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Monosodium Methanearsonate and Disodium Methanearsonate; Toxic Chemical Release Reporting; Community Right-to-Know
Note: EPA no longer updates this information, but it may be useful as a reference or resource.
[Federal Register: April 20, 1995]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 372
[OPPTS-400092; FRL-4946-2]
Monosodium Methanearsonate and Disodium Methanearsonate; Toxic
Chemical Release Reporting; Community Right-to-Know
AGENCY: Environmental Protection Agency (EPA).
ACTION: Denial of petition.
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SUMMARY: EPA is denying a petition to delist monosodium methanearsonate
(MSMA, CAS No. 2163-80-6) and disodium methanearsonate (DSMA, CAS No.
144-21-8) from the reporting requirements under section 313 of the
Emergency Planning and Community Right-to-Know Act of 1986 (EPCRA).
This action is based on EPA's conclusion that neither monosodium
methanearsonate or disodium methanearsonate meet the deletion criteria
of EPCRA section 313(d)(3). Specifically, EPA is denying this petition
because: (1) Monosodium methanearsonate and disodium methanearsonate
are known to cause toxic effects in experimental animals as a result of
chronic exposure to either of these substances; and (2) monosodium
methanearsonate and disodium methanearsonate can reasonably be
anticipated to cause cancer in humans.
FOR FURTHER INFORMATION CONTACT: Maria J. Doa, Petitions Coordinator,
202-260-9592, for specific information regarding this document. For
further information on EPCRA section 313, contact the Emergency
Planning and Community Right-to-Know Information Hotline, Environmental
Protection Agency, Mail Stop 5101, 401 M St., SW., Washington, DC
20460, Toll free: 800-535-0202, Toll free TDD: 800-553-7672.
SUPPLEMENTARY INFORMATION:
I. Introduction
A. Statutory Authority
This action is issued under sections 313(d) and (e)(1) of the
Emergency Planning and Community Right-to-Know Act of 1986 (EPCRA), 42
U.S.C. 11023. EPCRA is also referred to as Title III of the Superfund
Amendments and Reauthorization Act (SARA) of 1986 (Pub. L. 99-499).
B. Background
Section 313 of EPCRA requires certain facilities manufacturing,
processing, or otherwise using listed toxic chemicals to report their
environmental releases of such chemicals annually. Beginning with the
1991 reporting year, such facilities also must report pollution
prevention and recycling data for such chemicals, pursuant to section
6607 of the Pollution Prevention Act of 1990 (PPA), 42 U.S.C. 13106.
Section 313 established an initial list of toxic chemicals that was
comprised of more than 300 chemicals and 20 chemical categories.
Section 313(d) authorizes EPA to add or delete chemicals from the list,
and sets forth criteria for these actions. EPA has added and deleted
chemicals from the original statutory list. Under section 313(e), any
person may petition EPA to add chemicals to or delete chemicals from
the list. EPA must respond to petitions within 180 days, either by
initiating a rulemaking or by publishing an explanation of why the
petition is denied.
EPA issued a statement of petition policy and guidance in the
Federal Register of February 4, 1987 (52 FR 3479), to provide guidance
regarding the recommended content and format for submitting petitions.
On May 23, 1991 (56 FR 23703), EPA issued guidance regarding the
recommended content of petitions to delete individual members of the
section 313 metal compound categories. EPA has also published a
statement clarifying its interpretation of the section 313(d)(2)
criteria for adding and deleting chemical substances from the section
313 list (59 FR 61439, November 30, 1994).
II. Description of Petition and Relevant Regulations
On October 18, 1994, EPA received a petition from the ISK
Biosciences Corporation to remove monosodium methanearsonate (MSMA) and
disodium methanearsonate (DSMA) from the list of toxic chemicals
subject to the requirements of section 313 of the Emergency Planning
and Community Right-to-Know Act of 1986 (EPCRA). Specifically, the
petition requests that MSMA and DSMA be excluded from the arsenic
compounds category which is subject to annual release reporting
requirements under EPCRA section 313. The petitioner contends that MSMA
and DSMA should be deleted from the EPCRA section 313 arsenic compounds
category because, in their opinion, the available data show that
neither of these substances meet the criteria for inclusion on the list
of EPCRA section 313 chemicals. The petitioner did not provide EPA with
any of the studies cited in the petition.
MSMA and DSMA are organic arsenicals. EPA regulates arsenic and
certain arsenic compounds under the Clean Air Act (CAA), Clean Water
Act (CWA), Comprehensive Environmental Response, Compensation, and
Liability Act (CERCLA), Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA), Resource Conservation and Recovery Act (RCRA), Safe
Drinking Water Act (SDWA), and EPCRA. Arsenic emissions from smelters
and other facilities are regulated under the CAA. Under the CWA,
guidelines have been established controlling the environmental release
of arsenic compounds for certain industrial categories. Reportable
quantities have been established under CERCLA and CWA for arsenic and
certain arsenic compounds. Under RCRA, EPA regulates arsenic as a
hazardous constituent of waste. The SDWA limits arsenic in drinking
water to a maximum level of 0.05 milligrams/liter (mg/L). EPA and the
National Toxicology Program have classified inorganic arsenicals,
including arsenate, as known human carcinogens.
III. EPA's Technical Review of Monosodium Methanearsonate (MSMA)
and Disodium Methanearsonate (DSMA)
The technical review of the petition to delete MSMA and DSMA
included an analysis of the chemistry, health, ecological and
environmental fate data known for these substances and for
methanearsonic acid (MAA), the un-ionized form of MSMA and DSMA. From a
human health standpoint, MSMA and DSMA will exist largely as MAA (their
un-ionized form) under acidic conditions, such as those found in the
gastrointestinal tract. Also, following absorption into the systemic
circulation, MSMA, DSMA, and MAA will exist in an identical ionized
form at the physiological pH of 7.4, regardless of their route of
administration. EPA and the ISK Biosciences Corporation (as indicated
in their petition) believe, therefore, that mammalian toxicity data on
MAA should be suitable to assess the toxicity of MSMA and DSMA in cases
where such data on the latter two substances are not available.
A. Chemistry
Monosodium methanearsonate (CH<INF>4AsO<INF>3.Na; CAS No. 2163-80-
6), also known as MSMA, and disodium methanearsonate
(CH<INF>3AsO<INF>3.2Na; CAS No. 144-21-8), also known as DSMA, are the
monosodium and disodium salts, respectively, of methanearsonic acid
(also known as MAA). MSMA, DSMA, and MAA are often refered to as
organic arsenicals, because they each contain a methyl (-CH<INF>3)
group. Both MSMA and DSMA are highly water soluble crystalline solids,
and are used as herbicides for the postemergent control of grassy weeds
in cotton, sugarcane, nonbearing orchards, citrus groves, lawns, turf,
and in noncrop areas. The predominant use of MSMA and DSMA is for
postemergent control of Johnsongrass and other grassy weeds prior to
planting cotton.
B. Toxicological Evaluation
Information on the health and environmental effects of MSMA, DSMA,
and MAA were obtained from the following sources: a 1993 Agency for
Toxic Substances and Disease Registry [[Page 19704]] document entitled
Toxicological Profile for Arsenic (Update) (Refs. 2, 15, and 30); a
1984 EPA document entitled Health Assessment Document for Arsenic (Ref.
7); a 1994 National Toxicology Program document entitled Seventh Annual
Report on Carcinogens: 1994 Summary (Ref. 32); studies obtained from
EPA's Office of Pesticide Programs (Ref. 8, 10, 12-14, 16 and 19-24);
and studies found in the literature (Refs. 1, 3-6, 9, 11, 17, 18, 25,
26, 28, 29, and 31). Specifically, toxicological and related data on
MSMA, DSMA, and MAA (the un-ionized or free acid form of MSMA and DSMA)
were reviewed for evidence indicating: (1) Bioavailability and
metabolism to inorganic arsenic; (2) acute toxicity; (3) chronic
toxicity; (4) carcinogenicity; and (5) ecotoxicity.
- Bioavailability and metabolism. Shah and co-workers investigated
the absorption of MSMA and DSMA from the skin of young and adult rats
(Ref. 1). Both substances were very poorly absorbed through the skin of
all animals tested, particularly in the younger animals. No human
studies pertaining to the dermal absorption of MSMA and DSMA were
found. However, human and animal studies involving dermal exposure to
organic arsenicals closely related to MSMA and DSMA indicate that these
substances are poorly absorbed from the skin (Ref. 2).
Shariatpanahi and Anderson found that MSMA is readily absorbed from
the gastrointestinal tract following oral administration of the
substance to sheep and goats (Ref. 3). These investigators observed
that 90 percent of the arsenic content of orally administered MSMA was
excreted in the urine of test animals within 120 hours of
administration. Small amounts were excreted in the feces. Arsenic
accumulation in the tissues was low. It is noteworthy to point out that
metabolism of MSMA to other forms of arsenic (e.g., inorganic) was not
studied in this investigation, and only total arsenic concentrations
were determined. Specific assays for MSMA or other specific arsenicals
were not used. The results of this study were consistent with the
results of another study, which investigated the absorption,
distribution and elimination of MSMA in New Zealand white rabbits
following multiple oral doses of the substance (Ref. 4).
A 1991 EPA study investigated the absorption, distribution, and
elimination of radiolabeled MSMA ([<SUP>14C-methyl]MSMA) in rats (Ref.
8). Four groups of rats were used in this study. Each group consisted
of male and female animals. One group received a single oral dose of
[<SUP>14C-methyl]MSMA at 5 milligrams per kilogram (mg/kg), while
another group received a single oral dose of 200 mg/kg. A third group
received a single oral dose of MSMA at 5 mg/kg every day for 14
consecutive days, followed by a single oral dose of [<SUP>14Cmethyl]
MSMA. A fourth group received a single oral dose of MSMA at 5
mg/kg every day for 14 consecutive days, followed by a single
intravenous dose of [<SUP>14C-methyl]MSMA at 5 mg/kg or a single oral
dose of [<SUP>14C-methyl]MSMA at 5 mg/kg. In each of the test groups,
the majority (79.7 to 97.4 percent) of administered [<SUP>14Cmethyl]
MSMA was excreted unchanged in the urine and feces within 7 days
following dosing. Radiolabeled carbon dioxide (<SUP>14CO<INF>2) was
detected in all treated groups, and accounted for less than 0.5 percent
of administered [<SUP>14C-methyl]MSMA. An unidentified metabolite,
which accounted for 1.8 to 6.7 percent of administered [<SUP>14Cmethyl]
MSMA, was detected in the urine and feces of all test groups
except the group receiving 200 mg/kg [<SUP>14C-methyl]MSMA orally.
Another unidentified metabolite, accounting for 0.7 percent of
administered [<SUP>14C-methyl]MSMA was found in only one of the test
groups.
Buchet, et al., investigated the oral absorption and metabolism of
MSMA in humans (Ref. 9). In this study four adult males were
administered MSMA in a single oral dose equivalent to 500 micrograms of
arsenic. The MSMA was well absorbed, and nearly 70 percent of the dose
was excreted unchanged in the urine within 24 hours, while a small
percentage was excreted in the urine as cacodylic acid (dimethylarsonic
acid). Within 96 hours, 78.3 percent of the MSMA dose was excreted in
the urine unchanged and approximately 13 percent was excreted in the
urine as cacodylic acid. No inorganic arsenic metabolites were
identified (Ref. 9).
Stevens and co-workers investigated the toxicity of DSMA in rats
and mice exposed to the substance at aerosolized doses of 6.1 mg/L (for
the rats) and 6.9 mg/L (for the mice) for 2 hours (Ref. 5). Total
arsenic levels from body fluids or tissues were not determined, but the
authors believed that some absorption of DSMA occurred from the lung.
- Acute toxicity. Several rat oral median lethal dose (LD<INF>50)
values for MSMA and DSMA were found in the literature. For DSMA, the
rat oral LD<INF>50 values, in mg/kg, are (male, female): 2,005, 1,842
(Ref. 10); and 928, 821 (Ref. 11). For MSMA, the rat oral LD<INF>50
values are 1,105 and 1,059 mg/kg for males and females respectively
(Ref. 11). These data are consistent with rat median lethal dose data
provided by the petitioner.
Neither DSMA or MSMA produced significant toxicity in rabbits when
applied dermally at a dose of 2,000 mg/kg for 24 hours (Refs. 12 and
13). In the MSMA- treated group, however, there was evidence of
decreased muscle tone noted in approximately 50 percent of the animals
on observation days 5 through 9 (Ref. 13). By observation day 10,
muscle tone was normal in all treated animals.
In a study investigating the acute inhalation toxicology of DSMA,
mice and rats were placed in chambers and were exposed for 2-hours to
experimental atmospheres containing DSMA in concentrations of at least
8.6 mg/L (Ref. 5). The animals were observed to have respiratory
distress during the 2-hour exposure period, but recovered rapidly after
removal from exposure. Respiratory irritation was the main
toxicological effect observed. No mortality occurred in either species.
These results are consistent with those of a similar DSMA inhalation
study (Ref. 14). In the latter study, rats were exposed to experimental
atmospheres of 6.0 mg/L DSMA for 4 hours. No deaths were noted during
the 14-day post-exposure observation period. Clinical signs noted on
the first day post-exposure included body weight loss and respiratory
irritation. Lung discoloration in 40 percent of the animals was also
noted (Ref. 14).
- Chronic toxicity. Numerous studies investigating the chronic
toxicity of inorganic arsenicals have been conducted. Relatively few
studies, however, have investigated the potential for chronic toxicity
of organic arsenicals such as MSMA, DSMA, and MAA. The limited amount
of published mammalian toxicity data on these substances have been
summarized (Ref. 15). In addition, the petitioner summarized
unpublished chronic toxicity data that are available from EPA's Office
of Pesticide Programs. Some of these studies will be briefly discussed
here.
In a study investigating the health effects resulting from chronic
administration of MAA, four groups of rats (each group consisting of 60
males and 60 females) were fed diets containing 0 (the control group),
50, 400, and 1,300 parts per million (ppm) of MAA for 104 weeks (Ref.
16). Mortality was significantly increased in animals fed diets
containing 1,300 ppm MAA. Because of this increased mortality, the
1,300 ppm concentration was reduced to 1,000 ppm during week 53, and to
800 ppm at week 60. Animals in this group had acute gastrointestinal
inflammation, ulceration and perforation of the large intestines, and
[[Page 19705]] evidence of acute or chronic peritonitis. These
observations were less evident in animals receiving diets containing
400 ppm MAA. A reduction in the weight of the thyroid glands was noted
in female rats receiving the 1,300 ppm and 400 ppm MAA diets, and in
male rats receiving 400 ppm MAA. Thickening of the thyroid follicular
epithelium was noted in both sexes receiving the 1,300 and 400 ppm MAA
diets. An increased incidence of parathyroid adenomas may have occurred
in male rats receiving the 1,300 and 400 ppm MAA diets. This
observation is discussed in greater detail in unit III.B.4 below.
Jaghabir and co-workers investigated the health effects of low dose
MSMA exposure in white rabbits (Ref. 17). Three groups of rabbits were
used in this study. The first group consisted of four rabbits, which
were administered MSMA orally once a day for 40 days at a dose of 5 mg/
kg. The second group consisted of two animals, which were administered
MSMA at a dose of 10 mg/kg orally for 40 days. The third group (also
consisting of two animals) was similarly administered MSMA at a dose of
20 mg/kg. A control group of two animals was also used. All animals
were euthanized and examined at the end of the 40-day test period.
Post-mortem examination revealed distension and hyperemia of the
digestive tract, intestinal wall fragility, enlargement of the kidneys,
and intense peripheral hyperemia of the livers of all animals
administered MSMA. Histopathological findings revealed hepatic cellular
degeneration, periportal inflammation, renal tubular nephrosis,
interstitial nephritis and vascular hyperemia. These observations are
consistent with the observations of similar investigations cited in the
study (Ref. 17), and indicate that low dose exposure to MSMA can result
in tissue damage.
Results from several studies suggest that MSMA and DSMA may cause
developmental and reproductive toxicity. In an investigation reported
by Prukop and Savage (Ref. 18) it was observed that mice administered
MSMA at doses of either 11.9 or 119 mg/kg orally three times a week for
10 weeks had decreased reproductive capabilities (males) and altered
reproductive behavior (females). In another study, groups of beagle
dogs were administered MAA at 0 (control), 2.5, 8 or 40 mg/kg/day for 1
week, followed by administration of 0 (control animals), 2, 8, or 35
mg/kg/day for an additional 51 weeks (Ref. 19). Decreased body weight
gain occurred in male dogs that received the 35 mg/kg/day dose, and in
females that received the 8 or 35 mg/kg/day doses. The incidence of
female animals showing no corpora lutea were increased in the 35 mg/kg/
day animal test group when compared to control animals (Ref. 19).
In another study, groups of inseminated New Zealand white rabbits
were administered MAA orally at doses of 0 (control animals), 1, 3, 7,
and 12 mg/kg/day during days 7 thru 19 of gestation (Ref. 20). Maternal
toxicity at 12 mg/kg/day was characterized by abortion and decreases in
mean absolute body weight, body weight gain, and food consumption.
Decreases in body weight gain and food consumption were also noted in
the 7 mg/kg/day test group. An increased incidence of skeletal
variations was noted in the offspring of animals administered MAA at 12
mg/kg/day. These skeletal variations consisited of increased numbers of
ribs and thoracic and lumbar vertebrae (Ref. 20).
In a multigeneration toxicity study, groups of male rats were fed
MAA at doses of 0 (control group), 5.8, 17.8, or 63.5 mg/kg/day, and
groups of female rats were fed 0 (control group), 7.5, 22.5, and 77.6
mg/kg/day for 14 weeks. Animals were mated, and mated females continued
to receive MAA throughout gestation and lactation periods. Among other
toxic effects noted in the 63.5 (males) and 77.6 (females) mg/kg/day
dose groups, decreased pregnancy rates, male fertility rates, and
decreased weights of the prostate and testes also occurred for
parenteral generations F0 and F1 (Ref. 21).
A study was conducted in which MSMA was administered orally to
pregnant female rats at doses of 0, 10, 100, or 500 mg/kg once daily on
gestation days 6 through 15. No developmental effects were noted in the
offspring of animals receiving 10 or 100 mg/kg MSMA. Decreased body
weight gain and food consumption were noted in animals receiving 500
mg/kg MSMA. The fetuses of this test group had lower mean fetal body
weights when compared to control animals (Ref. 22).
Based on the results of the animal studies discussed in the
preceding paragraphs, EPA has determined that chronic exposure to
either MSMA or DSMA can reasonably be anticipated to cause
gastrointestinal toxicity, thyrotoxicity, nephrotoxicity,
hepatotoxicity, and developmental and reproductive toxicity in humans.
- Carcinogenicity. Data regarding the carcinogenic potential of
MSMA, DSMA, or MAA are extremely limited. In a study involving chronic
administration of MAA, four groups of rats, each group containing 60
males and 60 females, were fed diets containing 0 (the control group),
50, 400, and 1,300 ppm of MAA for 104 weeks (Ref. 16). Because of
excessive mortality, the 1,300 ppm concentration was reduced to 1,000
ppm during week 53, and to 800 ppm at week 60. An increased incidence
of parathyroid adenomas was observed in males receiving the 1,300 ppm
(4/45) and 400 ppm (4/53) MAA diets, and in females (4/45) receiving
the 1,300 ppm MAA diets. Evidence of parathyroid adenoma was also found
in 1 of 52 male control rats. The increased incidence of parathyroid
adenomas in the treated groups was found to be statistically
significant relative to the control animals.
As stated previously, cacodylic acid (dimethylarsonic acid, CAS No.
75-60-5) is a known human metabolite of MSMA: Buchet and co-workers
found that in human volunteers approximately 13 percent of an orallyadministered
dose of MSMA is converted into cacodylic acid (Ref 9). EPA
has recently categorized cacodylic acid as a Group B2 or probable human
carcinogen (Ref. 23). EPA's classification of cacodylic acid as a Group
B2 carcinogen was based on the results of two studies. The first was a
2-year dietary feeding study in male and female rats receiving
cacodylic acid at doses of 0, 2, 10, 40, and 100 ppm. An increase in
urinary transitional cell bladder tumors with hyperplasia was noted in
both sexes. The second study was a two year feeding study in which mice
were fed diets containing 0, 8, 40, 200, and 500 ppm cacodylic acid. An
increase in fibrosarcomas was noted in female mice fed 500 ppm
cacodylic acid (23).
EPA is unaware of any human epidemiological studies pertaining to
MSMA, DSMA or MAA and cancer. However, because MAA has been associated
with a possible increased incidence of parathyroid adenomas in
experimental animals, and cacodylic acid (a known human metabolite of
MSMA) is categorized by EPA as a probable human (B2) carcinogen, EPA
believes that it is reasonable to assume that MSMA, DSMA, and MAA may
be potential human carcinogens.
- Ecotoxicity. EPA has calculated a bobwhite quail oral LD<INF>50
of 425.2 mg MSMA/kg (Ref. 24). This value was based on 51 percent
active ingredient (MSMA) in the test material. EPA concluded from this
study that MSMA is moderately toxic to bobwhite quail. Based on the
same study, the petitioner gave an LD<INF>50 value of MSMA in bobwhite
quail as 834 mg/kg. This value, however, was not adjusted to take into
account that the test product contains only 51 percent MSMA. Moffett,
et al., have investigated the [[Page 19706]] toxicity of MSMA and DSMA
in honeybees (Refs. 25 and 26). In one of the studies, MSMA was sprayed
onto honeybees at a rate of 4 lb/acre in a carrier volume of 20
gallons/acre (Ref. 25). Mortalities were monitored for 14 days. Bee
mortalities reached 50 percent after only approximately 2 days.
Consequently, the investigators concluded that MSMA is highly toxic to
honeybees (Ref. 25). In the other study MSMA and DSMA were fed to newly
emerged honeybees in a 60 percent sucrose syrup (Ref. 26). Half-lives
(i.e. the number of days for 50 percent mortality to occur) for MSMA
and DSMA were 5.4 and 4.4 days at 100 parts per million by weight
(ppmw) concentrations, and 2.5 and 1.2 days at 1,000 ppmw,
respectively. The investigators concluded that both chemicals are
``extremely toxic'' at 100 and 1,000 ppmw. Of the 14 herbicides tested
in this study, MSMA and DSMA were found to be the most toxic to
honeybees (Ref. 26). EPA does not yet have toxicity criteria for
honeybees in EPA's Draft Hazard Assessment Guidelines for Listing
Chemicals on the Toxic Release Inventory (Ref. 27). EPA believes,
however, that the results of the studies described above strongly
indicate that MSMA and DSMA are quite toxic to honeybees.
The petitioner stated that for MSMA the acute median effective
concentration (EC<INF>50) producing lethality in the freshwater alga
Selenastrum capricornutum is 7.6 mg/L. The petitioner concluded (page
68 of the petition) from this and other information that MSMA and DSMA
are ``* * * .not particularly toxic to aquatic life * * * .'' However,
based on the draft criteria developed by EPA to assess the hazard of
chemical substances, EPA considers MSMA to be moderately toxic to
aquatic life because the algal acute EC<INF>50 value for MSMA is
between 100 micrograms per liter (ug/L) and 10 mg/L, the EC<INF>50
range considered by EPA to be moderately toxic for aquatic biota (Ref.
27). Other aquatic toxicity test data mentioned in the petition also
indicate MSMA and DSMA are moderately acutely toxic (i.e., have
EC<INF>50 or LC<INF>50 [median lethal concentration] values between 100
ug/L and 10 mg/L) to aquatic biota. The 96-h LC<INF>50 of MSMA in
bluegill, for example, is 4.2 mg/L.
EPA obtained MSMA and DSMA aquatic toxicity data not mentioned by
the petitioner (Ref. 28). The 28-day daphnid LC<INF>0 (zero percent
lethal concentration) value for DSMA is 0.83 mg/L. The LC<INF>0 for
DSMA in two species of invertebrates (a snail and a stonefly) and
rainbow trout was found to be 0.97 mg/L (Ref. 28). A 28-day LC<INF>40
(40 percent lethal concentration) value of 0.97 mg/L DSMA was reported
for a gammarid amphipod invertebrate. In bluegills, the 96-h LC<INF>50
for MSMA was found to be 1.9 mg/L. These data indicate that the
toxicity of MSMA and DSMA to aquatic species is greater than that
implied by the petitioner.
C. Environmental Fate
Anthropogenic input of arsenic into the environment occurs through
smelting, coal burning, and the use of arsenical herbicides (e.g., MSMA
and DSMA) (Refs. 29 and 30). Numerous investigators have studied the
environmental fate of arsenic-containing substances, including MSMA and
DSMA. Results from these studies have been summarized (Refs. 29, 30,
and 31). Arsenic-containing substances such as MSMA, DSMA, and MAA
undergo chemical and biochemical transformations in the environment
that include oxidation, reduction, and methylation. These
transformations are largely controlled by soil, sediment absorption/
desorption processes, and affect the overall environmental distribution
of arsenic-containing substances (Refs. 29, 30, and 31). Following
their release into the environment, MAA, MSMA, and DSMA bind reversibly
to ferrous and aluminum oxides contained on the surfaces of clay
particles of soils and sediments. The bound form of these substances
are insoluble in water, and exist in equilibrium with their unbound,
soluble forms in the water present in soils and sediments. While
unbound, MAA, MSMA, and DSMA undergo a cascade of biotic
transformations that include oxidation, reduction, methylation, and
demethylation (Ref. 31). Specifically, MAA, MSMA, and DSMA undergo
oxidative demethylation to arsenate (H<INF>2AsO<INF>4-), an inorganic
form of arsenic, and reductive methylation to cacodylic acid. The
arsenate can be methylated back to MAA, and the two species will exist
in equilibrium. Cacodylic acid can undergo further methylation to
dimethylarsine or trimethylarsine, which will exist in equilibrium with
cacodylic acid. These alkylarsine products volatilize from the soils
and waters in which they were formed and enter the atmosphere. While in
the atmosphere the alkylarsines can be transported to other locations,
and the transformation cascade is repeated: the alkylarsines are
oxidized back to cacodylic acid, MAA, and arsenate (Refs. 29-31). Thus,
anthropogenic releases of MSMA or DSMA may indirectly lead to increased
arsenic concentrations in areas where direct anthropogenic releases of
these substances do not occur (Refs. 29-31). Terrestrial plants may
accumulate arsenic-containing substances by root uptake from soils or
by absorption of airborne arsenic deposited on plant leaves (Ref. 30).
The predominant form of arsenic in surface waters (e.g., drinking
waters, sea waters, etc.) is usually arsenate (H<INF>2AsO<INF>4-), an
inorganic form of arsenic. Arsenate in surface waters can result from
(or enter into) the transformation cascade described in the preceding
paragraph. Above average exposure of the general population to arsenic
from drinking waters is possible in areas of high natural arsenic
levels in ground waters, or elevated arsenic levels in drinking waters
due to industrial discharges, application of arsenic-containing
pesticides, or leaching from hazardous waste facilities (Ref. 30).
Individuals living in the vicinity of large smelters and other
industrial emitters of arsenic substances may be exposed to greater
than average amounts of arsenate as a result of environmental
transformation of organic (e.g., MSMA or DSMA) or inorganic arsenic
substances to arsenate (Ref. 30).
Arsenate is an inorganic form of arsenic. An association between
skin cancer and consumption of drinking water containing inorganic
arsenic has been observed and confirmed (Ref. 32). Epidemiologic
studies in areas where drinking waters containing inorganic arsenic
concentrations ranging from 0.35 to 1.14 mg/L indicate elevated risks
for cancers of the urinary bladder, kidney, skin, liver, lung, and
colon in both men and women (Ref. 32). Increased incidences of cancer
in individuals occupationally exposed to inorganic forms of arsenic
have also been confirmed (Ref. 32). Because of these findings and the
findings from other studies regarding human exposure to inorganic forms
of arsenic and increased incidences of cancer, the National Toxicology
Program categorizes arsenic and certain arsenic compounds (e.g.,
arsenate) as known human carcinogens (Ref. 32). EPA also categorizes
inorganic arsenicals, including arsenate, as known human (Group A)
carcinogens. The categorization by EPA of cacodylic acid as a Group B2
(probable human) carcinogen was discussed in unit III.B.4. above. Thus,
releases of MSMA or DSMA into the environment will lead to the
formation of arsenate and cacodylic acid, which have been categorized
by the National Toxicology Program and EPA as
carcinogens. [[Page 19707]]
D. Technical Summary
MSMA and DSMA are highly water soluble organic arsenicals that are
used as herbicides for the postemergent control of grassy weeds. MSMA
and DSMA are poorly absorbed from the skin and lung, and well absorbed
from the gastrointestinal tract. In the gastrointestinal tract, both
MSMA and DSMA are expected to exist largely as MAA. Based on human and
animal studies, MAA, MSMA, and DSMA are expected to be completely
absorbed and widely distributed in humans following oral
administration. In humans, MSMA is excreted largely unchanged in the
urine, and approximately 13 percent is metabolized to cacodylic acid.
MSMA and DSMA are not believed to be metabolized to inorganic
arsenicals in humans.
The mammalian LD<INF>50 values of MSMA and DSMA following acute
oral exposure are quite high, indicating that these substances have a
low order of acute lethality. Some animal studies indicate, however,
that chronic exposure to lower doses of MSMA or DSMA produce
gastrointestinal toxicity, thyrotoxicity, nephrotoxicity,
hepatotoxicity, developmental and reproductive toxicity. Data regarding
the carcinogenic potential of MSMA, DSMA, or MAA are extremely limited.
A suggestion of an increased incidence of parathyroid adenomas was
observed in rats administered MAA in their diets. Cacodylic acid, a
known human metabolite of MSMA, is categorized by EPA as a Group B2
(probable human) carcinogen. Because MSMA and, presumably, DSMA are
converted into cacodylic acid, MSMA and DSMA may also be carcinogenic
in humans.
MSMA and DSMA are moderately toxic to terrestrial and aquatic
species that include, among others, bobwhite quail, honeybees,
freshwater algae, fish, and daphnids.
In the environment, MSMA, DSMA, and MAA undergo a cascade of
chemical and biochemical transformations that are controlled by soil,
sediment adsorption/desorption processes. In this cascade, MSMA, DSMA,
and MAA are converted into arsenate (inorganic arsenic), cacodylic
acid, dimethylarsine and trimethylarsine. Inorganic arsenicals,
including arsenate, are categorized by the National Toxicology Program
and EPA as known human carcinogens. In addition, cacodylic acid is
categorized by EPA as a Group B2 or probable human carcinogen.
IV. Rationale for Denial
EPA is denying the petition to delete MSMA and DSMA from the
section 313 list of toxic chemicals. This denial is based on the
Agency's determination that MSMA and DSMA: (1) May cause chronic toxic
effects in humans; and (2) are potential carcinogens. In regard to the
latter point, EPA has determined that because MSMA and, undoubtedly,
DSMA are metabolized in humans to cacodylic acid (a probable human
carcinogen), it is reasonable to assume that MSMA and DSMA are also
probable human carcinogens. In addition, it has been demonstrated that
MSMA and DSMA are converted into arsenate (an inorganic arsenic) and
cacodylic acid in soils and sediments. Inorganic arsenics, including
arsenate, are categorized by the National Toxicology Program and EPA as
known human carcinogens. EPA concludes that MSMA and DSMA meet the
EPCRA section 313(d)(2)(B) criteria because they can reasonably be
anticipated to cause cancer in humans as a result of their metabolism
to cacodylic acid or their environmental conversion to cacodylic acid
and arsenate. Thus, in accordance with EPCRA section 313(d)(2), EPA has
determined that MSMA and DSMA exhibit high chronic toxicity and,
therefore, should not be deleted from the section 313 list of toxic
chemicals.
EPA's denial of the petition to delist MSMA and DSMA from the
section 313 list of toxic chemicals is based, in part, on the
conversion of these substances to substances that are regarded as being
either known or probable human carcinogens, and is consistent with past
Agency decisions regarding section 313 delisting petitions. [See, e.g.,
Chromium (III) Oxide (56 FR 58859, November 22, 1991)]
V. References
(1) Shah, P.V., Fisher, H.L., Sumler, M.R., Monroe, R.J., Chernoff,
N., Hall, L.L. (1987) Comparison of the Penetration of 14 Pesticides
Through the Skin of Young and Adult Rats. J. Toxicol. Environ. Health.
21:353-366.
(2) Toxicological Profile For Arsenic (Update). Agency for Toxic
Substances and Disease Registry (ATSDR) Report No. ATSDR/TP-92/02; pp.
7-84.
(3) Shariatpanahi, M., Anderson, A.C. (1984) Distribution and
Toxicity of Monosodium Methanearsonate Following Oral Administration of
the Herbicide to Dairy Sheep and Goats. J. Environ. Sci. Health B19(4
5):427-439.
(4) Jaghabir, M.D., Abdelghani, A.A., Anderson, A.C. (1991)
Absorption, Distribution, and Elimination of Arsenic in New Zealand
White Rabbits (Oryctalagus cuniculus) Following Multiple Oral Doses of
Monosodium Methane Arsonate. Environmental Toxicology and Water
Quality: An International Journal 6:113-119.
(5) Stevens, J.T., DiPasquale, L.C., Farmer, J.D. (1979) The Acute
Inhalation Toxicology of the Technical Grade Organoarsenical
Herbicides, Cacodylic Acid and Disodium Methanearsonic Acid; A Route
Comparison. Bull. Environm. Contam. Toxicol. 21:304-311.
(6) Goyer, R.A. (1991) Toxic Effects of Metals. In: Amdur, M.O.,
Doull, J. Klaassen, C.D. eds., Casarett and Doull's Toxicology, The
Basic Science of Poisons. Fourth Edition. Pergamon Press: New York; pp.
631-632.
(7) U.S. Environmental Protection Agency. (1984). Health Assessment
Document for Arsenic. Criteria and Assessment Office, Research Triangle
Park, NC, Report No. EPA 600/8-83-021F.
(8) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Metabolism Data on [<SUP>14C-methyl]MSMA. MRID No. 42010501
(Office of Pesticide Programs).
(9) Buchet, J.P., Lauwerys, R., Roels, H. (1981) Comparison of the
Urinary Excretion of Arsenic Metabolites After a Single Oral Dose of
Sodium Arsenite, Monomethylarsonate, or Dimethylarsinate in Man. Int.
Arch. Occup. Environ. Health 48:71-79.
(10) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Rat Acute Oral Toxicity of DSMA 81P in the Rat. MRID No.
418920-04.
(11) Gaines, T.B., Linder, R.E. (1986) Acute Toxicity of Pesticides
in Adult and Weanling Rats. Fundam. Appl. Toxicol. 7:299-308.
(12) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Rabbit Acute Dermal Toxicity of DSMA. MRID No. 418920-05.
(13) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Rabbit Acute Dermal Toxicity of MSMA. MRID No. 418900-01.
(14) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Acute Inhalation Toxicity of DSMA 81P in the Rat. MRID No.
418920-06.
(15) Toxicological Profile For Arsenic. Agency for Toxic Substances
and Disease Registry (ATSDR) Report No. ATSDR/TP-92/02; pp. 7-84.
(16) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Methanearsonic Acid Combined Chronic Feeding and Oncogenicity
Study in the Rat. MRID No. 41669001.
(17) Jaghabir, M.T.W., Abdelghani, A.A., Anderson, A.C. (1989)
[[Page 19708]] Histopathological Effects of Monosodium Methanearsonate
(MSMA) on New Zealand White Rabbits (Oryctalagus cuniculus). Bull.
Environ. Contam. Toxicol. 42:289-293.
(18) Prukop, J.A., Savage, N.L. (1986) Some Effects of Multiple,
Sublethal Doses of Monosodium Methanearsonate (MSMA) Herbicide on
Hematology, Growth, and Reproduction of Laboratory Mice. Bull. Environ.
Contam. Toxicol. 36:337-341.
(19) U.S. Environmental Protection Agency. (1989) Data Evaluation
Report: Methanearsonic Acid Fifty Two Week Chronic Oral Toxicity Study
in Beagle Dogs. MRID No. 405461-01/412664-01.
(20) U.S. Environmental Protection Agency. (1986) Data Evaluation
Report: Methanearsonic Acid Teratology Study in the Rabbit. MRID No.
159390-01.
(21) U.S. Environmental Protection Agency. (1994) Data Evaluation
Report: a Two Generation Reproduction Study in Rats with Methanearsonic
Acid (MAA). MRID No. 431783-01.
(22) U.S. Environmental Protection Agency. (1990) Data Evaluation
Report: a Teratology Study in Rats with Methanearsonic Acid. MRID No.
419264-01.
(23) U.S. Environmental Protection Agency. (1994) Carcinogenicity
Peer Review Document for Cacodylic Acid.
(24) U.S. Environmental Protection Agency. (1991) Data Evaluation
Report: Monosodium Methane Arsonate (MSMA); Avian Single Dose Oral
LD<INF>50 Test (Bobwhite Quail). MRID No. 416100-02.
(25) Moffett, J.O., Morton, H.L., MacDonald, R.H. (1972) Toxicity
of Some Herbicidal Sprays to Honey Bees. J. Econ. Entomol. 65:32-36.
(26) Morton, H.L., Moffett, J.O., MacDonald, R.H. (1972) Toxicity
of Herbicides to Newly Emerged Honey Bees. Environ. Entomol. 1:102-104.
(27) Hazard Assessment Guidelines for Listing Chemicals on the
Toxic Release Inventory. Revised Draft (May 26, 1992). Office of
Pollution Prevention and Toxics, U.S. Environmental Protection Agency.
(28) Eisler, R. (1988) Arsenic Hazards to Fish, Wildlife, and
Invertebrates: A Synoptic Review. Dept. of the Interior, U.S. Fish
Wildl. Serv. Biol. Rep. 85(1.12) .
(29) Menzer, R.E. (1991) Water and Soil Pollutants. In: Amdur,
M.O., Doull, J. Klaassen, C.D. eds., Casarett and Doull's Toxicology,
The Basic Science of Poisons. Fourth Edition. Pergamon Press: New York;
pp. 891-893.
(30) Toxicological Profile For Arsenic. Agency for Toxic Substances
and Disease Registry (ATSDR) Report No. ATSDR/TP-92/02; pp. 99-108.
(31) Woolson, E.A. (1977) Fate of Arsenicals in Different
Environmental Substrates. Environmental Health Perspectives 19:73-81.
(32) Seventh Annual Report on Carcinogens: 1994 Summary. United
States Department of Health and Human Services, National Toxicology
Program; pp. 21-26.
VI. Administrative Record
The record supporting this decision is contained in docket control
number OPPTS-400092. All documents, including an index of the docket,
are available to the public in the TSCA NonConfidential Information
Center (NCIC), also known as the Public Docket Office, from noon to 4
p.m., Monday through Friday, excluding legal holidays. The TSCA NCIC is
located at EPA Headquarters, Rm. NE-B607, 401 M St., SW., Washington,
DC 20460.
List of Subjects in 40 CFR Part 372
Environmental protection, Chemicals, Community right-to-know,
Reporting and recordkeeping requirements, and Toxic chemicals.
Dated: April 14, 1995.
Lynn R. Goldman,
Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 95-9782 Filed 4-17-95; 12:11 pm]
BILLING CODE 6560-50-F