SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
SPONSORED CHEMICAL
Dichloroacetyl chloride (CAS No. 79-36-7)
[9th CI Name: 2,2-Dichloroacetyl chloride]
SUPPORTING CHEMICALS
Dichloroacetic acid (CAS No. 79-43-6)
Monochloroacetic acid (CAS No. 79-11-8)
August 2007
Prepared by
High Production Volume Chemicals Branch
Risk Assessment Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001
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SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making
publicly available screening-level health and environmental effects information on chemicals manufactured in or
imported into the United States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do
not exist, and making both new and existing data and information available to the public. Each complete data
submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that
are screening-level indicators of potential hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data
submitted in the HPV Challenge Program on approximately 1,400 sponsored chemicals. OPPT is using a hazard-
based screening process to prioritize review of the submissions. The hazard-based screening process consists of two
tiers described below briefly and in more detail on the Hazard Characterization website3.
Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established
criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as
submitted by the sponsor. It does not include evaluation of the quality or completeness of the data.
In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is
performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors.
EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have
become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent
data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical structures, properties and biological activities may be grouped together and their data shared across the
resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all
category members. As part of Tier 2, evaluation of chemical category rationale and composition and data
extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance.
The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing
chemicals review process. These hazard characterizations are technical documents intended to support subsequent
decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general
public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on
HPV chemicals and provide information previously not readily available to the public. The public, including
sponsors, may offer comments on the hazard characterization documents.
The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of
and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the
Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the
IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the
screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts
are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk-
based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production
Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.
1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html).
4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf.
6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm.
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SCREENING-LEVEL HAZARD CHARACTERIZATION
Dichloroacetyl chloride (CAS No. 79-36-7)
Introduction
The sponsor, E.I. du Pont de Nemours & Company, Inc., submitted a Test Plan and Robust Summaries to EPA for
dichloroacetyl chloride (CAS No. 79-36-7; 9th CI name: 2,2-dichloroacetyl chloride) on September 29, 2004. EPA
posted the submission on the ChemRTK HPV Challenge website on October 18, 2004
(http://www.epa.gov/chemrtk/pubs/summaries/dichlrac/cl5628tc.htm'). Public comments were also received and
posted to the website. EPA comments on the original submission were posted to the website on April 19, 2006. The
sponsor submitted revised documents on December 13, 2006, which were posted to the ChemRTK website on
January 31, 2007.
This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries
of studies submitted by the sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization,
EPA considered its own comments and public comments on the original submission as well as the sponsor's
responses to comments and revisions made to the submission. A summary table of SIDS endpoint data with the
structure(s) of the sponsored chemical(s) is included in the appendix. The screening-level hazard characterization
for environmental and human health toxicity is based largely on SIDS endpoints and is described according to
established EPA or OECD effect level definitions and hazard assessment practices.
Justification for Supporting Chemical
DCAC hydrolyzes rapidly in the presence of water (half-life < 0.22 seconds) yielding dichloroacetic acid (DCA,
CAS No. 79-43-6) and hydrochloric acid (HC1, CAS No. 7647-01-0). The sponsor provides this simple chemical
reaction as the rationale for using data on DCA as a logical analog for DCAC. In addition, the sponsor provided
data on the analog, monochloroacetic acid (MCA, CAS No. 79-11-8), for ecotoxicity endpoints.
EPA considers DCA, a hydrolysis product of DCAC, a reasonable analog for DCAC and DCA data adequate for
addressing all SIDS endpoints and use in hazard characterization. In addition, based on similar physical-chemical
properties, EPA agrees that MCA, a hydrolysis product of monochloroacetyl chloride (MCAC), supports the pattern
of aquatic toxicity observed for DCA.
Sum man-Conclusion
The log k indicates that the potential lor DC \ or \1C \ in hioaccuniulale is expected lo he low DC \ and NIC \
are readils biodegradable, indicating llial llie> lia\e low potential lo persisi in ilie en\ iroiinieni
The potential aquatic lo\ieil> of DC \C was assessed using data from the analog \1C \ The e\ alnation of a\ ailable
aqnalie lo\icil> data for \l( \ indicates the acute ha/ard lo fish and aquatic iii\ ertehrates is low and ha/ard lo
aquatic planls is high
DC \C and lis h\ drol\ sis product. DC V e\hihit ionic properties mi animal studies \ente lo\icil> of DC \C and or
DC \ is low \ la oral route, bin is moderate \ ia inhalation and dermal exposure DC \C and DC \ produced se\ere
skin and e\ e irritation mi rahhits Repeated oral exposure lo DC \ in hotli dogs and rals resulted in nioriahts.
neurological effects, hepatic, pancreatic and gall bladder effects and effects on the male reprodneti\ e organs
Th\ mie atrophs with marked depletion of l\ niphoid tissue was also ohser\ed mdogs ITfectsoii male reprodiieti\e
organs included se\ ere testicular lesions. s\ neMial giant cell formation, degeneration of germinal epithelium and
prostatic glandular atrophs in dogs In rats, morphological abnormalities ol sperm (distorted sperm heads and
decrease in the percentage of motile spermi. decreased sperm counts, increase in the number nf fused epididv mal
sperm and a decrease in epididv mal weight were reported follow ing DC \ exposure Results from the
dcNclopmeiiial lo.xicils studs indicate that DC \ affects de\ eloping fetuses Reduced fetal weight, reduced crow n-
rnnip length and eardio\ ascnlar abnormalities were seen w hen dams recei\ ed oral doses during gestation da>s (¦-15
In viirn and in \ iv" genetic loxicils assa\s using DC \C and DC \ pro\ ide positi\e e\ idenee for nintageiiieits \n in
viini mouse l> niphonia test indicated that DC \ induced chromosomal aberrations DC \C is a se\ere c\c and skin
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iilll;iiil I Aisium dala suuucsi lli;il DC \( and DC \ arc potential carciikiucus Repealed inhalation exposure In
DC \C mi nils resulted in n;is;il tumors Mice exposed to DC \C \ i;i subcutaneous injection dc\ eloped skin minors
DC \C is also show ii carcinogenic inilkiuh' properties w here mice were e\pi»sed once \ la llie derm;il route ;md
followed In ;i series of I'M \ (promoter) exposure. DC \ exposure \ i;i drinkum walcr induced hepatocellular
c;irciiK
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2. Environmental Effects - Aquatic Toxicity
EPA considered the data submitted for DCA inadequate because the study designs deviated significantly from those
recommended by the OECD guidelines. EPA considered MCA an appropriate analog for evaluating the aquatic
toxicity of DCAC for under the HPV Challenge Program.
Acute Toxicity to Fish
Monochloroacetic acid (CAS No. 79-11-8, supporting chemical)
Zebrafish (Brachydanio rerio) were exposed to MCA under semi-static conditions for 96-hours. Details regarding
the concentration range tested were not provided.
96-h LCso=370 mg/L
Acute Toxicity to Aquatic Invertebrates
Monochloroacetic acid (CAS No. 79-11-8, supporting chemical)
(1) Daphnia magna (20/concentration) were exposed to MCA under semi-static conditions for 24- and 48-hours.
The concentration range tested was not provided in the robust summary.
24-h ECS0 = 99 mg/L
48-h ECS0 = 77 mg/L
(2) Daphnia magna (20/concentration) were exposed to MCA at concentration of 0.032 - 100 mg/L under semi-
static conditions for 24-hours. The concentration range tested was not provided in the robust summary.
24-h ECS0 = 96 mg/L
Toxicity to Aquatic Plants
Monochloroacetic acid (CAS No. 79-11-8, supporting chemical)
(1) Scenedesmus subspicatus was exposed to MCA for 72 hours. The concentrations tested were not provided in the
robust summary.
72-h EC50 (biomass) = 0.025 mg/L
72-h EC50 (growth) = 0.033 mg/L
(2) Scenedesmus subspicatus was exposed to MCA at concentrations ranging from 0.0008 - 1.0 mg/L for 48-hours.
Biomass and growth inhibition were measured.
48-h EC50 (biomass) = 0.028 mg/L
48-h EC50 (growth) = 0.07 mg/L
Chronic Toxicity to Fish
Monochloroacetic acid (CAS No. 79-11-8, supporting chemical)
Zebrafish {Brachydanio rerio) were exposed to MCA at concentrations ranging from 25 - 400 mg/L for 28-days.
28-d LOEC = 25 mg/L
28-d NOEC = Not established
Chronic Toxicity to Aquatic Invertebrates
Monochloroacetic acid (CAS No. 79-11-8, supporting chemical)
Daphnia magna (20/concentration) were exposed to MCA at concentration of 0.032 - 100 mg/L under semi-static
conditions for 21-days.
21-d NOEC = 32 mg/L
Conclusion: The potential aquatic toxicity of DCAC was assessed using data from the analog MCA. The
evaluation of available aquatic toxicity data for MCA indicates the acute hazard to fish and aquatic invertebrates is
low and hazard to aquatic plants is high.
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3. Human Health Effects
Acute Oral Toxicity
Dichloroacetyl chloride (CAS No. 79-36-7)
Male Wistar or Sherman rats (5/dose group) were administered a geometric series four different doses of DCAC.
Actual doses administered were not provided in the robust summary. The results of this test were consistent with an
additional acute oral toxicity study in rats in which mortality was observed at doses of 1000 and 2250 mg/kg-bw and
an Approximate Lethal Dose (ALD) of 1000 mg/kg-bw was reported. Clinical signs included weakness in hind legs,
paleness and labored breathing.
LDS0 = 2460 mg/kg-bw
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
(1) Albino rats (10/dose group) were administered DCA at doses of 2200, 2500, 2800, 3200, 3600, 4000, 4400 and
4800 mg/kg-bw and observed for 6 days. The animals quickly passed into a state of narcosis or seminarcosis, and
within 36 hours either recovered or died without coming out of the narcosis.
LDS0 = 4480 mg/kg-bw
(2) Albino mice (10/dose group) were administered DCA at doses of 3000, 3162, 4000, 5012, 5623, 6310, 7943 and
8913 mg/kg-bw and observed for 6 days. The quickly passed into a state of narcosis or seminarcosis, and within 36
hours either recovered or died without coming out of the narcosis.
LDS0 = 5520 mg/kg-bw
Acute Inhalation Toxicity
Dichloroacetyl chloride (CAS No. 79-36-7)
Groups of male albino rats were exposed to a saturated vapor of DCAC for 4 hours. An LCi0 was established based
on mortality in 2 of 6 rats. No other clinical signs of toxicity were reported.
LCio = 2000 ppm (approximately 12 mg/L)
Acute Dermal Toxicity
Dichloroacetyl chloride (CAS No. 79-36-7)
Rabbits (5/dose) were exposed to undiluted DCAC by application to clipped skin at concentrations up to 20 mL/kg.
LDS0 = 0.65 mL/kg-bw (995 mg/kg-bw)
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
Rabbits (5/dose) were exposed to undiluted DCA by application to clipped skin at concentrations up to 20 mL/kg.
LDS0 = 0.51 mL/kg-bw (801 mg/kg-bw)
Repeated-Dose Toxicity
Dichloroacetyl chloride (CAS No. 79-36-7)
Male rats (50/dose) were exposed to DCAC via inhalation at 0, 0.5, 1.0 or 2.0 ppm (approximately 0.12 mg/L) for 6
hours/day, 5 days/week for 30 days. The post-exposure period was 128 weeks. Nasal tumors were reported
following exposure to 2.0 ppm DCAC; 2 of 50 rats developed squamous cell carcinoma or mixed cell carcinoma of
the nasal mucosa, which was attributed to DCAC exposure.
Oncogenic effects were observed at the highest dose tested.
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Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
(1) Male and female Beagle dogs were orally administered DCA once daily in gelatin capsules at 0, 12.5, 39.5 and
72 mg/kg-bw/day for 90 days. Dyspnea, bilateral conjunctivitis, slight bilateral posterior paresis, and diarrhea were
major signs of toxicity. Significant decreases in body weight, food consumption and water consumption were noted
at doses of 39.5 mg/kg-bw/day and above. At necropsy, several changes were noted in animals from the high-dose
group—mottled, discolored lungs, pale and discolored kidneys, white frothy material in the trachea and mild yellow
discoloration of liver. Liver weights were significantly greater in all dosed animals when compared to controls.
Increased kidney weights of the animals dosed at 39.5 mg/kg-bw/day and above; increased lung weight and relative
brain weights in the 72 mg/kg-bw/day dose group animals were seen. Microscopic examination showed incidence
of mild vacuolization of white myelinated tracts in the brain in all treated animals. In some dogs, the vacuolization
was present in the cerebrum and cerebellum. Some males from the 72 mg/kg-bw/day group had vacuolar changes in
the medulla and spinal cord. Dose-dependent hepatic and pancreatic lesion incidents were reported. Testicular
lesions were reported in all male animals exposed to DCA with severity increasing in the mid- and high-dose
groups. These lesions included syncytial giant cell formation, degeneration of germinal epithelium and prostatic
glandular atrophy. Thymic atrophy seen in high-dose males was characterized by marked depletion of lymphoid
tissue.
NOAEL = Not established
LOAEL = 12.5 mg/kg-bw/day (based on liver weight increase)
(2) Male and female Beagle dogs (3-4/sex/dose) were orally administered DCA once daily in gelatin capsules at 0,
50, 75 or 100 mg/kg-bw/day for 13 weeks. Additional groups (control and high-dose) were included as recovery
animals and were monitored for an additional 5 weeks following the 13-week dosing period. Mortality occurred in
two high-dose groups (75 and 100 mg/kg/day). Dose-dependent body weight loss was seen in both sexes. All
treated animals had high incidence of ocular abnormalities, progressive depression in hematology parameters
(erythrocyte count, hematocrit, and hemoglobin) and decreases in the following clinical chemistry: pyruvate, lactate
and glucose. Except for lenticular opacities, these changes were reversible following cessation of treatment.
Histopathological examination revealed slight to moderate vacuolization of the myelinated tracts of the cerebrum in
all treated dogs (persistent in some recovery animals), as well as increased incidence of hemosiderin-laden Kupffer
cells in the liver, cystic mucosal hyperplasia in the gall bladder and lung consolidation. Prostate glandular atrophy
and testicular changes were reported in all male dogs receiving DCA. Prostate appeared normal and germinal
epithelium regeneration with spermatogenesis was evident in recovery animals. However, liver and gall bladder
changes were still evident in recovery animals.
NOAEL = Not established
LOAEL = 50 mg/kg-bw/day (based on effect on body weight, ocular anomalies, histopathological changes in brain,
liver and gall bladder in both sexes and prostate and testicular changes in males)
(3) Male and female rats were orally administered DCA once daily by gavage at 0, 125, 500 or 2000 mg/kg-bw/day
for 13 weeks. Additional groups (control and high-dose) were included as recovery animals and were monitored for
an additional 4 weeks following the 13-week dosing period. Mortality occurred in high-dose groups with hindlimb
paralysis and pollakiuria as major signs of toxicity. Reductions in body weights and food consumption were seen all
DCA-treated rats—reversal was seen during the recovery period. Moderate but significant suppression of erythroid
parameters were induced at all dose levels—bone marrow and spleen appeared normal histologically and no effects
were seen during the recovery period. Changes in blood chemistry seen during the treatment period returned to
normal during the recovery period. Small testes observed following treatment with the high dose persisted in
recovery animals. However, changes in liver weights (increases in all animals of both sexes), kidney weights
(females at all doses) and adrenal weights (500 mg/kg-bw/day males and 2000 mg/kg-bw/day males and females)
were dose-dependent and were comparable to the control animals following the recovery period. Histopathological
examination revealed brain and testes were the target organs for toxicity. Brain lesions included edema, mainly in
the cerebrum, which persisted in some animals after cessation of treatment. Testicular lesions included germinal
epithelium degeneration at 500 and 2000 mg/kg-bw/day. In all males treated at 2000 mg/kg-bw/day, the testes were
aspermatogenic and contained syncytial giant cells in the germinal epithelium while the epididymis ducts were
devoid of spermatozoa. After the recovery period, some germinal epithelium regeneration was noted; however, the
majority of the testes were aspermatogenic and showed loss of germinal epithelium.
NOAEL = Not established
LOAEL = 125 mg/kg-bw/day (based on effects on body weight, food consumption and suppression of erythroid
parameters)
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Reproductive Toxicity
No data were submitted to address the reproductive toxicity endpoint. Evaluations of reproductive organs reported
in the repeated-dose toxicity studies along with the submitted developmental toxicity study (next section) were used
to address the reproductive endpoints for the purposes of the HPV Challenge Program. Therefore,
NOAEL/LOAELs for fertility and/or reproductive toxicity cannot be determined for these studies.
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
(1) Male rats were orally administered the DCA daily at 0, 18, 54, 160, 480 or 1440 mg/kg-bw/day for 14-days. The
reproductive tracts were used to determine effects on testes and epididymes. Sperm count and sperm morphology
were investigated. Delayed spermiation and formation of atypical residual bodies were seen at doses of 54 mg/kg-
bw/day and above. Distorted spermheads and acrosomes were seen at doses of 480 and 1440 mg/kg-bw/day.
Morphological abnormalities occurred at doses of 160 mg/kg-bw/day and above. In the highest dose groups,
distorted sperm heads, decreased percentage of motile sperm and sperm counts, increased number of fused
epididymal sperm and decreased epididymal weight were effects attributed to DCA exposure.
(2) In the repeated-dose toxicity study described previously, severe testicular lesions were reported in all male dogs
exposed to DCA via oral gavage at 0, 12.5, 39.5 or 72 mg/kg-bw/day for 90-days. Lesions included syncytial giant
cell formation, degeneration of germinal epithelium, and prostatic glandular atrophy.
(3) In the repeated-dose toxicity study described previously, male and female dogs were orally administered DCA
once daily in gelatin capsules at 0, 50, 75 or 100 mg/kg-bw/day for 13 weeks. Additional groups (control and high-
dose) were included as recovery animals and were monitored for an additional 5 weeks following the 13-week
dosing period. Prostate glandular atrophy and testicular changes were reported in all male dogs receiving DCA.
Prostate appeared normal and germinal epithelium regeneration with spermatogenesis was evident in recovery
animals.
(4) In the repeated-dose toxicity study described previously, male and female rats were orally administered DCA
once daily by gavage at 0, 125, 500, or 2000 mg/kg-bw/day for 13 weeks. Additional groups (control and high-
dose) were included as recovery animals and were monitored for an additional 4 weeks following the 13-week
dosing period. Testicular lesions included germinal epithelium degeneration at 500 and 2000 mg/kg-bw/day. In all
males at 2000 mg/kg-bw/day, the testes were aspermatogenic and contained syncytial giant cells in the germinal
epithelium while the epididymis ducts were devoid of spermatozoa. At recovery, some germinal epithelium
regeneration was noted; however, majority of them were aspermatogenic and showed loss of germinal epithelium.
Developmental Toxicity
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
Pregnant female rats were administered DCA via oral gavage at 0, 14, 140 and 400 mg/kg-bw/day during gestation
days 6-15. Maternal toxicity occurred in dams at doses of 140 mg/kg-bw/day and above. Effects include reduced
growth rate and increased liver, spleen and kidney weights. Fetal body weight and crown-rump length were reduced
in fetuses of rats receiving 400 mg/kg-bw/day. An increased incidence of soft tissue malformations (cardiovascular
system and ascending aorta and right ventricles) were seen in fetuses of rats receiving doses of 140 mg/kg-bw/day or
greater.
LOAEL (maternal/developmental toxicity) = 140 mg/kg-bw/day (based on increased incidence of soft tissue
malformations)
NOAEL (maternal/developmental toxicity) = 14 mg/kg-bw/day
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Genetic Toxicity - Gene Mutation
In vitro
Dichloroacetyl chloride (CAS No. 79-36-7)
(1) DCAC tested positive in an in vitro bacterial reverse mutation assay using Salmonella typhimurium TA 100
strain, with and without exogenous metabolic activation and using bag vaporization method. The results were
positive in TA 100 without metabolic activation at 600 ppm and negative in TA 100 with metabolic activation when
tested up to 700 ppm.
DCAC was mutagenic in this assay.
(2) In an in vitro bacterial reverse mutation assay, S. typhimurium strains TA 98 and TA 100 were exposed to up to
6666 ng/plate with and without metabolic activation systems. DCAC was positive in TA 100 without metabolic
activation and negative in TA 98 with and without metabolic activation.
DCAC was mutagenic in this assay.
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
(1) DCA tested positive in an in vitro bacterial reverse mutation assay in S. typhimurium TA 100 strain, with and
without metabolic activation system using the bag vaporization method.
DCA was mutagenic in this assay.
(2) In an in vitro bacterial reverse mutation assay using S. typhimurium strains TA 102 and TA 2638 and two
Escherichia coli strains, DCA was negative when tested with and without metabolic activation systems.
DCA was not mutagenic in this assay.
(3) Using S. typhimurium TA 98, TA 100, TA 1535 and TA 1537, and E. coli WP2 uvrA strains, the results were
negative with and without metabolic activation when tested in triplicate assay.
DCA was not mutagenic in this assay.
Genetic Toxicity - Chromosomal Aberrations
In vitro
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
(1) In an in vitro clastogenicity study using mouse lymphoma cell line, the results were weakly positive. Dose-
related cytotoxic and mutagenic effects were reported. There was no significant increase in micronuclei or
aneuploidy frequencies.
DCA was clastogenic in this assay.
(2) A chromosomal aberration assay in Chinese hamster ovary cell was negative.
DCA did not induce chromosomal aberrations in this assay.
In vivo
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
When tested in two in vivo assays, DCA was positive, but was negative in one mouse micronucleus test. Several
other non-standard tests (mutagenicity in mouse liver, 8-OH DNA adduct test, DNA strand-break test) for DNA
effects show mostly positive results. .
DCA was mutagenic in several of these assays.
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Additional Information
Skin Irritation
Dichloroacetyl chloride (CAS No. 79-36-7)
Undiluted DCAC was applied to the skin of rabbits and the animals observed for 24-hours. Severe irritation and
edema were noted.
DCAC caused severe skin irritation in this assay.
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
Undiluted DCA was applied to the skin of rabbits and the animals observed for 24-hours. Severe irritation and
edema were noted.
DCA caused severe skin irritation in this assay.
Eye Irritation
Dichloroacetyl chloride (CAS No. 79-36-7)
Undiluted DCAC (0.001, 0.005, 0.02, 0.1 and 0.5 mL) was applied to the eyes of rabbits and the animals observed
for 24-hours. Severe eye injury was observed.
DCAC caused severe eye irritation in this assay.
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
Undiluted DCA (0.001, 0.005, 0.02, 0.1 and 0.5 mL) was applied to the eyes of rabbits and the animals observed for
24-hours. Severe eye injury was observed.
DCA caused severe eye irritation in this assay.
Carcinogenicity
Dichloroacetyl chloride (CAS No. 79-36-7)
An 18- to 22-month carcinogenicity study of DCAC was carried out using female mice. Three different exposure
scenarios were followed in this study: dermal exposure to DCAC (3 times/week), one-time dermal exposure to
DCAC followed by promoter exposure (PMA) 3 times/week, and subcutaneous injections in the right flank once/
week. The one-time exposure to DCAC followed by repeated exposure to PMA resulted in incidence of
carcinogenicity (papilloma and squamous carcinoma), where DCAC acted an initiator. In addition, the
subcutaneous injections of DCAC resulted in squamous carcinoma, papilloma, sarcoma and hemangioma.
Furthermore, in the critical inhalation study, male rats exposed to 2.0 ppm DCAC via inhalation for 6 hours/day, 5
days/week for 30 days developed nasal tumors.
Dichloroacetic acid (CAS No. 79-43-6, supporting chemical)
In a carcinogenicity study conducted using male rats exposed to DCA via drinking water for approximately 100
weeks, an increase in the incidence of hepatocellular carcinomas was observed.
Conclusion: DCAC and its hydrolysis product, DCA, exhibit toxic properties in animal studies. Acute toxicity of
DCAC and/or DCA is low via oral route, but is moderate via inhalation and dermal exposure. DCAC and DCA
produced severe skin and eye irritation in rabbits. Repeated oral exposure to DCA in both dogs and rats resulted in
mortality; neurological effects; hepatic, pancreatic and gall bladder effects and effects on the male reproductive
organs. Thymic atrophy with marked depletion of lymphoid tissue was also observed in dogs. Effects on male
reproductive organs included severe testicular lesions, syncytial giant cell formation, degeneration of germinal
epithelium and prostatic glandular atrophy in dogs. In rats, morphological abnormalities of sperm (distorted sperm
heads and decrease in the percentage of motile sperm), decreased sperm counts, increase in the number of fused
epididymal sperm and a decrease in epididymal weight were reported following DCA exposure. Results from the
developmental toxicity study indicate that DCA affects developing fetuses. Reduced fetal weight, reduced crown-
rump length and cardiovascular abnormalities were seen when dams received oral doses during gestation days 6-15.
In vitro and in vivo genetic toxicity assays using DCAC and DCA provide positive evidence for mutagenicity. An in
vitro mouse lymphoma test indicated that DCA induced chromosomal aberrations. DCAC is a severe eye and skin
irritant. Existing data suggest that DCAC and DCA are potential carcinogens. Repeated inhalation exposure to
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DCAC in rats resulted in nasal tumors. Mice exposed to DCAC via subcutaneous injection developed skin tumors.
DCAC is also shown carcinogenic initiator properties where mice were exposed once via the dermal route and
followed by a series of PMA (promoter) exposure. DCA exposure via drinking water induced hepatocellular
carcinoma in male rats.
The potential health hazard of DCAC and DCA is high based on repeated-exposure toxicity via all routes of
exposure. Available data also indicates DCAC and DCA have the potential to be genotoxic.
4. Hazard Characterization
The log Kow indicates that the potential for DCA or MCA to bioaccumulate is expected to be low. DCA and MCA
are readily biodegradable, indicating that they have low potential to persist in the environment.
The potential aquatic toxicity of DCAC was assessed using data from the analog MCA. The evaluation of available
aquatic toxicity data for MCA indicates the acute hazard to fish and aquatic invertebrates is low and hazard to
aquatic plants is high.
DCAC and its hydrolysis product, DCA, exhibit toxic properties in animal studies. Acute toxicity of DCAC and/or
DCA is low via oral route, but is moderate via inhalation and dermal exposure. DCAC and DCA produced severe
skin and eye irritation in rabbits. Repeated oral exposure to DCA in both dogs and rats resulted in mortality;
neurological effects; hepatic, pancreatic and gall bladder effects and effects on the male reproductive organs.
Thymic atrophy with marked depletion of lymphoid tissue was also observed in dogs. Effects on male reproductive
organs included severe testicular lesions, syncytial giant cell formation, degeneration of germinal epithelium and
prostatic glandular atrophy in dogs. In rats, morphological abnormalities of sperm (distorted sperm heads and
decrease in the percentage of motile sperm), decreased sperm counts, increase in the number of fused epididymal
sperm and a decrease in epididymal weight were reported following DCA exposure. Results from the
developmental toxicity study indicate that DCA affects developing fetuses. Reduced fetal weight, reduced crown-
rump length and cardiovascular abnormalities were seen when dams received oral doses during gestation days 6-15.
In vitro and in vivo genetic toxicity assays using DCAC and DCA provide positive evidence for mutagenicity. An in
vitro mouse lymphoma test indicated that DCA induced chromosomal aberrations. DCAC is a severe eye and skin
irritant. Existing data suggest that DCAC and DCA are potential carcinogens. Repeated inhalation exposure to
DCAC in rats resulted in nasal tumors. Mice exposed to DCAC via subcutaneous injection developed skin tumors.
DCAC is also shown carcinogenic initiator properties where mice were exposed once via the dermal route and
followed by a series of PMA (promoter) exposure. DCA exposure via drinking water induced hepatocellular
carcinoma in male rats.
The potential health hazard of DCAC and DCA is high based on repeated-exposure toxicity via all routes of
exposure. Available data also indicates DCAC and DCA have the potential to be genotoxic.
5. Data Gaps
No data gaps have been identified under the HPV Challenge Program.
A reproductive toxicity study was not submitted for DCAC or its analog DCA. Evaluation of reproductive organs
submitted with repeated-dose studies along with a developmental toxicity study were used to address the
reproductive endpoints for the purposes of the HPV Challenge Program. Repeated (oral) exposure to DCA resulted
in effects on male reproductive organs. Effects of these chemicals on female reproductive parameters have not been
provided, but the developmental toxicity study identified maternal and fetal effects. Hence, while the data submitted
are adequate for performing this screening-level hazard characterization, the results of the reproductive organ
evaluation and the developmental toxicity study indicate DCAC (DCA) has the potential to cause reproductive
toxicity.
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APPENDIX
Summary Tabic of the Screening Information Data Set
as submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Dichloroacctvl chloride
(DCAC)
(79-36-7)
SUPPORTING
CHEMICAL
Dichloroacctic acid
(DCA)
(79-43-6)
SUPPORTING
CHEMICAL
Monochloroacctic acid
(MCA)
(79-11-8)
CI
CI
CI O
H
CI OH
O
c'vX
^ OH
Summary of Physical-Chemical Properties and Environmental Fate Data
Melting Point (°C)
-32.51 (estimated)
13.5
61.3
Boiling Point (°C)
108
193-194
189
Vapor Pressure
(hPa at 25°C)
30.7
0.24
0.09
Log K„w
-0.04 (estimated)
0.92 (measured)
0.34 (estimated)
Water Solubility
(mg/L at 25°C)
Hydrolyzes to DCA + HC1
> 100 g/L
421 g/100 g H20
Direct Photodegradation
(cm3/molecule-sec)
Photodegradation will not
occur under environmental
conditions because DCAC
hydrolyzes rapidly with
atmospheric moisture.
Indirect (OH ) Photodegradation
Half-life (t1/2)
-
22 days
-
Stability in Water (Hydrolysis) (year)
Hydrolyzes to DCA + HC1
-
-
Fugacity
(Level III Model)
Water (%)
Sediment (%)
Soil (%)
Air (%)
49.5
0.096
35.1
15.3
38.8
0.077
57.2
4.05
38.3
0.0712
61.4
0.216
Biodegradation at 28 days (%)
DCAC is unstable in water
97 (14-days)
Readily biodegradable
53-100
Readily biodegradable
Summary of Environmental Effects - Aquatic Toxicity Data
Fish
96-h LCS0 (mg/L)
-
-
370
Aquatic Invertebrates
48-h ECS0 (mg/L)
-
-
77
Aquatic Plants
72-h ECS0 (mg/L)
(growth)
(biomass)
0.025
0.033
Chronic Toxicity to Fish
28-day NOEC, (mg/L)
-
-
25
Chronic Toxicity to Invertebrates
21-day NOEC, (mg/L)
—
—
32
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Summary Tabic of the Screening Information Data Set
as submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Dichloroacctvl chloride
(DCAC)
(79-36-7)
SUPPORTING
CHEMICAL
Dichloroacetic acid
(DCA)
(79-43-6)
SUPPORTING
CHEMICAL
Monochloroacctic acid
(MCA)
(79-11-8)
Summary of Human Health Data
Acute Oral Toxicity
LDS0 (mg/kg-bw)
2460
2820 - 5520
-
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
995
801
-
Acute Inhalation Toxicity
LC50 (mg/L/6h/day)
LClo ~ 12.1
-
-
Repeated-Dose Toxicity
NOAEL/LOAEL (mg/kg-bw/day)
No Data
NOAEL = Not established
LOAEL = 12.5 - 50
—
Reproductive Toxicity
NOAEL/LOAEL
(mg/kg-bw/day)
Effects were seen on
reproductive organs in the
repeated-dose toxicity study
"
"
Developmental Toxicity
NOAEL/LOAEL
(mg/kg-bw/day)
No Data
NOAEL (mat/dev.) = 14
LOAEL (mat/dev.) = 140
Genetic Toxicity - Gene Mutation
In vitro
Positive
-
-
Genetic Toxicity - Gene Mutation
In vivo
Positive
-
-
Genetic Toxicity - Chromosomal
Aberrations
In vitro
Positive
—
—
Genetic Toxicity - Chromosomal
Aberrations
In vivo
Positive
—
—
Additional Information -
Skin Irritation
Severe
Severe
-
Additional Information -
Eye Irritation
Severe
Severe
-
Additional Information
Carcinogenicity
Carcinogenicity
-
- indicates that the endpoint was not addressed for this chemical; mat/dev = maternal/developmental
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