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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is 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 Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), 1s provided.
These potency estimates are derived for both oral and inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genldty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxldty and cardno-
genldty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer based RQs are defined 1n U.S.
EPA, 1984 and 1986, respectively.
111
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EXECUTIVE SUMMARY
Pure chloroacetlc add 1s a colorless, deliquescent solid that 1s highly
soluble In water. Because of the blfunctlonal nature of the compound 1t 1s
chemically reactive both at the chlorine and carboxyllc ends of the molecule
(Frelter, 1978). Currently, three companies with a combined annual produc-
tion capacity exceeding 80 million pounds manufacture this chemical 1n the
United States (SRI, 1987; USITC, 1987; CMR, 1986). In 1984, 8.08 million
pounds of the chemical was Imported to the United States through principal
custom districts (USDC, 1985). The U.S. annual demand for chloroacetlc acid
was 80 million pounds 1n 1986 and the demand 1s projected to be 87 million
pounds 1n 1990 (CMR, 1986). Of the total usage, -45% of chloroacetlc add
Is used as 1n the manufacture of cellulose ethers and 15% 1n the manufacture
of thloglycoUc add and glydne. About 40% of this compound 1s used as a
postemergent herbicide and defoliant and 1n the manufacture of other
herbicides (CMR, 1986; Worthing, 1983).
The most significant atmospheric processes that are likely to remove
chloroacetlc add present 1n the atmosphere both 1n the vapor and aerosol
forms are wet and dry deposition. In water, the half-life of mineralization
of this compound that 1s due to blodegradatlon will be <8 days (BoethUng
and Alexander, 1979). It will not sorb significantly to suspended solid and
sediments In water, and bloaccumulatlon 1n aquatic organisms will be Insig-
nificant. Blodegradatlon 1s probably the most significant process 1n soil,
although the half-life from this process cannot be given. Because of Us
predicted weak sorptlon In soil, chloroacetlc add Is likely to leach Into
groundwater In cases where the blodegradatlon half-life may be longer than
the Infiltration half-life.
1v
-------
Limited monitoring data are available for this compound to assess Us
human exposure potential from any environmental medium. Chloroacetlc add
was detected In the concentration range 3.2-7.8 vg/m3 1n flue gas
(volume normalized to 10% C02> 0°C and 100 kPa pressure) from a municipal
Incinerator In Sweden (Mowrer and Nordln, 1987). It was also detected 1n
kraft pulp-spent bleach liquors at a concentration <4 g/ton-pulp (Carlberg
et al., 1986; Undstrom and Osterberg, 1986). ChloMnatlon of terrestrial
humlc add at both high and low chlorlnatlon rates (C,2/C molar ratio of
0.39 and 3.35) has been qualitatively shown to produce Chloroacetlc add (De
Leer et al., 1985). Polyvlnyl pipes used for the transmission of drinking
water may leach vinyl chloride Into drinking water. This may,-In turn,
react with chlorine used for disinfection to produce Chloroacetlc add;
however, H was shown that the formation of Chloroacetlc add will markedly
decrease with the aging of pipe and lowering of pH of water (Ando and
Sayato, 1984).
Reports of the toxldty of Chloroacetlc add to aquatic organisms are
limited to a single oral dosing study conducted with carp, CypMnus carplo.
Carp (sample size = 3) were force-fed encapsulated Chloroacetlc add at dose
levels of 177, 191 and 196 mg/kg and monitored for 24 to >40 hours at 65°F
(Loeb and Kelly, 1963). Fish were collected from the field with an electric
boat shocker; the fish ranged In size from 1-10 pounds (average ~3 pounds).
Test fish at the lowest dose were sick-and died In <23 hours after the
chemical was administered. At 191 mg/kg, fish experienced sickness at 25
hours and death at 28 hours. F1sh treated with the highest dose died In <54
hours. The authors concluded that the results of this study and of studies
with 1495 other chemicals could not be explained adequately because of a
lack of any trends 1n the results.
-------
Pertinent data regarding the effects of chronic exposure of aquatic
organisms or the effects of exposure of aquatic plants to chloroacetlc add
were not located 1n the available literature cited 1n Appendix A.
Pertinent data regarding the absorption or distribution of chloroacetlc
add were not located In the available literature cited In Appendix A. The
metabolism of chloroacetlc add appears to proceed principally by conjuga-
tion with glutathlone and degradation to thlodlacetlc add, dlthloacetlc
add or thloacetlc add. A minor pathway Involves hydrolysis to glycollc
add, which Is mainly oxidized to COp. Data from an 1ntraper1toneal
Injection study with mice and a case report of human dermal exposure.
Indicate that metabolism of chloroacetlc add and urinary excretion of
chloroacetlc add and metabolites are rapid and extensive.
Subchronlc studies were conducted 1n which chloroacetlc acid was admin-
istered to F344 rats and B6C3F1 mice dally by Intubation, 5 days/week for 13
weeks (IROC, 1982a,b). Dosages were 0, 30, 60, 90, 120 and 150 mg/kg for
the rats and .0, 25, 50, 100, 150 arrd 200 mg/kg for the mice. Compound-
related effects In the rats Included myocarditis at >30 mg/kg and mortality
that results from myocardlal failure at >90 mg/kg. Treatment-related
mortality and hepatic vacuolar degeneration occurred 1n the mice at 200
mg/kg primarily within the first 4 weeks (IRDC, 1982b).
Chloroacetlc add was not tumorlgenlc to mice when administered orally
at an approximate TWA dose of 20.4 mg/kg dally for 81 weeks (BRL, 1968),
when applied to the skin at a dose of 2 mg, 3 times/week for life (Van
Duuren et al., 1974), when administered by subcutaneous Injection at a dose
of 0.5 mg weekly for life (Van Duuren et al., 1974) or when administered as
a single 100 mg/kg subcutaneous Injection followed by 78 weeks of observa-
tion (BRL, 1968).
v1
-------
Chloroacetlc acid was not mutagenlc In the Salmonella/Ames assay, did
not Inhibit the growth of DNA repair-deficient strains of E_. coll or B_.
subtnis. did not Induce mutation to 8-azaguanlne or ouabaln resistance In
Chinese hamster V-79 cells, and was not clastogenlc In Chinese hamster lung
flbroblasts. Mutagenldty was demonstrated 1n the L5178Y tkVtk" mouse
lymphoma cell assay (Amacher and Turner, 1982; McGregor et a!., 1987).
Information regarding the teratogenlclty or other reproductive effects
of Chloroacetlc add were not located In the available literature.
Pertinent guidelines and standards, Including EPA ambient water and air
quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA toler-
ances for raw agricultural commodities or foods, and AC6IH, NIOSH or OSHA
occupational exposure limits were not located In the literature dted In
Appendix A.
The LOAEL for myocarditis from the subchronlc oral rat study was used to
calculate subchronlc and chronic oral RfDs of 1 mg/day and 0.1 mg/day,
respectively. Mortality In -the same study was used to calculate a chronic
toxldty RQ of 100.
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TABLE OF CONTENTS
Page
1. INTRODUCTION. 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.2. WATER 6
2.3. SOIL 7
2.4. SUMMARY. . 8
3. EXPOSURE. 9
4. AQUATIC TOXICITY 10
5. PHARMACOKINETCS 11
5.1. ABSORPTION 11
5.2. DISTRIBUTION 11
5.3. METABOLISM. . . . 11
5.4. EXCRETION. 12
5.5. SUMMARY. 13
6. EFFECTS ........................ • 14
6.1. SYSTEMIC TOXICITY. 14
6.1.1. Inhalation Exposure 14
6.1.2. Oral Exposure . 14
6.1.3. Other Relevant Information 17
6.2. CARCINOGENICITY 18
6.2.1. Inhalation 18
6.2.2. Oral 18
6.2.3. Other Relevant Information. 19
6.3. MUTAGENICITY . 20
6.4. TERATOGENICITY 20
6.5. OTHER REPRODUCTIVE EFFECTS 20
6.6. SUMMARY 20
7. EXISTING GUIDELINES AND STANDARDS 24
V111
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TABLE OF CONTENTS (cont.)
Page
8. RISK ASSESSMENT . 25
8.1. CARCINOGENICITY. 25
8.1.1. Inhalation 25
8.1.2. Oral 25
8..1.3. Other Routes 25
8.1.4. Weight of Evidence 25
8.1.5. Quantitative Risk Estimates 26
8.2. SYSTEMIC TOXICITY 26
8.2.1. Inhalation Exposure , 26
8.2.2. Oral Exposure 26
9. REPORTABLE QUANTITIES 28
9.1. BASED ON SYSTEMIC TOXICITY 28
9.2. BASED ON CARCINOGENICITY 30
10. REFERENCES 32
APPENDIX A: LITERATURE SEARCHED 41
APPENDIX B: SUMMARY TABLE FOR CHLOROACETIC ACID. . 44
1x
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LIST.OF TABLES
No. Title Page
1-1 U.S. Manufacturers and the Annual Capacity of
Chloroacetlc Add 3
6-1 Genotoxldty Testing of Chloroacetlc Acid 21
9-1 Composite Scores for the Oral Toxlclty of Chloroacetlc
Acid 1n Rats 29
9-2 Chloroacetlc Add: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 31
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
CS Composite score
DNA . DeoxyMbonuclelc add
Kow Octanol/water partition coefficient
LDso Dose lethal to 50% of recipients
(and all other subscripted dose levels)
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
MTD Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
ppt Parts per trillion
PVC Polyvlnyl chloride
RfD . Reference dose
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
TWA Time-weighted average
x1
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Chloroacetlc acid 1s also called monochloroacetlc add; chloroethanolc
acid; o-chloroacet1c add; and monochloroethandc add (HSDB, 1988). The
structure, molecular formula, molecular weight and CAS Registry number for
this compound are as follows:
0
//
C1CH2-C
\
OH
Molecular formula: C2H3C102
Molecular weight: 94.50
CAS Registry number: 79-11-8
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Pure chloroacetlc add Is a colorless, deliquescent solid that exists In
four crystalline modifications (I.e., alpha, beta, gamma and delta);
Commercial chloroacetlc add consists of the alpha form. Chloroacetlc add
Is highly soluble 1n water and 1s soluble 1n acetone, methylene chloride and
benzene (FreHer, 1978). Since this compound Is blfunctlonal, having both
reactive halogen and carboxyllc functional groups, 1t undergoes a variety of
reactions. The carboxyllc group can react with bases and alcohols to form
the corresponding salts and esters. The chlorine atom In this compound
undergoes a variety of nucleophlUc substitution reactions (FreHer, .1978).
Selected physical properties of this compound are as follows:
Melting point: 63°C (a-form), 55-56°C (B-form), FreHer, 1978
50°C (y-form), 42.75°C (\-form)
Boiling point: 187.8-187.9°C (all forms) Weast, 1985
0113d -1- 05/10/88
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Density: 1.4043 at 40/4°C Weast, 1985
Vapor pressure: 0.23 mm Hg at 20°C Weber et al.,
0.065 mm Hg at 25°C 1981
pKa: 2.81 at 25°C Foy, 1969
Water solubility: . 614 g/100 ml Frelter, 1978
Log Kow: 0.22 Hansch and Leo,
1985
1.3. PRODUCTION DATA
The U.S. EPA TSCA plant and production data base (U.S. EPA, 1977} listed
six companies as major manufacturers of chloroacetlc acid In the United
States In 1977. At least 12 companies Imported the chemical In the United
States during the same year (U.S. EPA, 1977). Current U.S. manufacturers
and their annual capacities are listed In Table 1-1. In 1984, 8.08 million
pounds of chloroacetlc add was Imported In the United States through
principal custom districts (USDC, 1985). The U.S. demand for chloroacetlc
acid was 80 million pounds In 1986 and has been projected to be 87 million
pounds In 1990 (CMR, 1986). Two processes used for the manufacture of
chloroacetlc acid are the chlorlnatlon of acetic add, which 1s used primar-
ily In the United States and Canada, and the hydrolysis of trlchloroethylene
with sulfurlc add, which 1s primarily used In Europe. Another potential
Industrial method for the manufacture of chloroacetlc add 1s the hydrolysis
of chloroacetyl chloride (Frelter, 1978).
1.4. USE DATA
In the United States, chloroacetlc add 1s used 1n the manufacture of
cellulose ethers used mainly for drilling muds, detergents, food and pharma-
ceutlcals, 45%; 1n the manufacture of herbicides and Hself as a post-
emergent herbicide and defoliant, 40%; and 1n the manufacture of glyclne and
th1oglyco!1c add, 15% (CMR, 1986; Worthing, 1983).
0113d -2- 05/10/88
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TABLE 1-1
U.S. Manufacturers and the Annual Capacity of Chloroacetlc Add*
Producer Annual Capacity Remarks
(millions of pounds)
Dow Chem., Midland, MI 30 partly captive use
Hercules Inc., Hopewell, VA 50 captive use
Pfizer Inc., Groton, CT unknown captive use
'Source: SRI, 1987; CMR, 1986; USITC, 1987
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1.5. SUMMARY
Pure chloroacetic acid 1s a colorless, deliquescent solid that 1s highly
soluble In water. Because of the blfunctlonal nature of the compound 1t Is
chemically reactive both at the chlorine and carboxyllc ends of the molecule
(Frelter, 1978). Currently, three companies with a combined annual produc-
tion capacity exceeding 80 million pounds manufacture this chemical 1n the
United States (SRI, 1987; USITC, 1987; CMR, 1986). In 1984, 8.08 million
pounds of the chemical was Imported to the United States through principal
custom districts (USDC, 1985). The U.S. annual demand for chloroacetic add
was 80 million pounds 1n 1986 and the demand 1s projected to be 87 million
pounds 1n 1990 (CMR, 1986). Of the total usage, ~45%-of chloroacetic add
Is used as 1n the manufacture of cellulose ethers and 15% In the manufacture
of thloglycollc add and glydne. About 40% of this compound Is used as a
postemergent herbicide and defoliant and 1n the manufacture of other
herbicides (CMR, 1986; Worthing, 1983).
0113d .-4- 05/10/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
The probable sources of chloroacetlc add In the environment are
emissions during Us production and use as an Intermediate primarily 1n the
manufacture of chlorophenoxy herbicides and carboxymethyl cellulose. The
use of chloroacetlc add Itself as a postemergent herbicide and defoliant 1s
also likely to cause significant environmental emissions. Chlor1nat1on of
humlc add produces chloroacetlc acid (De Leer et al., 1985); therefore,
effluents from kraft bleaching and wastewater treatment plants are Hkely
sources of this compound. It also may originate from municipal waste
Incinerations (Mowrer and Nordln, 1987).
2.1. AIR
The fate of chloroacetlc add In the atmosphere has not been adequately
studied. The extinction coefficient of chloroacetlc add 1n aqueous
solution for light absorption at 300-360 nm 1s <0.2 l/mol-cm (Draper and
Crosby, 1983). Since direct photolysis of this compound In aqueous solution
with light of wavelength >300 nm was slow (Section 2.2.), direct photolysis
1n the atmosphere 1s not likely to be significant. The rate constant for
the reaction of this compound with OH radicals In aqueous solution was
reported to be ~3xl07 l/mol-sec (Anbar and Neta, 1967). Therefore, this
reaction Is not likely to be significant In the atmosphere. Based on Its
high water solubility, a significant amount of chloroacetlc acid present In
the vapor and aerosol phases 1n the atmosphere would probably be removed by
wet deposition. In addition, chloroacetlc add that exists as atmospheric
aerosol as a result of Us use as a pesticide may be removed by dry
deposition.
0113d -5- 05/10/88
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2.2. WATER
The direct photolysis of chloroacetlc add 1n aqueous solution with
light of wavelength 300 and 360 nm was studied by Draper and Crosby (1983).
Photolysis Is followed by a dechlorlnatlon mechanism. PhotodechloMnatlon
of chloroacetlc add was, however, slow at these wavelengths; after 11 hours
of Irradiation 1n air-saturated solution, <0.4% of the compound was
converted Into free chloride 1on. The direct photodechlorlnatlon was found
to be stimulated by oxygen and by using an unknown mechanism since the yield
of free chloride was greatly reduced under a nitrogen atmosphere. The
photolysis of chloroacetlc add with shorter wavelength light (253.7 nm)
produced the following compounds: hydroxyacetlc add (glycollc add), carbon
dioxide, acetic add, formaldehyde and methane (Neumann-Spallart and Getoff,
1975). 0111s (1985) reported complete heterogeneous photom1nera!1zat1on of
chloroacetlc add Into HC1 and CO- with black-light fluorescent lamps
(wave-length 300 to <400 nm). With T102 as a catalyst and a specially
designed photoreactor, the rate constant for mineralization was 5.5
ppm/mln-g (catalyst). The photodechlorlnatlon of chloroacetlc add Is also
sensitized by compounds such as tryptophan, tryptophol, tyroslne, aniline
and other compounds that can produce superoxlde radicals under photolytlc
conditions. For example, the photodechlorlnatlon of chloroacetlc add
Increased by a factor of 16 In the presence of tryptophol when Irradiated
with light of wavelength 300 nm (Draper and Crosby, 1983). The hydrolysis
of chloroacetlc acid was negligible during these experiments (Draper and
Crosby, 1983). Aqueous chloroacetlc add reacts with OH radicals and the
rate constant for this reaction 1s ~3xl07 l/mol-sec (Anbar and Neta,
1967). A combination of this rate constant with a value of 3xlO~17
mol/9. for the concentration of OH radicals 1n eutroplc waters (Mill and
0113d -6- 06/16/88
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Mabey, 1985) will show that the estimated half-life for this reaction Is too
high and the reaction would probably be Insignificant In most natural waters.
The blodegradabmty of chloroacetlc acid with pure cultures of micro-
organisms was studied by several authors. Pure organisms such as Pseudo-
monas sp., Arthrobacter sp., Alcallgenes sp. TMchoderma v1r1de. Clono-
stachys sp., Acrostalagmos sp., Pen1c11l1um rouquefortl and Norcardla sp.
have been shown to degrade chloroacetlc add (Kearney et al., 1965; Slater
and Bull, 1982; Foy, 1969; Hlrsch and Alexander, 1960). Thorn and Agg (1975)
reported that chloroacetlc add should be degradable by microbes 1n sewage
provided suitable acclimatization can be achieved. In laboratory blodegra-
datlon studies with Inocula obtained from sewage or acclimated sludge,
>70-90% of the compound degraded 1n 5-10 days (Zahn and Wellens, 1974, 1980;
D1as and Alexander, 1971). Jacobson and Alexander (1981) reported that
prelncubatlng sewage with nonchloMnated organic substrates (e.g., sucrose)
enhanced the dechlorlnatVng blodegradatlon process. Mineralization of >50%
of chloroacetlc add; to C0? occurs In river water In .<8 days, although the
rate of blodegradatlon fell markedly with lower Initial concentration (from
47 ppm to 47 ppb) (Boethling and Alexander, 1979).
No experimental data regarding the physical transport processes for
chloroacetlc acid In water were located In the literature. Based on Us pKa
value of 2.81, this compound 1s expected to exist 1n Ionic form In most
natural waters. Therefore, significant volatilization of the compound from
water Is unlikely. Similarly, Us low log K value Indicates that
neither sorptlon to suspended solid and sediments 1n water nor bloconcentra-
tlon 1n aquatic organisms would be Important for chloroacetlc add.
2.3. SOIL
Data regarding the fate of chloroacetlc acid 1n soil are extremely
limited. Based on the predicted fate 1n water (see Section 2.2.), the loss
0113d -7- 06/16/88
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of this compound from photolysis, hydrolysis and volatilization 1n soil
would be Insignificant. This compound blodegrades with several pure
cultures of microorganisms Isolated from soil (Foy, 1969), Indicating that
blodegradatlon may be. a significant process for chloroacetlc add. Foy
(1969) reported that chlorinated aliphatic adds may be readily biodegrad-
able 1n soil. Jensen (1959) reported that chloroacetlc add was blodegraded
1n soil; however, the compound was comparatively resistant to blodegradatlon
1n addle soils and at low soil temperatures. While no quantitative data
regarding the rate of blodegradatlon In soil were located, the blodegrada-
tlon studies In water suggest that 1t would be a relatively rapid process.
Given Us high water solubility and Us predicted low soil sorptlon capabil-
ity, chloroacetlc add 1s expected to leach readily Into groundwater under
most circumstances; however, the half-life corresponding to blodegradatlon
must be substantially longer than the half-life that is due to Infiltration
for significant leaching to occur.
2.4. SUMMARY
The most significant atmospheric processes that are likely to remove
chloroacetlc add present 1n the atmosphere both In the vapor and aerosol
forms are wet and dry deposition. In water, the blodegradatlon half-life of
mineralization of this compound will be <8 days (BoethUng and Alexander,
1979). It will not sorb significantly to suspended solid and sediments 1n
water, and bloaccumulation in aquatic organisms will be insignificant.
Blodegradatlon Is probably the most significant process in soil, although
the half-life attributed to this process cannot be given. Because of Us
predicted weak sorptlon In soil, chloroacetlc add 1s likely to leach into
groundwater 1n cases where the blc°radatlon half-life 1s longer than the
half-life that Is due to infiltration.
0113d -8- 05/10/88
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3. EXPOSURE
Limited monitoring data are available for this compound to assess Us
human exposure potential from any environmental medium. Chloroacetlc acid
was detected 1n the concentration^ range 3.2-7.8 yg/m3 1n flue gas
(volume normalized to 10% CO-, 0PC and 100 kPa pressure) from a municipal
Incinerator In Sweden (Mowrer and NordVh, 1987). It was also detected In
kraft pulp-spent bleach liquors at a concentration <4 g/ton-pulp (Carlberg
et al., 1986; Llndstrom and Osterberg, 1986). ChloMnatlon of terrestrial
humlc add at both high and low chlorlnatlon rates (C,2/C molar ratio of
0.39 and' 3.35) has been qualitatively shown to produce Chloroacetlc add (De
Leer et al., 1985). Polyvlnyl pipes used for the transmission of drinking
water may leach vinyl chloride Into drinking water. This may, 1n turn,
react with chlorine used for disinfection to produce Chloroacetlc add;
however, It was shown that the formation of Chloroacetlc add will markedly
decrease with the aging of pipe and Towering of pH of water (Ando and
Sayato, 1984).
0113d -9- 05/10/88
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4. AQUATIC TOXICITY
Reports of the toxldty of chloroacetlc add to aquatic organisms are
limited to a single oral dosing study conducted with carp, CypMnus carplo.
Carp (sample size = 3) were force-fed encapsulated chloroacetlc add at dose
levels of 177, 191 and 196 mg/kg and monitored for 24 to >40 hours at 65°F
(Loeb and Kelly, 1963). F1sh were collected from the field with an electric
boat shocker; the fish ranged In size from 1-10 pounds (average ~3 pounds).
Test fish at the lowest dose were sick and died In <23 hours after the
chemical was administered. At 191 mg/kg, fish experienced sickness at 25
hours and death at 28 hours. Fish treated with the highest dose died 1n <54
hours. The authors concluded that the results of this study and of studies
with 1495 other chemicals could not be explained adequately because of a
lack of any trends 1n the results.
Pertinent data .regarding the effects of chronic exposure of aquatic
organisms or the effects of exposure of aquatic plants to chloroacetlc add
were not located 1n the available literature dted In Appendix A.
0113d -10- 06/16/88
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5. PHARMACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the absorption of chloroacetlc add following
oral or Inhalation exposure were not located 1n the available literature
dted 1n Appendix A.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of chloroacetlc add were not
located 1n the available literature cited In Appendix A.
5.3. METABOLISM
Single doses of ~2 mg aqueous [1-14C] chloroacetlc add were admin-
istered to female albino mice by Intraperltoneal Injection (Yllner, 1971).
Urine, feces and expired air were collected for 3 days and analyzed for
radioactivity and metabolites. Results of these analyses showed that most
of the radioactivity appeared 1n the urine (82-88%) and expired air (8%).
Paper chromatographVc and Isotope dilution analyses of the urine showed the
following compounds (mean percentage of urinary activity excreted Tn 24
hours): 13% (range 6-22) chloroacetlc acid, 39% (33-43) S-(carboxymethyl )-
cysteine, 3% (range 1-6) conjugated S-(carboxymethyl)cysteine, 37% (range
33-42) th1od1acet1c acid, 4% (range 3-5) glycollc add and 0.2% (range
0.1-0.2) oxalic acid. Carbon dioxide was the major metabolite 1n the
expired air.
Similar results were found following Intragastrlc administration of
single 50 mg/kg doses of aqueous [1-1AC] chloroacetlc add or [2-14C]
chloroacetlc add to male rats (Jones and Hathway, 1978). Chromatographlc
analyses showed the following urinary metabolites (mean percentage of
urinary activity excreted 1n 48 hours): 90.0% th1od1acet1c add, 2.0%
0113d -11- 06/16/88
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S-(carboxymethyl)cyste1ne, 3.0% d1th1oacet1c add, 3.0% thloacetlc acid and
0.554 urea. The amount of administered radioactivity recovered In the urine
was not Indicated.
2
14CO was detected 1n the breath of a worker who accidentally
spilled hot liquid [1-14C] chloroacetlc add on his fingers (Dancer et
a!., 1965). Breath samples were collected 15 and 23 days after exposure.
Two metabolic pathways for chloroacetlc add have been proposed (Yllner,
1971; Jones and Hathway, 1978). The principal pathway Involves reaction
with glutathlone and subsequent degradation, yielding thlodlacetlc add,
d1th1oacet1c add or thloacetlc add as ultimate products. The second
pathway (minor) Involves hydrolysis of the carbon-chlorine bond with
formation of glycollc add, which 1s mainly oxidized to carbon dioxide.
5.4. EXCRETION
Metabolism studies Indicate that the urine Is the primary route of
elimination of choroacetlc add; however, quantitative data for elimination
following oral or Inhalation exposure were not located 1n the available
literature.
Intraperltoneal Injection of single 2 mg [1-14C] doses of aqueous
chloroacetlc add to mice resulted 1n the occurrence of 82-88, 8, 2-3 and
0.2-354 of the administered radioactivity 1n the urine, expired air, feces
(contaminated with urine) and carcass, respectively, In 3 days (Yllner,
1971). Between 80 and 90% of the radioactivity was eliminated during the
first 24 hours. Urinary excretion of radioactivity by a human following
accidental dermal exposure to an unknown quantity of hot [1-14C] chloro-
acetlc add was blphaslc (Dancer et al., 1965). The half-time of the rapid
e> phase was calculated to be ~15 hours. The data from the Injection and
dermal studies Indicate that metabolism and elimination of chloroacetlc add
are rapid and extensive.
0113d -12- 06/16/88
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5.5. SUMMARY
Pertinent data regarding the absorption or distribution of chloroacetlc
acid were not located 1n the available literature dted In Appendix A. The
metabolism of chloroacetlc add appears to proceed principally by conjuga-
tion with glutathlone and degradation to thlodlacetlc add, d1th1oacet1c
add or thloacetlc add. A minor pathway Involves hydrolysis to glycollc
•.,'
add, which Is mainly oxidized to COp. Data from an IntraperHoneal
Injection study with mice and a case report of human dermal exposure
Indicate that metabolism of chloroacetlc add and urinary excretion of
chloroacetlc add and metabolites are rapid and extensive.
0113d -13- 06/16/88
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC -- Pertinent data regarding the subchronlc
toxldty of Inhaled chloroacetlc add were not located 1n the available
literature cited 1n Appendix A.
6.1.1.2. CHRONIC ~ An English summary of a Russian study (Makslmov
and Dub1n1na, 1974} reported that chronic Inhalation of chloroacetlc add
caused weight reduction, decreased oxygen uptake and rectal temperature,
hemoglobinemia and Inflammatory changes In the respiratory organs of rats
and guinea pigs at concentrations >5.8 mg/m3. Additional Information
regarding the design and results of this study was not reported In the
summary.
6.1.2. Oral Exposure.
6.1.2.1, SUBCHRONIC — Subchronlc oral studies of chloroacetlc add
conducted by IRDC (T982a,b) were designed to provide data for selecting
dosage levels for chronic bloassays. In these studies, F344 rats (age 29-36
days) and B6C3F1 mice (age 36-43 days) were administered chloroacetlc acid
(purity >97.2%) dally by Intubation, 5 days a week for 13 weeks. Dosages
were 0 (vehicle control), 30, 60, 90, 120 and 150 mg/kg for the rats and 0
(vehicle control), 25, 50, 100, 150 and 200 mg/kg for the mice. Groups of
10 anlmals/sex/dose of each species were treated with the chemical dissolved
1n water and 10 animals/sex/dose were treated with the chemical suspended 1n
corn oil. Appearance and behavior were evaluated weekly, and body weights
were measured at study Initiation, weekly, and before Interim (4 and 8
weeks) and final sacrifices. Hematology, clinical chemistry, urinalysis and
bone marrow smear evaluations were performed on five animals/sex/dose of
0113d -14- 06/16/88
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each species from the water vehicle groups at the Interim sacrifices, and on
all surviving animals 1n the water vehicle groups at study termination.
Comprehensive gross and hlstologlcal examinations, Including organ weight
determinations, were performed on all animals that died spontaneously or
were sacrificed \n_ extremis or at study termination. The report of the rat
study (IRDC, 1982a) appears to be a draft.
Signs of toxldty In the rats Included unspecified Incidences of rattled
breathing or respiratory congestion In all water vehicle treated groups
(IRDC, 1982a). Mortality was high at >90 mg/kg In both the water and corn
oil groups. Survival at study termination 1n the 0, 30, 60, 90, 120 and 150
mg/kg water groups was 10/10, 10/10, 8/10, 1/10, 0/13 and 0/15 1n males, and
10/10, 9/10, 9/10, 0/10, 0/15 and 0/17 1n females, respectively. Survival
at study termination 1n the 0, 30, 60, 90, 120 and 150 mg/kg corn oil groups
was 10/10, 10/10, 9/10, 2/10, 0/10 and 0/10 1n males, and 10/10, 10/10,
9/10, 2/10, 0/10 and 0/10 1n females, respectively. The deaths that
occurred at 30 and 60 mg/kg were not considered to be compound-related
{IRDC, 1982a). There were no treatment-related alterations 1n mean body
weight or hematology, clinical chemistry or urlnalysls Indices 1n any of the
groups throughout the study. Results of the bone marrow smear evaluations
were not provided.
Gross pathologic alterations, consisting of lung congestion and clear/
red fluid or blood 1n the thoracic cavity, were observed only 1n the rats
that died (IRDC, 1982a). These effects were considered to be secondary to
myocarditis, which was observed microscopically. Statistically significant
alterations In absolute or relative organ weights occurred 1n several dose
groups; these Included decreased heart weight In females at 30 and 60 mg/kg
and males at 60 mg/kg (water vehicle only), and Increased adrenal weight In
males and females'at 30, 60 and 90 mg/kg (corn oil vehicle only). Because
0113d -15- 06/16/88
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these effects did not occur with both vehicles and were not dose-related,
they are not considered to be unequivocally attributable to treatment.
Treatment-related hlstologlc alterations Included acute/subacute myocarditis
1n males and females receiving chloroacetlc acid 1n either water or corn
oil; this effect occurred at >30 mg/kg 1n rats that survived until terminal
sacrifice and 1n rats that died during the study. There was mild to severe
multlfocal or diffuse acute passive congestion 1n the lungs of rats that
died, but not 1n. rats that survived until terminal sacrifice. The lung
congestion was considered to be secondary to myocardlal failure. Other
treatment-related hlstologlcal alterations were not observed In the rats.
Infrequent signs of toxldty were observed 1n the mice treated with 200
mg/kg chloroacetlc add 1n corn oil; these Included plloerectlon, body
tremors, hypoactlvHy, ataxla, hypothermia, bradycardla, low carriage, pros-
tration and hypopnea (.IRDC, 1982b). Treatment-related mortality occurred at
200 mg/kg 1n both sexes 1n both the water and corn oil vehicle groups.
Survival at study termination 1n the 0, 25, 50, 100, 150 and 200 mg/kg water
groups was 8/10, 10/10, 10/10, 10/10, 10/10 and 0/10 In males, and 10/10,
10/10, 10/10, 9/10, 10/10 and 8/10 1n females, respectively. Survival at
study termination 1n the 0, 25, 50, 100, 150 and 200 mg/kg corn oil groups
was 10/10, 10//10, 10/10, 10/10, 7/10 and 0/10 In males, and 10/10, 10/10,
10/10, 9/10, 10/10 and 3/10 1n females, respectively. Most of the deaths
occurred before the fourth week; the deaths of the two female mice at 100
nig/kg were attributed to gavage Injury. There were no compound-related
effects on mean body weight, hematology, clinical chemistry or urlnalysls
Indices, absolute or relative organ weights, or macroscopic appearance of
tissues. Results of the bone marrow smear evaluations were not provided.
0113d -16- 06/16/88
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Hlstologlcal examinations revealed a trace to severe vacuolar degeneration
1n the livers of some of the mice that died during the study; Incidences
were 1/3 males at 150 mg/kg 1n corn oil, 3/10 males and 4/7 females at 200
mg/kg In corn oil, and 5/12 males and 1/2 females at 200 mg/kg 1n water.
The liver lesions were not considered sufficient to constitute the cause of
death and were not observed among surviving mice.
6.1.2.2. CHRONIC — Pertinent data regarding the chronic oral
toxlclty-of chloroacetlc add were not located 1n the available literature
cited 1n Appendix A. Noncardnogenlc effects were not reported In the BRL
(1968) chronic oral carclnogenldty study summarized In Section 6.2.2.
6.1.3. Other Relevant Information. Acute oral LD5Qs of 130 and 98
mg/kg (water vehicle) and 98 and 113 mg/kg (corn oil vehicle) were deter-
mined for chloroacetlc add with male and female F344 rats, respectively
(IRDC, 1982a). Groups of five F344 rats of each sex were administered
choloroacetlc add 1n water or corn oil by Intubation at dosages of 7.5, 15,
30, 60 or 120 mg/kg dally for 12 dose days, not including weekends (IRDC,
1982a). One male (water vehicle) and one female (corn oil vehicle) died at
120 mg/kg, but treatment-related macroscopic or microscopic alterations were
not observed at any dosage.
Acute oral LD5Qs of 226 and 226 mg/kg (water vehicle) and 299 and 453
mg/kg (corn oil vehicle) were determined for male and female B6C3F1 mice,
respectively (IRDC, 1982b). Groups of five B6C3F1 mice of each sex were
administered choloroacetlc add in water or corn oil by intubation daily for
12 dose days, not including weekends (IRDC, 1982b). Dosages were 15, 30,
60, 120 or 240 mg/kg in the males and 30, 60, 120, 240 or 480 mg/kg 1n the
females. Treatment-related signs of toxlcity and mortality occurred at >240
mg/kg, but there were no macroscopic or microscopic alterations unequivo-
cally attributable to treatment at any dose.
0113d -17- 06/16/88
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Approximately 10% of male Swiss-Webster mice that survived single oral
LD5Q (260 mg/kg) or LD8Q (380 mg/kg) doses of monochloroacetlc add for
24 hours exhibited neurological dysfunction 1n which the front paws were
rigidly clasped together and the hind limbs splayed, causing difficulty In
walking (Berardl et al., 1987). The effect appeared to be permanent, as H
persisted up to 6 months after treatment. Hlstologlcal examination of the
brain and blood-brain barrier Integrity studies showed that both death and
neurological dysfunction resulted from damage to the blood-brain barrier.
IntraperHoneal Injection of a single 119 mg/kg dose of chloroacetlc
add Induced hypothermia 1n mice (Masuda and Nakayama, 1983).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled chloroacetlc add were not located In the available literature cited
In Appendix A. .
6.2.2. Oral. Groups of 18 B6C3F1 and 18 • B6AKF-1-'mice -of • each sex-were
administered chloroacetlc add in distilled water by stomach tube dally at a
dose of 46.4 mg/kg from days 7-28 of age (weaning) (BRL, 1968). The mice
were subsequently treated 1n the diet at a concentration of 149 ppm for 78
weeks. Treatment represented the MTO for young mice determined in pre-
chronic studies; the dose was not adjusted to changing body weight during
the 3 weeks of gavage treatment, but a single adjustment was made at the
time of conversion from stomach tube to Incorporation 1n the feed. If it is
assumed that daily food consumption was 13% of body weight (U.S. EPA, 1980),
then the TWA dosage was 20.4 mg/kg/day. Four untreated groups and one
gelatin treated group containing 18 mice/strain/sex each served as controls.
Following the treatment period, all surviving mice were dissected and
examined grossly, and tissue samples from the chest contents, liver, spleen,
0113d -18- 06/16/88
-------
kidneys, adrenals, stomach, Intestines and genitals were examined micro-
scopically. Mice that were sacrificed when moribund were subjected to gross
pathologic examinations, but histologlcal examinations were performed only
when deemed appropriate (criteria not specified). Fifteen to 17 of the 18
mice 1n the treated groups survived to the end of the study. No statis-
tically significant (p<0.05) Increases 1n tumor Incidences were found when
any group or combination of treated groups was compared with Individual or
pooled control groups.
A National Toxicology Program cardnogenesls bloassy of chloroacetlc
add, 1n which rats and mice were exposed by gavage, 1s currently In the
hlstopathology phase (NTP, 1988).
6.2.3. Other Relevant Information. A dose of 2 mg chloroacetlc add 1n
acetone was .applied to the shaved Interscapular skin of 50 female ICR/Ha
mice (6-8 weeks old), 3 times/week for life (Van Duuren et al., 1974). The
median survival time and study duration were 506 and 580 days, respectively.
Skin papHlomas or carcinomas or macroscopic tumors at distant sites'did not
develop In any of the treated mice.
Subcutaneous injections of 0.5 mg chloroacetlc acid in trlcaprylln
vehicle were administered once a week to 50 female ICR/Ha mice (6-8 weeks
old) for life (Van Duuren et al., 1974). The median survival time and study
duration were 454 and 580 days, respectively. There were no treatment-
related Increased Incidences of injection site tumors or macroscopic distant
tumors.
Groups of 18 B6C3F1 and B6AKF1 mice of each sex were administered single
subcutaneous Injections of 100 mg/kg chloroacetlc acid 1n distilled water in
the neck on day 28 of age and observed for 78 weeks (BRL, 1968). Systemic
histopathologlcal examinations, conducted as in the BRL (1968) oral
0113d -19- 06/16/88
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carcinogenldty study (Section 6.2.2.), showed no treatment-related
Increased Incidence of tumors.
6.3. MUTAGENICITY
The genotoxldty of chloroacetlc add has been evaluated 1n Ui vitro
assays with bacteria and mammalian cells. As detailed 1n Table 6-1, chloro-
acetlc acid was not mutagenlc 1n the Salmonella/Ames assay, did not Inhibit
the growth of DNA repair-deficient strains of E_. coll or IB. subtilis. did
not Induce mutation to 8-azaguan1ne or ouabaln resistance 1n Chinese hamster
V-79 cells, and did not produce clastogenlc effects (chromosome aberrations
or s1ster-chromat1d exchange) 1n Chinese hamster lung flbroblasts. Positive
responses were demonstrated in the L5178Y tk /tk~ mouse lymphoma cell
forward mutation assay 1n two studies (Amacher and Turner, 1982; McGregor et
al., 1987).
6.4. TERATOGENICITY
Pertinent data regarding the teratogenicity of chloroacetlc acid were
not located in the available literature cited in Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of chloroacetlc acid
were not located 1n the available literature cited 1n Appendix A.
6.6. SUMMARY
Subchronic studies were conducted In which chloroacetic add was admin-
istered to F344 rats and B6C3F1 mice dally by intubation, 5 days/week for 13
weeks (IRDC, 1982a,b). Dosages were 0, 30, 60, 90, 120 and 150 mg/kg for
the rats and 0, 25, 50, 100, 150 and 200 mg/kg for the mice. Compound-
related effects In the rats included myocarditis at >30 mg/kg and mortality
that was due to myocardlal failure at >90 mg/kg. Treatment-related
mortality and hepatic vacuolar degeneration occurred In the mice at 200
mg/kg primarily within the first 4 weeks (IRDC, 1982b).
0113d -20- 06/16/88
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TABLE 6-1
Genotoxtctty Testing of Chloroacettc Acid
to
a.
Assay Indicator
Organism
Reverse Salmonella
mutation typhlmurlum
TA100
TA98
TA1535
1A1537
TA1538
S. typhlmurlum
TA100
TA98
TA1535
TA1537
S. typhlmurturo
TA1530
i
^j
i
S. typhlmurlua
TA1535
S. typhlmurlum
TA100
TA98
TA1535
TA1537
DNA repair Escherlchla
col 1 UP2/WP100
(uvrA", recA~)
HP2/UP67 Pol
U3110/p3478 Pol
DNA repair Bacillus subtllls
MC-1
§? Prophage E. coll GY5027
^ Induction envA uvrB~
<7>
Purity
NR
purest
grade
available
purest
grade
available
NR
99*
NR
analyti-
cally pure
highest
purity
available
Application
plate
Incorporation
plate
Incorporation
plate
Incorporation
prelncubatlon
prelncubatlon
spot test
(wells)
spot test
(filter discs)
plate
Incorporation
Concentration
or Dose
1 rag/plate
NR
NR
NR
NR
<1 ing/plate
<1 rag/plate
<1 rag/plate
<1 rag/plate
1.1. 10.8 and
108 pmol/plate
0.1. 0.5 and
1.5 mH
10-333 pg/plate
10-333 yg/plate
10-333 pg/plate
10-333 pg/plate
<400 pg/well
NR
NR
NR
<2000 pg/plate
Activating Response Comment
System
NC
none
none
none
none
none
NC
* S-9
» S-9
f S-9
7 S-9
» S-9 - toxlclty at >10.8
iimol/plate
•
none - NC
rat and hamster S-9
* S-9 - used; toxlclty at
7 S-9 - >2000 pg/plate
* S-9
» S-9
S-9 NC
S-9
NR
NR
none - NC
S-9 - NC
Reference
NcCann
et al.. 1975a
HcCann
et al., 1975b
Bartsch
et al.. 1975.
1980;
Nalavetlle
et al.. 1975
Rannug
et al.. 1976
Hortelmans
et al.. 1986
Namber
et al.. 1983
Elmore
et al.. 1976
Namber
et al.. 1984
CO
CD
-------
-1 (cont.)
Assay
Hutatlon to
8-azaguanlne
or ouabaln
resistance
Nutation
thymldlne
ktnase
deficiency
Chromosome
aberration
la vitro
Sister-
chroma t Id
exchange
Indicator Purity
Organism
Chinese hamster NR
V79 cells
mouse lymphoma 99X
L5178Y cells
mouse lymphoma NR
L5178Y cells
Chinese hamster >99X
lung flbroblasts
Chinese hamster >99X
lung flbroblasts
Application Concentration Activating
or Dose System
liquid' <2100 |Jt . none
suspension
liquid 139-785 Mg/mi S-9
suspension
liquid 31-800 vq/aA none
suspension
monolayer 0.06-0.5 rag/ml •_ S-9
roonolayer 0.06-0.25 iwj/ml t_ S-9
Response Comment
NC
f mutagenlc at toxic to
concentrations
> Inconclusive In one
of three trials
NC
• NC
Reference
Huberman
et al., 1975
Amacher and
Turner. 1982
McGregor
et al., 1987
Sawada
et al., 1987
Sawada
et al., 1987
NK - Not reported; NC = no comment
-------
Chloroacetlc acid was not tumorlgenlc to mice when administered orally
at an approximate TWA dose of 20.4 mg/kg dally for 81 weeks (BRL, 1968),
when applied to the skin at a dose of 2 mg, 3 times/week for life (Van
Duuren et al., 1974), when administered by subcutaneous Injection at a dose
of 0.5 mg weekly for life (Van Duuren et al., 1974) or when administered as
a single 100 mg/kg subcutaneous Injection followed by 78 weeks of observa-
tion (BRL, 1968).
Chloroacetlc acid was not mutagenic 1n the Salmonella/Ames assay, did
not Inhibit the growth of DNA repair-deficient strains of E.. coll or B.
subtnis. did not Induce mutation to 8-azaguan1ne or ouabaln resistance 1n
Chinese hamster V-79 cells, and was not clastogenlc 1n Chinese hamster lung
flbroblasts. Hutagenldty was demonstrated In the L5178Y tkVtk" mouse
lymphoma cell assay (Amacher and Turner, 1982; McGregor et al., 1987).
Information regarding the teratogenldty or other reproductive effects
of Chloroacetlc add were not located 1n the available literature.
0113d -23- 06/16/88
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7. EXISTING GUIDELINES AND STANDARDS
Pertinent guidelines and standards, Including EPA ambient water and air
quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA
tolerances for raw agricultural commodities or foods, and ACGIH, NIOSH or
OSHA occupational exposure limits were not located 1n the literature dted
1n Appendix A.
0113d -24- 06/16/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled chloroacetlc acid were not located 1n the available literature cited
In Appendix A.
8.1.2. Oral. Chloroacetlc add was not tumorlgenlc to groups of 18
B6C3F1 or B6AKF1 mice of either sex when administered orally over a period
of 81 weeks (BRL, 1968). Dosing In this study consisted of dally gavage
treatment with 46.4 mg/kg from day 7 to day 28 of age, and subsequent treat-
ment 1n the diet at a concentration of 149 ppm for 78 weeks. Assuming that
mice consume food equivalent to 13% of their body weight/day, the dally TWA
dose for the entire study was 20.4 mg/kg.
A National Toxicology Program cardnogenesls bloassay of chloroacetlc
acid, 1n which rats and mice were exposed by gavage, Is currently In the
hlstopathology phase (NTP, 1988).
8.1.3. Other Routes. Chloroacetlc add was not tumorlgenlc to mice when
applied to the skin at a dose of 2 mg/anlmal 3 times/week for life (Van
Duuren et al., 1974), when administered by subcutaneous Injection at a dose
of 0.5 mg/an1mal weekly for life (Van Duuren et al., 1974) or when admin-
istered as a single 100 mg/kg subcutaneous Injection followed by 78 weeks of
observation (BRL, 1968).
8.1.4. Weight of Evidence. Chloroacetlc add was not tumorlgenlc In mice
when admlnlsterd orally, by dermal application or by subcutaneous Injection.
The oral study 1s limited by a single dose, and somewhat limited by duration
(81 weeks) and number of animals (18/sex/straln). The dose that was used 1n
the oral study was the HTD; although this adds some degree of confidence to
0113d -25- 06/16/88
-------
the negative results, limitations of this study and the lack of cardnogen-
1c1ty data for other species Indicate that the evidence for noncardnogen-
Idty of chloroacetlc acid should be regarded as Inconclusive. Applying the
U.S. EPA weight-of-evidence criteria for Cancer Risk Assessment Group (U.S.
EPA 1986), chloroacetlc add 1s classified In Group 0 (not classifiable as
to human cardnogenldty).
8.1.5. Quantitative Risk Estimates. The lack of cardnogenldty data for
chloroacetlc add precludes quantitative estimation of carcinogenic risk.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding the subchronic or
chronic Inhalation toxlclty of chloroacetlc add were not located 1n the
available literature cited 1n Appendix A.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES -- Subchronlc studies were
conducted In which chloroacetlc add was administered to F344 rats- and
B6C3F1 mice dally by Intubation, 5 days/week for 13 weeks (IRDC, 1982a,b).
Dosages were 0 (vehicle control), 30, 60, 90, 120 and 150 mg/kg for the rats
and 0 (vehicle control), 25, 50, 100, 150 and 200 mg/kg for the mice.
Groups of 20 animals/sex/dose of each species were treated with the chemical
dissolved In water and 10 animals/sex/dose were treated with the chemical
suspended 1n corn oil. As detailed 1n Section 6.1.2.1., compound-related
effects In the rats Included myocarditis at >30 mg/kg and mortality that was
due to myocardlal failure at >90 mg/kg. The LOAEL 1n rats therefore was 30
mg/kg, the lowest dose tested. Treatment-related mortality and hepatic
vacuolar degeneration occurred 1n the mice only at the highest dose, 200
mg/kg (IROC, 1982b). The hepatic lesions were observed only 1n the mice
that died; most of the mice died within the first 4 weeks. The hepatic
0113d -26- 06/16/88
-------
lesions were not considered sufficient to cause death, and additional
effects were not observed 1n the mice.
The LOAEL for myocarditis In the rats (30 mg/kg) 1s slightly higher than
the lowest NOEL In the mice (25 mg/kg). Because of the proximity of the rat
LOAEL to the mouse NOEL and the apparent species differences 1n target organ
toxUHy, 1t 1s Inappropriate to use the mouse NOEL as the basis for a sub-
chronic oral RfD for chloroacetlc add. Multiplying the LOAEL by 5 days/7
days to adjust for partial weekly exposure results In a dose of 21.4 mg/kg/
day. Application of an uncertainty factor of 1000 (10 for LOAEL to NOAEL
extrapolation, 10 for Interspecles extrapolation and 10 for protection of
sensitive humans) yields a subchronlc oral RfD of 0.02 mg/kg/day, or 1
mg/day for a 70 kg human. Confidence 1n this RfD 1s low because of uncer-
tainty regarding proximity of the LOAEL to the threshold region and the lack
of corroborating data from other studies.
8.2.2.2. CHRONIC EXPOSURES — Pertinent data regarding the chronic
oral toxlclty of chloroacetlc add are not available. A chronic oral RfD of
0.002 mg/kg/day or 0.1 mg/day for a 70 kg human can be derived by dividing
the subchronlc oral LOAEL by an additional uncertainty factor of 10 to
extrapolate from subchronlc to chronic exposure. Ongoing NTP (1988) chronic
cardnogenesls bloassays may provide data that are more appropriate for
derivation of oral RfDs.
0113d -27- 06/16/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Chronic toxldty data are not available for chloroacetlc add. Sub-
chronic studies have been conducted In which chloroacetlc add was adminis-
tered to F344 rats and B6C3F1 mice dally by Intubation, 5 days a week for 13
weeks (IRDC, 1982a,b). Dosages were 0 (vehicle control), 30, 60, 90, 120 and
150 nig/kg for the rats and 0 (vehicle control), 25, 50, 100, 150 and 200
mg/kg for the mice. Groups of 20 animals/sex/dose of each species were
treated with the chemical dissolved In drinking water and 10 animals/sex/
dose were treated with the chemical suspended 1n corn oil. As detailed In
Section 6.1.2.1., compound-related effects 1n the rats- Included myocarditis
at >30 mg/kg and mortality that was due to myocardlal failure at >90 mg/kg.
Composite scores are calculated for these effects. Treatment-related
mortality and hepatic vacuolar degeneration occurred 1n the mice at 200
mg/kg (IRDC, 1982b). It 1s Inappropriate to calculate CSs for the effects
1n mice because they occurred predominantly within the first 4 weeks,
Indicating that they should be considered acute responses.
Multiplying the 30 and 90 mg/kg LOAELs by 5 days/7 days to adjust for
partial weekly exposure results 1n transformed animal doses of 21.4 and 64.3
mg/kg/day, respectively. Multiplying the transformed animal doses by the
cube root of the ratio of rat body weight (0.17 kg for females, estimated
from reported data) to reference human body weight (70 kg) yields equivalent
human doses of 2.9 and 8.6 mg/kg/day. Multiplying the equivalent human
doses by 70 kg and dividing by 10 to extrapolate from subchronlc to chronic
exposure gives human MEDs of 20 for myocarditis and 60 mg/day for death
(Table 9-1). An appropriate RV for myocarditis Is 7 and the RV for
death 1s 10. As detailed In Table 9-1, CSs for myocarditis and death are
0113d -28- 06/16/88
-------
CO
CL
TABU 9-1
Composite Scores for the Oral Toxlclty of Chloroacettc Acid In Ratsa
vD
I
Treatment
Transformed
Animal Dose
(mg/ky/day)
Equivalent
Human Doseb
(mg/kg/day)
Human HEDC RVd Effect
(mg/day)
RVe CS RQ
30 mg/kg,
5 days/week
for 13 weeks
90 mg/kg,
5 days/week
for 13 weeks
21.4
64.3
2.9
8.6
20.3
60.2
3.5 Myocarditis
2.8 Death
10
24.5 100
28
100
aSource: IRDC. 1982a
^Calculated by multiplying the transformed animal dose by the cube root of the ratio of the animal body
weight (0.17 kg for female rats, estimated from reported data) to reference human.
Calculated by multiplying the equivalent human dose by 70 kg to express In units of mg/day and dividing
by an uncertainty factor of 10 to approximate chronic exposure.
CO
00
-------
calculated to be 24.5 and 28, respectively. Both of these CSs correspond to
an RQ of 100. An RQ of 100, based on the higher CS of 28, Is selected to
represent the hazard associated with chronic exposure to chloroacetlc add
(Table 9-2).
9.2. BASED ON CARCINOGENICITY
Cardnogenldty studies of chloroacetlc add were reviewed In Section^
6.1. Chloroacetlc add was not tumoMgenlc to mice when administered orally
at an approximate TWA dose of 20.4 mg/kg dally for 81 weeks (BRL, 1968),
when applied to the skin at a dose of 2 mg, 3 times/week for life (Van
Duuren et al., 1974), when administered by subcutaneous Injection at a dose
of 0.5 mg weekly for life-(Van Duuren et al., 1974;) or when administered as
a single 100 mg/kg subcutaneous Injection followed by 78 weeks of observa-
tion (BRL, 1968). Limitations of these negative studies and the lack of
cardnogenldty data for species other than the mouse Indicate that chloro-
ace.tlc add should be classified In CAG Group D. The lack, of data precludes
derivation of a cardnogen1c1ty-based RQ for chloroacetlc add.
0113d -30- 06/16/88
-------
TABLE 9-2
CHLOROACETIC ACID
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite score:
RQ:
oral
60.2
death
IRDC,
2.8
10
28
100
mg/day
1982a
*Equ1valent human dose
0113d -31- 06/16/88
-------
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0113d -40- 06/16/88
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM "TADS
STORET
SRC Environmental Fate Data Bases
SANSS •
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted 1n October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
0113d -41- 06/16/88
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Grayson, M. and D. Eckfbth, Ed. 1978-1984. Klrk-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, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NiTP (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 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0113d -42- 06/16/88
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from- the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0113d -43- 06/16/88
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APPENDIX B
Summary Table for Chloroacetlc Add*
Species
Exposure
Effect
RfD or q-|*
Inhalation Exposure
Subchronlc
Chronic
Oral Exposure
Subchronlc
Chronic
rat
rat
30 mg/kg
by gavage,
5 days/week
for 13 weeks
30 mg/kg
by gavage,
5 days/week
for 13 weeks
ID
ID
myocarditis 1 mg/day
myocarditis 0.1 mg/day
REPORTABLE QUANTITIES
Based on chronic toxldty:
Based on cardnogenlclty:
100 pounds
ID
^Source: IRDC, 1982a
ID = Insufficient data
0113d
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06/16/88
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