalent human dosage
0128d
-57-
08/30/89
-------
in developmental toxlclty studies are not considered appropriate to use In
derivation of a CS, the RQ derived here differs from that 1n U.S. EPA (1987).
9.2. BASED ON CARCINOGENICITY
Cancer studies were limited to long-term experiments which tested mice
administered MTDs by the oral route (BRL, 1968; Innes et al., 1969) and by
subcutaneous administration (BRL, 1968). Results of the studies were
negative (see Section 6.1.). Although the sample sizes 1n these studies
were small and were confined to one species (mice), they are the best
studies available to date. Both IARC (1980) and U.S. EPA (1982) concluded
that available data do not suggest that there Is oncogenlc risk. Cacodyllc
acid Is categorized as an EPA Group D compound, not classifiable as to human
carclnogenlclty (U.S. EPA, 1986a).
Cancer study data for this compound are Inadequate for calculating a
Potency Factor. Therefore, since cacodyllc Is assigned to EPA Group D, It
Is given a no hazard ranking, and no RQ for cancer can be assigned.
0128d
-58-
08/30/89
-------
10. REFERENCES
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BRL (81onet1cs Research Laboratories). 1968. Evaluation of Carcinogenic,
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excretion of arsenic "metabolites after a single oral dose of sodium
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Chernoff, N. and R.J. Kavlock. 1982. An in vivo teratology screen
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Cox, D.P. and H. Alexander. 1973. Production of trlmethylarslne gas from
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Crockett, P.H.,, B. Klllan, K.S. Crump and R.8. Howe. 1985. Descriptive
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Del Rlvero, J.M. 1981. Preliminary screening trials of some herbicides for
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t
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f
Durkln, P. and W. Meylan. 1988. User's Guide for D2PLOT: A Program for
Dose/Duration Graphs. Prepared by Syracuse Research Corporation for the
Environmental Criteria and Assessment Office, U.S. EPA, Cincinnati, OH.
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Galnes, T.8. and R.E. Under. 1986. Acute toxlclty of pesticides In adult
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j
Garrett, N.E., H.F. Stack and M.D. Waters. 1986. Evaluation of the genetic
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Holm, T.R., M.A. Anderson, R.R. Stanforth and D.G. Iverson. 1980. The
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alkyl arsenlcals In model ecosystem. Environ. Scl. Technol. 7(9): 841-845.
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Jones, D.C.I., V.F. Simmon, K.E. Mortelmans, et al. 1984. jji vitro and In
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chemical and biological significance of arsenical compounds 1n a heavily
->
contaminated watershed. Part 1. The fate and speclatlon of arsenical
compounds In aquatic environments - A literature review. J. Environ. Sci.
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Lewis, R.G. and R.E. Lee, Jr. 1976. A1r pollution from pesticides:
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Agricultural Processes, R.E. Lee, Jr., Ed. CRC Press, Cleveland, OH.
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Lyman, W.J., W.F, Reehl and D.H. Rosenblatt, Ed. 1982. Handbook of
Chemical Property Estimation Methods. Environmental Behavior of Organic
Compounds. McGraw-Hill Book Co., New York, NY. p. 5-5.
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Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer Res. 35: 1379-1386.
Marafante, £., H. Vahter, H. Norln, et al. 1987. Blotransformatlon of
dlmethylarslnlc acid In mouse, hamster and man. J. Appl. Toxlcol. 7(2):
111-117.
Mastradone, P.J. and E.A. Woolson. 1983. Levels of arsenical species In
cotton after field application of a cacodyllc add defoliant. Bull.
Environ. Contam. Toxlcol. 31: 216-221.
Mayer, F.L., 3r. and H.R. Ellersleck. 1986. Manual of Acute Toxldty:
Interpretation and Data Base for 410 Chemicals and 66 Species of Freshwater
Animals. U.S. Dept. Int. Fish and Wildlife Serv. Res. Pub. 160, Washington,
DC.
Mel'nlkov, N.N. 1971. Chemistry of Pesticides. Springer Verlag. p. 393.
Mukal, H., Y. Ambe, T. Muku, K. Takeshlta, et al. 1986. Seasonal variation
of methylarsenlc compounds In airborne partlculate matter. Nature. 324:
239-241.
Nees, P.O. 1960. Report on cacodyllc acid toxlclty to animals. Wisconsin
Alumni Res. Found. EPA Pesticide Petition No. OF0911. (Cited In U.S.
EPA,80975}
0128d
-64-
03/31/89
-------
Nees, P.O. 1968. Report on cacodyllc acid toxldty to animals. Wisconsin
Alumni Res. Found. EPA Pesticide Petition No. OF0911. (Cited In U.S. EPAA
1975)
Morris, L.A. 1985. Exposure of applicators to monosodlum methanearsonate
and cacodyllc acid 1n forestry. I_n: ACS Symp. Ser. 273(Dermal Exposure
Relat. Pestle. Use): 109-121.
NTP (National Toxicology Program). 1988. Management stat'us report,
05/06/88. NTP, Research Triangle Park, NC.
Odanaka, Y., N. Tsuchlya, 0. Matano and S. Goto. 1985a. Metabolic fate of
the arsenical fungicide ammonium Iron methanearsonate In soil. J. Pest.'
Sci. 10: 681-689.
Odanaka, Y., N. Tsuchlya, 0. Matano and S. Goto. 1985b. Metabolic fate of
the arsenical fungicide, ferric methanearsonate, In soil. J. Pest. Sc1.
10: 31-39.
[ \
Oliver, K.H., Jr., 6.H. Parsons and C.T. Huffstetler. 1966. An ecological
study on the effects of certain concentrations of cacodyllc add on selected
fauna and flora. USGRDR6715.
OPP (Office of Pesticide Programs). 1987. Report on the Status of Chemi-
cals In the Special Review Program, Registration Standards Program Data
Call-In Program and Other Registration Activities. OPP, Washington, DC.
0128d -65- 03/31/89
-------
OSHA (Occupational Safety and Health Administration). 1985. Occupational
Standards. Permissible Exposure Limits. 29 CFR 1910.1000.
Parrls, G.E. and F.E. Brlnckman. 1976. Reactions which relate to environ-
mental mobility of arsenic and antimony. II. Oxidation of trlmethylarslne
and trlmethylstlblne. Environ. Sc1. Technol. 10: 1128-1134.
Plzak, V., M. Root and J. Ooull. 1963. The University of Chicago. USAF
Radiation Laboratory Quarterly Progress Report No. 46, Jan. 15, 1963. AD
295-864. p. 94-96, 102.
Ramel, C. and J. Magnusson. 1979. Chemical Induction of nondlsjunctlon 1n
Drosophlla. Environ. Health Perspect. 31: 59-66.
R1cc1o, E., G. Shepherd, A. Pomeroy, K. Mortelmans and M.O. Waters. 1981.
Comparative studies between the £. cereylslae 03 and 07 assays of eleven
pesticides. Environ. Mutagen. 3(3): 327.
Roederer, G. 1986. Poterloochromonas malhamensls - A unicellular alga as
test system In ecotoxlcology, toxicology and pharmacology. Toxic. Assess.
1(1): 123-138.
Rogers, E.H., N. Chernoff and R.J. Kavlock. 1981. The teratogenlc poten-
tial of cacodyllc acid In the rat and mouse. Drug Chem. Toxlcol. 4(1):
49-61.
0128d
-66-
03/31/89
-------
Schuth, C.K., ,A.R. Isensee, E.A. Woolson and P.C. Kearney. 1974. Distribu-
tion of carbon-14 and arsenic derived from carbon-14-labeled cacodyllc acid
1n an aquatic ecosystem. J. Agrlc. Food Chem. 22(6): 999-1003.
Simmon, V.F., A.O. Mitchell and T.A. Jorgenson. 1977. Evaluation of
selected pesticides as chemical mutagens Jin vitro and ^n vivo studies. EPA
600/1-77/028. NTIS PB268647/5. p. 6-24, 82, 139, 148, 152.
SRI (Stanford Research Institute). 1987. 1987 Directory of Chemical
Producers. United States of America. SRI International, Menlo Park, CA.
p. 841.
Stary, J. and K. Kratzer. 1982. The cumulation of toxic metals on alga.
Int. J. Environ. Anal. Chem. 12(1): 65-71.
Stary, I.J., K. Kratzer, B. Havllk, J. PrasHova and 0. Hanusova. 1980.
The cumulation1 of methylmercury In fish (Poedlla reticulata). Int. J.
Environ. Anal. Chem. 8: 189-195.
Stary, I.J., K. Kratzer, J. Prasllova and T. Vrbska. 1982. The cumulation
of chromium and arsenic species In fish (Poedlla retlculata). Int. J.
Environ. Anal. Chem. 12(3-4): 253-257.
Stevens, J.T., L.L. Hall, N. Chernoff, 0. Farmer, W.F. Durham and L.C.
DIPasquale. 1977. Disposition of 14C and/or 74As-cacodyl1c acid In
rats after Intravenous, Intratracheal or peroral administration. Environ.
Health Perspect. 19: 151-157.
0128d -67- 03/31/89
-------
Stevens, J.T., L.C. DIPasquale and 0.0. Farmer. 1979. The acute Inhalation
toxicology of the technical grade organoarsenlcal herbicides, cacodyllc add
and chsodium methanearsonlc add; a route comparison. Bull. Environ.
Contam. Toxlcol. 21(3): 304-311.
Tanaka, S., M. Kaneko and Y. Hashimoto. 1984. Chemical form and behavior
of arsenic compounds In the atmosphere. Nippon Kagaku Kalshl. 4: 637-642.
(CA 100:214809c)
Tarrant, R.F. and 3. Allard. 1972. Arsenic levels In urine of forest
workers applying sllvlcldes. Arch. Environ. Health. 24(4): 277-280.
Taylor, R.T., S.A. Stewart and M.L. Hanna. 1984. Cocytotoxlclty/comutagen-
Iclty of arsenic In a Chinese hamster ovary triple auxotroph. Trace Subst.
Environ. Health. 18: 64-77.
USDI (U.S. Department of the Interior). 1988. Mineral Commodity Summaries
1988. Bureau of Mines, U.S. Dept. of the Interior, Washington, DC. p. 14.
U.S. EPA. 1975. Initial Scientific Review of Cacodyllc Add. Office of
Pesticide Programs, Criteria and Evaluation Dlv., Washington, DC. EPA
540/1-75-021. NTIS PB-251-241.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
0128d
-68-
03/31/89
-------
U.S. EPA. 1982. Completion of Pre-RPAR Review; Five Chemicals. Federal
Register. 47(92): 20376-20377.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxldty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 19865. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
>
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1987. Reportable Quantity Document for Cacodyllc Acid. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response, Washington, DC.
U.S. EPA/OWRS (Office of Water Regulations and Standards). 1986.
Guidelines for Deriving Numerical Water Quality Criteria for the Protection
of Aquatic Organisms and Their Uses. Office of Research and Development,
Washington, DC. NTIS PB85-227049/XAB.
0128d -69- 03/31/89
-------
USITC (U.S. International Trade Commlslon). 1987. Synthetic Organic
Chemicals. United States Production and Sales, 1986. USITC Publ. 2009,
Washington, DC. p. 188.
Vahter, M. 1983. Metabolism of arsenic. Ir»: Biological and Environmental
Effects of Arsenic, B.A. Fowler, Ed. Elsevler, NY. p. 171-198.
Valencia, R. 1981. Mutagenesls screening of pesticides "Drosophila."
EPA-600/1-81-017; PB81-160848. 82 p.
Wagner, S.L. and P. Weswlg. 1974. Arsenic In blood and urine of forest
workers. Indexes of exposure to cacodylic acid. Arch. Environ. Health.
28: 77-79.
Waters, H.D., S. Nesnow, V.F. Simmon, A.D. Mitchell, T.A. Jorgenspn and R.
Valencia. 1981. Pesticides: Mutagenic and carcinogenic potential.
Pesticide Chemist and Modern Toxicology. ACS Symp. Ser. 160: 89-113.
Wauchope, R.D. 1975. Fixation of arsenical herbicides, phosphate and
arsenate In alluvial soils. J. Environ. Qual. 4: 355-357.
Wauchope, R.D. 1976. Acid dissociation constants of arsenic acid, methyl-
arsonic acid {MAAJ, dlmethylarslnic add (cacodyUc acid) and N-(phosphono-
methyl)glycine (glyphosate). J. Agrlc. Food Chem. 24: 717-721.
Wauchope, R.D. and L.L. McDowell. 1984. Adsorption of phosphate, arsenate,
methanearsonate and cacodylate by lake and stream sediments: Comparisons
with soils. J. Environ. Qual. 13: 499-504.
0128d -70- 03/31/89
-------
Weed Science Society of America. 1983. Herbicide Handbook, 5th ed.
Humphrey Press, Inc., Geneva, NY. p. 86-88.
Wlllhlte, C.C. 1981. Arsenic-induced axial skeletal (dysrapnlc) disorders.
Exp. Mol. Pathol. 34(2): 145-158.
Windholz, M., Ed. 1983. Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 222.
Wong, P.T.S., Y.K. Chau, L. Luxon and G.A. Bengert. 1977. Hethylatlon of
arsenic In the aquatic environment. Trace Sub. Environ. Health. 11:
100-106.
Woolson, E.A. 1976. Organoarsenlcal herbicides. ITK Herbicides:
Chemistry, Degradation and Mode of Action, 2nd ed., P.C. Kearney and O.D.
Kaufman, Ed. Marcel Dekker, Inc.. New York, NY. p. 741-777.
Woolson, E.A. 1986. Burning cacodyllc acid-treated oak trees - How safe.
Forest Products J. 36(5): 49-52.
Woolson, E.A. and P.C. Kearney. 1973. Persistence and reactions of
14C-cacodyl1c add 1n soils. Environ. Sc1. Technol. 7: 47-50.
Worthing, C.R., Ed. 1983. The Pesticide Manual, 7th ed. British Crop
Protection Council, p. 206.
0128d -71- 03/31/89
-------
Yamauchl, H. and Y. Yamamura. 1984. Metabolism and excretion of orally-
administered dimethylars1n1c add tn the hamster. Toxlcol. Appl. Pharmacol.
74(1): 134-140.
0128d
-72-
03/31/89
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSOB
SCISEARCH
Federal Research In Progress
These searches were conducted in May, 1988, and the following secondary
sources were reviewed:
ACGIH {American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH {American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
^-
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0128d
-73-
02/01/89
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and 0. Eckroth, Ed. 1978-1984. Kirk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, MHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.H. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0128d -74- 02/01/89
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Hater Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed. .
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0128d -75- 02/01/89
-------
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APPENDIX C
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO CACODYLIC ACID
C.I. DISCUSSION
A dose/duration-response graph for oral exposure to cacodyllc add
generated by the method of Crockett et al. (1985) using the computer
software by Durkln and Meylan (1988) under contract to ECAO-C1nc1nnat1 1s
presented 1n Figure C-l. Data used to generate this graph are presented 1n
Section C.2. In the generation of this figure all responses are classified
as adverse {PEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for plotting.
If data are available for Inhalation exposure: The ordlnate expresses
concentration In either of two ways. In flgure(s) (—), the experimental
concentration expressed as mg/m3 was multiplied by the time parameters of
the exposure protocol (e.g., hours/day and days/week) and Is presented as
expanded experimental concentration [expanded exp cone {mg/m3}]. In
f1gure(s) {—), the expanded experimental concentration was multiplied by
the cube root of the ratio of the animal :human body weight to estimate an
equivalent human or scaled concentration [scaled cone (mg/m3)] (U.S. EPA,
1980; Mantel and Schnelderman, 1975).
The boundary for adverse effects (solid line) 1s drawn by Identifying
the lowest-adverse-effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point an Infinite
line Is extended upward parallel to the dose axis. The starting point Is
then connected to the lowest-adverse-effect dose or concentration at the
next longer duration of exposure that has an adverse-effect dose or
concentration equal to or lower than the previous one. This process Is
continued to the lowest-adverse-effect dose or concentration. From this
point a line 1s extended to the right parallel to the duration axis. The
region of adverse effects lies above the adverse effects boundary.
0128d -77- . 03/31/89
-------
188000
31
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eei 0.01 a!i J
HUNAN EQUIV DURATION (fraction lifespan) |
re> "
N NOEL
n NOAEL
L LOAEL
F FEL
0 NOCEL
FIGURE C-1
Dose/Duration-Effects from Oral Exposure to Cacocyllc Acid:
Envelope Method
Source: Crockett et al.t 198S
0128d
-78-
03/31/89
-------
Using the envelope method, the boundary for no adverse effects (dashed
line) 1s drawn by Identifying the highest no-adverse-effects dose or
concentration. From this point a line parallel to the duration axis Is
extended to the dose or concentration axis. The starting point 1s then
connected to the next highest or equal no-adverse-effect dose or
concentration at a longer duration of exposure. When this process can no
longer be continued, a line Is dropped parallel to the dose or concentration
axis to the duration axis. The region of no adverse effects lies below the
N,
no-adverse-effects boundary. At both ends of the graph between the
adverse-effects and no-adverse-effects boundaries are regions of ambiguity.
The area (If any) resulting from Intersection of the adverse-effects and
no-adverse-effects boundaries Is defined as the region of contradiction.
In the censored data method, all no-adverse-effect points located 1n the
region of contradiction are dropped from consideration and the
no-adverse-effect boundary Is redrawn so that It does not Intersect the
adverse-effects boundary and no region of contradiction Is generated. This
method results In the most conservative definition of the no-adverse-effects
region.
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Chemical Name: Cacodyllc Add
CAS Number: 75-60-5
Document Title: Health and Environmental Effects Document on Cacodyllc Acid
Document Number: pending
Document Date: pending
Document Type: HEED
0128d -79- 03/31/89
-------
RECORD #1:
Comment:
Citation:
RECORD #2:
Comment:
Citation:
RECORD #3:
Species: Rats
Sex: Male
Effect: PEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1050 value
Galnes and Under,
Species: Rats
Sex: Female
Effect: PEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1050 value
Galnes and Linden,
Species: Rats
Sex: Both
Effect: PEL
Route: Gavage
10
5
DEATH
NR
9
1986
10
5
DEATH
NR
9
1986
Dose: 1315.000
Duration Exposure: 1.0 days
Duration Observation: 14.0 days
i
Dose: , 644.000
Duration. Exposure: 1.0 days
Duration Observation: 14.0 days
(
Dose: 1433.000
Duration Exposure: 1.0 days
Duration Observation: 14.0 days
Comment:
Citation:
Number Exposed: 10
Number Responses: 5
Type of Effect: DEATH
SHe of Effect: NR
Severity Effect: 9
1050 value for weanlings, both sexes
Galnes and Under, 1986
0128d
-80-
03/31/89
-------
RECORD #4:
Species: Rats
Sex: NS
: Effect: PEL
Route: Oral (NOS)
Dose:
Duration Exposure:
Duration Observation:
700.000
1.0 days
1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
,S1te of Effect: NR
Severity Effect: 9
Comment:
Citation:
RECORD #5:
1050 value, details not
Farm Chemical Handbook,
Species: Rats
Sex: Both
Effect: PEL
Route: Oral (NOS)
available
1987
Dose:
Duration Exposure:
Duration Observation:
830.000
1.0 days
1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SHe of Effect: NR
Severity Effect: 9
Comment:
Citation:
RECORD #6:
1059 value* details not
Weed Science Society of
Species: Rats
Sex: NS
Effect: PEL
Route: Oral (NOS)
reported
America, 1983
Dose:
Duration Exposure:
Duration Observation:
1350.000
1.0 days
1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 9
Comment:
Citation:
Ll>50 value, details not
Bailey and White, 1965
reported
0128d
-81-
03/31/89
-------
RECORD #7:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Gavage
Dose: 700.000 -
Duration Exposure: 1.0 days
Duration Observation: 14.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 9
Comment:
Citation:
RECORD #8:
1050 value, Incomplete description of study
Nees, 1960
Species:
Sex:
Effect:
Route:
Rats
NS
LOAEL
Food
Dose:
Duration Exposure:
duration Observation:
280.000
20.0 days
20.0 days
Number Exposed: 10
Number Responses: NR
Type of Effect: ATROP
Site of Effect: TESTE
Severity Effect: 7
Reduced activity of sperma'togonia cells; atrophlc changes
seminiferous tubules among weanlings.
Nees, 1960
In
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
140.000
20.0 days
20.0 days
Comment:
Citation:
Number Exposed: 10
Number Responses: NR
Type of Effect: ATROP
Site of Effect: TESTE
Severity Effect: 3
Among weanlings, no hlstologlcal effects noted on testes,
brain; heart, lungs, abdominal organs or bone.
Nees, 1960
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RECORD #10;
Comment:
CHatlon:
Comment:
CHatlon:
Comment:
CHatlon;
Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Food
Dose: 9.200
Duration Exposure: 90.0 days
Duration Observation: 90.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 1
No effects noted on body weight, food consumption, organ
weights, hematology. Unclear whether testls was examined.
\ •
Nees, 1968
RECORD 111:
Species:
Sex:
.Effect:
Route:
Rats
N.S.
NOEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
118.000
3.0 weeks
3.0 weeks
Number Exposed: 10
Number Responses: NR
Type of Effect: ATROP
Site of Effect: TESTE
Severity Effect: 1
No atrophlc changes In seminiferous tubules or decrease In
activity of spermatogonla cells.
Meed Science Society of America, 1983
RECORD #12:
Species:
Sex:
Effect:
Route:
Rats
N.S.
LOAEL
Food
Dose:
Duration
duration
Exposure:
Observation:
226.000
3.0 weeks
3.0 weeks
Number Exposed: 10
Number Responses: NR
Type of Effect: ATROP
SHe of Effect: TESTE
Severity Effect: 7
tubules, decreased activity of
Heed Science Society of America, 1983
Atrophy of seminiferous
spermatogonla cells
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RECORD #13:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Dogs
Both
NOEL
Food
Number Exposed: 8
Number Responses: NR
Type of Effect: ELIMI
Site of Effect: KIDNY
Severity Effect: 3
Dose:
Duration Exposure:
Duration Observation:
8
NR
ATROP
BODY
3
0.750
90.0 days
90.0 days
No effects noted on kidney or liver function, uMnalysls.
hlstopathology of major organs or tissues; unclear whether
testes were examined.
Derse, 1968
RECORD #14:
Species:
Sex:
Effect:
Route:
Mice
Both
NOCEL
Gavage
Dose:
Duration
duration
Exposure:
Observation:
15.700
80.0 weeks
80.0 weeks
Comment:
Citation:
Number Exposed: 18
Number Responses: NR
Type of Effect: CANCR
Site of Effect: BODY
Severity Effect: 7
Incidence of pulmonary adenoma, uterine lelomyoma and Inci-
dental lesions was not significantly different from that of
untreated and pooled controls
BRL, 1968; Innes et al., 1969
RECORD #15:
Species:
Sex:
Effect:
Route:
Rats
Female
NOAEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
15.000
10.0 days
21.0 days
Comment:
Citation:
Number Exposed: 21
Number Responses: NR
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 3
No palatine effects noted 1n this
administered on gestation days 7-16.
Rogers et al., 1981
teratology study. Dose
01280
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RECORD #16:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Gavage
Dose: 30.000
Duration Exposure: 10.0 days
Duration Observation: 21.0 days
Number Exposed: 21
Number Responses: NR
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 3
Teratogenlc effects: Irregular palatine rugae;
Istered on gestation days 7-16.
Rogers et a!., 1981
dose admin-
RECORD #17:
Species:
Sex:
Effect:
Route:
Mice
Female
LOAEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
200.000
10.0 days
21.0 days
Number Exposed: 30
Number Responses: NR
Type of Effect: WGTIN
Site of Effect: BODY
Severity Effect: 3
Comment:
Citation:
RECORD #18:
Maternal toxlclty: reduced weight gain; dose administered on
gestation days 7-16.
Rogers et
Species:
Sex:
Effect:
Route:
al., 1981
Mice
Female
LOAEL
Gavage
Dose: 400.000
Duration Exposure: 10.0 days
Duration Observation: 21.0 days
Number Exposed: 30
Number Responses: 1
Type of Effect: TERAS
Site of Effect: FETUS
Severity Effect: 3
Comment:
Citation:
Teratogenlc effect: cleft palates In 57% of
administered on gestation days 7-16.
Rogers et al., 1981
litters; dose
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RECORD #19;
Comment:
Citation:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
PEL
Gavage
Dose: 1600.000
Duration Exposure: 1.0 days
Duration Observation: 18.0 days
Number Exposed: 20
Number Responses: 5
Type of Effect: DEATH
Site of Effect: N.S.
Severity Effect: 9
20
NR
WGT1N
BODY
3
20
NR
dEATH
FETUS
9
20
NR
WGTIN
FETUS
3
20
NR
TERAS
FETUS
3
Maternal and fetotoxlclty (death, reduced weight gain);
teratogenlc effects (delays In ossification and renal papilla
development; skeletal and soft tissue abnormalities markedly
higher than controls
Kavlock et al., 1985
RECORD #20:
Species:
Sex:
Effect:
Route:
Mice
Female
FEL
Water
Dose:
Duration
Duration
Exposure:
Observation:
3.400
5.0 days
17.0 days
Number Exposed: 24
Number Responses: 4
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Maternal death; reduced fetal and maternal body weight gain
Chernoff and Kavlock, 1982
NR = Not reported
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