United States
Environmental Protection Off ice of Water EPA 811/R-92-006
Agency (WH-550) October 1992
&EPA STATUS REPORT ON THE
DEVELOPMENT OF DRAFT MCLGs
FOR DISINFECTANTS AND
BY-PRODUCTS
Printed on Recycled Paper
-------
-------
-------
-------
1992
How MCLGs Are Develop^
^s.^-ss^rfeas.-sia.s ^^rliv D
groups represent consensus on risk assessments for the Agency and
can be used by the respective regulatory programs as the SaL
%z ^^^^-^^^ S
™
Uncertainty factors are used in order to
sensitive subpopulations andthe possibility ol syner?istic '
action between chemicals (see 52 FR 25690 for JnJSf^9i-p •
on the use of uncertainty factors) for further discussion
-------
Uncertainty Factors fUFsl
0 Use a '1- to 10-fold factor when extrapolating from valid
experimental results from studies using prolonged exposure
to average healthy humans. This factor is intended to
account for the variation in sensitivity among the members
, of the human population,
0 .Use'an additional .ID-fold factor when extrapolating from .
valid results of long-term studies on experimental animals
when results of studies of human exposure are not available
or are inadequate,. This factor is intended to account for
the uncertainty >n extrapolating animal data to the case of
humans.
0 Use an additional 10-fold factor when extrapolating from
less than chronic results on experimental animals when there
are no useful long-term human data. This factor is intended
to account for the uncertainty in extrapolating from less
than chronic NOAELs to chronic NOAELs.
0 Use an additional 10-fold factor when deriving an RfD from a
LOAEL instead of a NOAEL. This factor is intended to
account for the uncertainty in extrapolating from LOAELs to
NOAELs,
An additional uncertainty factor may be used according to
scientific judgment when justified.
0 Use professional judgment to determine another uncertainty
factor (also called a modifying factor, MF) that Is greater
than zero and less than or equal to 10. The magnitude of
the MF depends upon the professional assessment of
scientific uncertainties of the study and data-base not
.explicitly treated above, e.g.; the completeness of the
overall data base and the number of species tested. The
default value for the MF is l.
From the RfD, a drinking water equivalent level (DWEL) is
calculated. The DWEL represents a lifetime exposure
concentration to a drinking water contaminant at which adverse
non-cancer health effects are not expected to occur. The DWEL is
calculated by multiplying the RfD by an assumed adult body weight
(generally 70 kg) and then dividing by an average daily water
consumption of 2 liters per day [NAS, 1977]. The DWEL assumes
the total daily exposure to a substance is from drinking water
exposure. The MCLG is determined by multiplying the DWEL by the
percentage of the total daily exposure expected to be contributed
by drinking water, called the relative source contribution (RSC).
Generally, EPA assumes that the RSC from drinking water is
20 percent of the total exposure, unless other exposure data for
the chemical are available [see 54 FR 22069 and 56 FR 3535].
-------
suss
The calculation below expresses the derivation of the MCLG
RfD = - NOAEL or T.naTTT.
uncertainty f actor (s) ~ ra9/kg bo<*y weight/day
daily water consumption in I/day
= Ground etng W?S? cont^bution = mg/L
(rounded to one significant figure)
assess^? lor^on-^eS ££* C?Cin°**nic to ^ans, the
evidence of carc?nogenJci?y in huSan^ uT?^* °f the Weight of
and human epidemiollgical stuSiesS weS *? *J1;assays . in animals
provides indirect evidence r i i asjwell as information that
term test results) T^SSbjeclivesI?^101117 ™* ^^short-
determine the level or strfn«?h X? °^the assessment are to
scheme is [uSpff ' isssTt general carcinogen classification
.— .
humans (Group B2) 7 animals with inadequate or no data in
animal studies) . Pecies or m both epidemiological and
-------
EPA follows a three-category approach in developing MCLGs
for drinking .water contaminants (Table 1) .
TABLE 1. EPA'S THREE-CATEGORY APPROACH
• FOR ESTABLISHING MCLGs
Category
Evidence of
Carcinogenicity via
Drinking Water
MCLG Approach
II
III
Strong evidence
considering weight of
evidence, pharmaco-
kinetics, potency an<£
exposure route
Limited evidence
considering weight of
evidence, pharmaco-
kinetics, potency and
exposure route
Inadequate or no animal
evidence
Zero
RfD approach with
added safety margin
of l to 10 or ICT5
to icr6 cancer risk
range
RfD approach
Each chemical is evaluated for evidence of carcinogenicity
from drinking water. For volatile contaminants, inhalation data
are also considered. EPA takes into consideration the overall
weight of evidence for carcinogenicity, pharmacokinetics, potency
and exposure route.
. . EP.A's policy is to set MCLGS -for .Category I contaminants at
'zero. The MCLG for Category II contaminants is calculated-by
using the RfD approach with an added margin of safety to account
for possible .cancer effects. If adequate data are not available
to calculate an RfD, then the MCLG is based on a cancer risk
range of icr5 to lo-6. MCLGs for Category III contaminants are
calculated using the RfD approach.
Category I contaminants are those for which EPA has
determined that there is strong evidence of carcinogenicity from
drinking water. The MCLG for Category I contaminants is set at
zero because it is assumed, in the absence of other data, that
there is no threshold for carcinogenicity. In the absence of
route specific data (e.g., oral) on the potential cancer risk
from drinking water exposure, chemicals classified as Group A or
B carcinogens are generally placed in Category I.
-------
._•?-• .. ' '_-;"•
r.™ vcat®9ory II contaminants include those contaminants which
EPA has determined that there is limited evidence of
carcinogenicity from drinking water considering weight of
evidence, pharmacokin.etics, potency and exposure. In the absence
o,f route specific data, chemicals classified in Group ?tre
generally placed in Category II. For Category II contaminants
£?„ °gtl0"S are used to set the MCLG. The first option «S thii
•MCLG. based upon noncarcinpgenic endpoints of toxicity (the RfD)
then applying an additional safety factor of 1 to 10 to the MCLG
=La^U£rr0H p°Jsible carci™*enicity. The second op?ion is to
set the MCLG based upon a theoretical lifetime excess cancer riSk
range of 10'5 to 10* using a conservative mathematical
extrapolation model. EPA generally uses the first option;
however, the second approach is used when valid noncarcinogenic
data are not available to calculate an RfD and adequate
experimental data are available to quantify the cancer risk.
Wh^hho Z" conta*inar>ts- include those contaminants for
which there is inadequate evidence of carcinogenicity from
drinking water. If there is no additional inf o^mStion to
consider, contaminants classified as Group D or E chemicals are
aSSfrfh1; Ca^ego^ ZI1- For ^ese "
established using the RfD approach.
Development of MCT.GS for Disinfectants and BY
Chlorine, hvnochloritie ion and hvpochlorous I
t - .
Chlorine (CAS # 7782-50-5) hydrolvses in
5 oou
acia (CAS #7681-52-9) . Because of their oxidizing
characteristic and solubility, chlorine and hypochlorites are
used in water treatment to disinfect drinking water sewaae Jn
wastewater, swimming pools, and other types of water 'rJse??oi?2
They are also used for general sanitation and conlrofol
bacterial odors in the food industry. "^oj. ox
Chlorine is a highly reactive species and water
^
Occurrence and Human Exposure
evaluf^f^J^0^63 fr°m swimming Pools and hot tubs are not
evaluated in this document. For the purpose of settina an Mrfr
consideration is given to chlorine levels rSsSltingfrlm '
disinfection of drinking water. Persons who swim frequently or
-------
use a hot tub may have greater dermal or inhalation exposure to
chlorine.
Chlorine is added to drinking water as chlorine gas (C12) or
as calcium or sodium hyppchlorite. In drinking water, the
chlorine gas hydrolyses to hypochlorous acid and hypochlorite ion
and can be measured as the free chlorine residual. Maintenance
of a chlorine residual throughout the distribution system is
important for minimizing bacterial growth and for indicating (by
the absence of a residual) failures in the distribution system.
Currently, maximum chlorine dosage is limited by tastie and odor
constraints and for systems needing to comply with the total
trihalomethane (TTHM) standard regularly. Additionally, for.
systems using chlorination, the surface water treatment rule
(SWTR) requires a minimum residual of 0.2 mg/L, measured as total
chlorine, prior to the entry point to the distribution system and
the presence of a detectable residual throughout the distribution
.system. .
The following table presents the most recent and
comprehensive occurrence information available for chlor.in.e.::'in'
drinking water. Descriptions of these surveys and other data are
detailed in "Occurrence Assessment for Disinfectants and
Disinfection By-Products (Phase 6a) in Public Drinking Water,"
USEPA August 1992. The table lists five surveys conducted by
Federal, as well, as private agencies. Median concentrations of
chlorine in drinking water appear to range from
-------
-------
8
Exposure to chlorine residual varies both between systems
and within systems, chlorine residual within systems will vary
based on where customers are located within the distribution
system and changes in the system's disinfection needs over time.
Using residual concentrations from the 1989-1991 AWWA
Disinfection Survey and WIDE, exposure to chlorine due to
drinking water can be estimated using a consumption'.rate of
, 2 liters per day. Based on the estimated 25 percentile and
75 percentile chlorine residuals in the '1991 AWWA- Disinfection
Survey, exposure was determined to range from 1.5 to 3,.8 mg/day
and the median would be 2.2 mg/day. Using the WIDB data,
exposures to the average customer from surface and ground water
sources using chlorination, respectively, were determined to be
1.9 mg/day and 1.7 mg/day.
Little information is available concerning the occurrence of
chlorine in food and indoor air in the United States. The Food
and Drug Administration (FDA) does not analyze for chlorine in
foods. However, there are several uses of chlorine in food
production; for example, disinfection of chicken in poultry
plants and the superchlorination of water at soda and beer
bottling plants (Borum, 1991). Therefore, the possibility exists
for dietary exposure to chlorine from its use in -food production.
However, monitoring data are not available to characterize
adequately the extent of such potential exposures. Additionally,
preliminary discussions with FDA suggest that there are not
approved uses for chlorine in most foods consumed in the typical
diet. Similarly, the Indoor.Air Division of EPA's Office of Air
and Radiation is not currently conducting any sampling studies
for chlorine in air. Data on levels of chlorine in ambient air
are forthcoming from EPA's Office of Air Quality Planning and
Standards.
t • > Considering the limited number of food groups that are
believed to contain chlorine.and" that no significant levels of
chlorine are expected in ambient or indoor air, it is-anticipated
that-drinking water is the predominant source of exposure to
chlorine. Air and food are believed to provide only small
contributions, although the magnitude and frequency' of these
potential exposures are issues currently under review. EPA,
therefore, is considering setting an MCLG for chlorine in
drinking water using a relative source contribution (RSC) value
of 80%, the current exposure assessment policy ceiling. EPA
requests any additional data on known concentrations of chlorine
in drinking water, food and air.
Health Effects
The health effects information for chlorine is summarized
from the draft Drinking Water Health Criteria. Document for
Chlorine, Hypochloro'us Acid and Hyperchlorate Ion (USEPA, I992a)
-------
Sect*°n are .™-«i««» in the draft
criteria document.
Chlorine and the hypochlorites are very reactive and thus
can react with the constituents of saliva and possibly food and
gastric fluid to yield a variety of reaction by-products °e.g
trihalomethanes). Thus, the health effects associated with the
. administration of chlorine and/or the hypochlorites in various
' """S^TSS1?* mfi^bedueto.these reaction by-products, and not
disinfectant itself. Oxidizing species such as chlorine and
^ vo~.,«-es_are probably short lived in biological systems
i:,r reactivity and the large number of organic
I-in vivo.
Oral studies with radiolabeled (i.e., *ci) hypochlorite and
hypochlorous acid indicate that, as measured by the radiolabel
IhrSnSS^^H^K^-^ WSl1 absorbed and distributed throughout
the body with the highest levels measured in plasma and bone
marrow. However, considering the reactivity of the
hypochlorites, these results may only reflect the presence of--'-
reaction by-products (e.g., chloride). The major ?oS?JSf
excretion appears to be urine and then the feces.
Acute oral LD50 values for calcium and sodium hypochlorite
have been reported at 850 mg/kg in rats and 880 mg/kg in mice
g
SSTSrTS' ?TanS hr? cons™ed hyperchlorinatedwaer for
short periods of time, at levels as high as 50 mg/L (1.4 mg/kg)
with no ™9/*g;
,
with no apparent adverse effects.
in bin«rt> ?tud^es in animals have indicated decreases
liver Jnlod^1?1?!1^613' hemolvsis and biochemical changes in
liver in rodents following a gavage dose of hypochlorite in
water. No adverse effects on reproduction (Druckery, 1968) or
°nt --t al" 1982> were observed in rits
svste™^c Affects were observed in rodents following oral
uno * ?hlorine as hypochlorite in distilled water at leve
up to 275 mg/L over a 2 years period. j-evei
har,.u chlorinated water has been shown to be mutagenic to
bacterial strains and mammalian cells. Investigations with
rodents to determine the potential carcinogenicity o? chlorine
(NTP,
However, NTP observed a marginal inceas in .
-------
10
incidence of monocellular leukemia in mid-dose female F344 rats
but not in male rats or male and female mice (NTP, 1990).
Monocellular leukemia has a high spontaneous rate of occurrence
in F344 rats. EPA believes that monocellular leukemia can not be
solely attributed to exposures to.chlorine in drinking water but
rather may reflect the high background rate of monoceilular
leukemia in the test species.
' EPA has'not, as yet, evaluated the carcinogenic potential of
chlorine, hypochlorite or hypochlorous acid. However, the •
International Agency for Research on Cancer (IARC, 1991) recently
evaluated chlorinated drinking water and hypochlorite for
potential human carcinogenicity. IARC determined that there was
inadequate, evidence for carcinogenicity of chlorinated drinking
water and hypochlorite salts in humans and animals. IARC
concluded that chlorinated drinking water and hypochlorite salts
were not classifiable as to their carcinogenicity to humans and
thus assigned these chemicals to IARC Group 3. This category is
similar to EPA cancer classification Group D. EPA will initiate a
'cancer evaluation of these compounds in the fall of 1992.
Based on the previous discussion, EPA is considering-placing
chlorine, hypochlorite and hypochlorous acid in Category III for
the purpose of setting an MCLG. The study selected for
determining an RfD is the previously mentioned 2 year rodent
study that was conducted by the National Toxicology Program (NTP,
1990). In this study, male and female F344 rats and B6C3F1 mice
were given chlorine in distilled drinking water at levels of 0,
70, 140 and 275 mg/L for 2 years. Based on body weight and water
consumption values, these concentrations correspond to doses of
approximately 0, 8, 13 and 24 mg/kg/day for male rats; 0, 5, 7,
and 15 mg/kg/day for female rats.; 0, 8, 15, and 24 mg/kg/day for
male mice and 0, 7, .13 and 22 mg/kg/day fpr. female mice. There
was a dose related decrease in water consumption, for both rats
and mice, presumably due to taste aversion. No effect on body
weight or survival .were observed fpr any of the treated animals.
A NOAEL of 15 mg/kg/day in female rats is proposed as the
basis of the RfD (i.e., the highest dose received by female rats
is lower than the highest dose received by either mice or male .
rats in the NTP study). The 15 mg/kg/day NOAEL is supported by
EPA's analysis of other studies which reported NOAELs of 10 to
24 mg/kg/day for rodents.
'An RfD of 0.15 mg/kg/day is calculated after dividing the
NOAEL of 15 mg/kg/day by an uncertainty factor of 100, which is
appropriate for use with a NOAEL from a chronic animal study. A
DWEL of 5 mg/L is determined by adjusting the RfD for both human
adult body weight and water consumption. EPA is considering
adjusting the DWEL by an RSC of 80 percent to.account for the
likely exposure'to chlorine, hypochlorite and hypochlorous acid.
•from drinking water. This would result in an MCLG of 4 'mg/L.
-------
DWEL = °-15 rca/kg/day v
MCLG = 0.8 x 5 mg/L,.= 4 mg/L
= 5 mg/L
Issues
1. Setting an RSC percentage at 30%. t
and hypochlorous acid -in
3. Selection of the NTP study for the RfD.
Chlorine Dioxide r rhlorite and
and odors in water treatment
contr°l tastes
dioxide is fairly unstable and
and chlorate in wate?? &
chlorite converting back to
generally the primary product
int°
ri reversible with
hlorite ion is
"
•th.. sodium salt, was ne
as
="°rate,- as
Occurrence and Human
community ground wtr ™SS.'4 m^lllon Pe°Ple and 1% of
SSI
-------
12
dioxide, chlorate, and chlorite in drinking. water. Descriptions
of these surveys and other data are detailed in "Occurrence
Assessment for Disinfectants and Disinfection By-Products (Phase
6a) in Public Drinking Water," USEPA, August 1992. Typical
dosages of chlorine dioxide used as a disinfectant in drinking
water treatment facilities appear to range from 0.6 to 1.0 mg/L.
For plants using chlorine dioxide., median concentrations of
chlorite and chlorate were found to be 240 and 200
respectively. • • ....
-------
III
J2 §
"§•<*.
i o
-------
14
No information is available on the occurrence of chlorine
dioxide, chlorate, and chlorite in food or ambient air.
.Currently, the Food and Drug Administration (FDA) does not
analyze for these compounds in foods. Preliminary discussions
with FDA suggest that-.there are not approved uses for chlorine
dioxide in foods consumed in the typical diet. In addition,.the
EPA Office of Air and Radiation does not require monitoring for
these compounds in air. However, chlorine dioxide is used as a
sanitizer for air ducts (Borum, 1991) ..
EPA believes that drinking water is the predominant source
of exposure for these compounds. Air and food exposures are
considered to provide only small contributions to the. .total
chlorine dioxide, chlorate, and chlorite exposures, although the
magnitude and frequency of these potential exposures are issues
currently under review. Therefore, EPA is considering proposing
to regulate these compounds in drinking water with a relative
source contribution value of 80 percent, the current exposure
assessment policy ceiling. EPA requests any additional data on
known concentrations of chlorine dioxide, chlorate and chlorite
in drinking water, food and air. • '.
Health Effects .
The following health effects information is summarized from
the draft Drinking Water Health Criteria Document for Chlorine
Dioxide, Chlorite and Chlorate (USEPA, 1992b). Studies cited in
this section are summarized in the draft criteria document. '
The main health effects associated with chlorine dioxide and
its anionic by-products include oxidative damage to red blood
cells, decreased • thyroxine hormone levels and delayed
rieurodevelopment. Chlorine dioxide, chlorite and chlorate are
well absorbed by the gastrointestinal tract and excreted
primarily in urine. Once absorbed, 36Cl-radiolabeled chlorine
dioxide, chlorite and chlorate are distributed randomly
throughout the body. Lethality data for ingested chlorine
dioxide have not been located in the available literature. A
lethal concentration for guinea pigs by inhalation was reported
at 150 ppm. Oral LD50 values for chlorite have been reported at
100 to 140 mg/kg in rats. Limited data suggest an oral LD50 value
between 500 to 1500 mg/kg for chlorate in dogs.
•In subchronic and chronic studies, animals given chlorine
dioxide treated water exhibited osmotic fragility of red blood
cells, decreased thyroxine hormone levels, possibly due to
altered iodine metabolism and hyperplasia. of goblet cells and
inflammation of nasal tissues. It is not clear if the nasal
effects are due to qff-gassing of chlorine dioxide from the
sipper tube of the animal water bottles, or from dermal contact
while the animal drinks from the sipper tube.
-------
15,;
£~i?Lr;^!??_*?™lopa«ntal or reproductive
Subchronic studies with chlorite administered to rai-c: „<«'
chlorate also demonstrate effects on
ssr^iS!-"0" °f -«-™n,
tujori?fnic activity has been observed in chlorine
the
Based on
These effects were not
-------
16
observed at the 3 mg/kg/d dose level. In a second experiment,
pups were given 14 mg/kg/d chlorine dioxide directly by gavage
during postnatal days 5 through 20. A greater and more
consistent delay in neurpbehavioral activity was observed along
wi?h a greater depression .in thyr.oxine. Analysis of the DNA_ • ,
SSS&LSS1^^ ^^^^^^^^
•2J.Fl^^^^^^^^^^^^ by
decreased brain cell proliferation in rats exposed postnatally by
gavage (Toth et al., 1990)..
In a monkey study (Bercz et al., 1982), animals were given
chlorine dioxide at concentrations of 0, 30, 100 or 200 mg/L in
drinking water following a rising dose protocol. These
concentrations correspond to doses of 0, 3.5, 9.5 and 11 .mg/kg/d
based on animal body weight and water consumption. Animals
showed signs of dehydration at the high dose and were
iiscontiiuel at that dose. A slight depression of thyroxine was
observed following exposure to 9.5 mg/kg/d. No effects were seen
with 3.5 mg/kg/d, which is considered the NOAEL.
EPA is considering following a Category III approach for
setting an MCLG for chlorine dioxide. Using a NOAEL of 3 rag, Kg,, d
and an uncertainty factor of 100, an RfD of 0.03 mg/kg/d for
chlorine dioxide is calculated. This RfD is approximately equa.
to the NOAEL of 0.03 mg/kg/d identified from the Lubbers et a,.
(1982) human clinical study (see USEPA, 1992b). Typically, an
uncertainty factor of 1,000 would be used for a NOAEL from an
animal study of less than lifetime duration. However, in this
case an uncertainty factor of 100 is considered with the NOAEL
instead of 1,000 since the endpoints of toxicity are observed
following a 'short period, of .exposure.
A DWEL of 1 mg/L is derived'by adjusting the RfD of •
0 03 mg/kg/d for an adult body weight and water consumption. An
RSC of 80 percent is used in calculating an MCLG of 0.8 mg/L,
since most chlorine dioxide exposure is likely to come fron i
drinking water source.
DWEL = ^ loo^x'? L/day^ = X mg/L
MCLG = 1 mg/L x .0.8 = 0.8 mg/L
If the uncertainty factor were increased to 1,000, the
resulting MCLG would be 0.08 mg/L. If the uncertainty factor
were a total of 300 (100 for a NOAEL and 3 for less than
lifetime), the resulting MCLG would be 0.3 mg/L.
• The Drinking Water Committee of the Science -Advisory Bciri
(SAB) has suggested that a child's body weight of 10 kg and •. i»-r
-------
17
consumption of 1 L/d may be more appropriate for settina >>,« m^r
than the adult parameters, given the acutfna^re of S2 WEL
toxicity. If a 10 kg weight and 1 L/d water consumption were
bfo.rmg/L0 uncertainty,fact°r of 1000, the resulting £CL1 would
Issues • • •
1. Appropriateness of the 100-fold uncertainty factor
i . .• • • .
forItheniJovioJ°nai uncertafntY factor of 3 is needed to account
for the lack of a 2-generation reproduction study?
3. Use of a child »-s body weight and water consumption rate
in setting an MCLG. sumption rate
For chlorite, the subchronic rat study by Heffernan et si
(1979) would be selected as the basis for theRfD in foJlSwina'a
?nneg?^ Iir aPProaeh to set an MGLG. Rats were given oia 50
t °°4 2?n' ?J 5°° mg/L chlorite (as sodium salt; eluivaleAt to 0
1, 5, 10, 25, or 50 mg/kg/d) in drinking water fol 30 to 90 davs
In evaluating hematological parameters , the three highest doses
were found to produce transient anemia after 30 days" At 90
days, red blood cell glutathione levels were 40 pSr^nt be!ow
controls in the 10 mg/kg/d group and 20 percent lower in ?he
5 mg/kg/d group. This NOAEL of 1 mg/kg/d is identified TH,
NOAELjis supported by a 2 year study in ratl thlt idiSti f i IH
notncudhH
published hlstoPathol°gy on all treated animals and was never
01 mg/k^/d can be calculated from the NOAEL of
by an uncertainty factor of 100. This RfD is
approximately equal to the NOAEL of 0.03 mg/kg/d identified
-
From the RfD, a DWEL of 0.4 mg/L is calculated after
adjusting for an adult body weight and water consumption An RSC
S3T
DHEL =
MCLG = 0.4 X 0,80 =0.3 mg/L
-------
18
The SAB made the same suggestion for chlorite as for
chlorine dioxide. That is, to consider use of 10 kg and 1 L/d
for determining the DWEL. The resulting MCLG would be 0.08 mg/L.
Data are considered inadequate to develop an MCLG for
chlorate at this time. A NOAEL of 0.036 mg/kg/d was identified.
in the Lubbers et al. (1982) human clinical study following a 12
week exposure to chlorate in drinking water* NOAELs identified
from animal studies' are considerably higher (approximately 250
mg/kg/d) . However, this is equivalent to doses that are lethal
to humans (200 mg/kg/d). No information is available to
characterize the potential human toxicity between the doses of
0.036 and 200 mg/kg/d. Thus, EPA considers the data..base too
weak to derive a separate MCLG for chlorate.
EPA is considering, setting a Lifetime Health Advisory (HA)
(a non-enforceable guidance), for chlorate as an interim measure
to provide some health guidance while more data are being
collected to set an MCLG. EPA is considering basing the Lifetime
HA on the NOAEL from the Lubbers et al. (1982) study. An
uncertainty factor of 10 would be used to account for a NOAEL....
from a human study.' The resulting Lifetime HA value would be 0.1
mg/L.
0.036 ma/ka/d x 70 x 0.8 _ n - W|_/T
Lifetime HA = io x 2 L/d °-1 mg/;L
EPA currently has a guideline value of 1 mg/L for total
residual oxidants when chlorine dioxide is used. Since chlorine
dioxide, chlorite and chlorate are so reactive and undergo
conversion from one form to another, it is likely that the
experimental studies with chlorine dioxide actually include
exposures to chlorite and chlorate as well. Although the
toxicity elicited by each compound can vary, this variation .may
exist within the range of uncertainty employed in the risk
assessment. Thus, EPA is considering establishing one MCLG for
all'residual oxidants when chlorine dioxide is used-as a
disinfectant. This MCLG could be based on the chlorine dioxide.
studies discussed above, resulting in a value of 0.8 mg/L.
Alternatively, the MCLG for residual oxidants could be based on
the chlorite (0.3 mg/L) value since it is the predominant
degradation species.
Issues
1. Use of an uncertainty factior of 100.
2. Is it reasonable to set an MCLG for total residual oxidants
and what would be the basis for that MCLG?
3. The chlorate MCLG issue as well "as the separate MCLGs for
chlorite and chlorine dioxide that are being considered.
-------
19 •;-„;.
Water
Chloraminoa
rate in
for Kono-^and'triShioramine^res ective"l5"~9°~3 a"d 1?025-85-l
dichloramines and"trichloraSineS^Ji^31^01113: Mon°chloramineS,
is the principal ^Im^^SS^ln Sh f°fJ^Ai ^Monochloramine
wastewater at a neutral BH%«ST^ chlorinated natural and
environment. neutral PH and is much more persistent in the
in drinking water to
chlorinated disinfection hv»^ * the fo«nation of
the distribution s?sterfonSnSSlfinrbiS?^tain a residual t
typical pHs of most drinkino S?K2i S? bJ-°fHm growth. At
specie is monochloramine lor Dur»;s^e £r:doininant chloramine
monochloramine will be considered s?nS ?h ^ re9ulation, only
occur at much lower con
Monochloramine has also
of
aS an intermediate in the manufacture
formed in
the environment. FirsoSr Ieca3 ne?tral PH- i« Persistent
0.075 hr-< for monochloramine in the S*S? V Constants °f 0.03 to
constants of 0.28 to 0.31 hr'1 SuSoni aboratorv' and, higher rate
effluents, have been reported I? °°""s^g chlorinated
waters containing bromide monochfo^ ^ arg^d into re^eiving
probably through the ?or^at?on of SSrC^and^ deCOmP?se ^Iter,
dihalamane. The rate of monochlorsmfnf Ct.and ^composition of the
a function of pH and salin??S 5 disappearance is primarily
the half-life If. monoch^mine -Irs^SJ^ at EH 7 •»**££*•
(PPt) salinity and 0.75 hr at |5 nnl Sfi^-f Parts per thousand
25 °C, the half-life is 188 hr at ??nn? ?^; at pH 8'5 *"*
35 ppt salinity. Monochloramin^ f PP sallnity and 25 hr at
wastewater discharge! recSSES J£ expected to decompose in
organic nitrogen-c^n?aIV V" Chl°rine ^ansfer to
as a by-product and
chlorination when source waters cnniff e 1? forraed during
as a primary or secondary diSnflSant SS?^' -P is als° »**<*
being generated on site by the aSSi?ioA ^Ually Vlth chloramine
following treatment by chLrinaJ^nr^^ has
-------
20
been shown to reduce the formation of certain by-products,
nSSbly trihalomethanes, relative to chlorination alone._
Chlorination by-product formation can be minimized when the
anmonia is added prior to or in combination with chlorine by
SSing lhfchlo?.ine. residual of the water being treated In
™«3h nlants however, ammonia is added s'ome time after the _
addition ol'chloSe- "allow- for more effective disinfection
since cSlorineil a much stronger disinfectant than.chloramines.
The following table presents the most recent and
comprehensive occurrence information available for chloramine in
SrSSling water. Descriptions of these surveys and other data are
detailed in "Occurrence Assessment for Disinfectants and
DisinflctSn Byproducts (Phase 6a) in Pub-lie Drinking Water, •'
SslpA August1992. Typical dosages of chloramine used as a
disinfectant in drinking water treatment facilities range from
? Ito 2.7 ig/L. Median concentrations of chloramine in drinking
water were found to range from 1.1 to 1.8
-------
-------
22
Based on the residual concentrations given above, a high and
low estimate for exposure to chloramine from drinking water can
be calculated using an assumed consumption of 2 liters per day.
Using the target range of 1.5 to 2 mg/L,.the exposure may range
from 3 to 5 mg/day. Some systems, may deviate significantly from
this range. .
No information is available on the occurrence of chloramine: ;
in food or air. Currently, the Food and Drug Administration •
(FDA) does not measure for chloramine in foods since the
analytical methods have not been developed. Preliminary •
discussions with FDA suggest that there are not approved uses for
chloramine in foods consumed in the typical diet. Similarly, the
Air Division of EPA'-s Office of Air and Radiation is not sampling
chloramines in air (Borum, 1991).
Based on the previous discussion, EPA assumes that drinking
water is the predominant source of. exposure to chloramine. Air
and food intakes are believed to provide only small
contributions, although the magnitude and frequency of these
potential exposures are issues currently under review. EPA,
therefore, is proposing to establish an MCLG for chloramine-in
drinking water with'a relative source contribution (RSC) value of
80%, the current exposure assessment policy ceiling. EPA
requests any additional data on known concentrations of
chloramine in drinking water, food and air.
Health Effects
The health effects information in this, section is summarized
from the draft Drinking Water Health .Criteria Document for
Chloramines (USEPA, 1992c). Studies mentioned in this section
are summarized in the Criteria Document. , • ...
Short-term inhalation exposures to high levels (500 ml-of 5%
household ammonia mixed with 5% hypochlorite bleach) chloramines
in humans result in burning in the eyes and throat, dyspnea,
coughing, nausea and vomiting. Inhalation of the chloramine
fumes resulted in pneumonitis but did not result in permanent
pulmonary damage.
Short-term exposures in drinking water, in which human
subjects were administered concentrations ranging between 1 and
24 mg/L (1, 8, 18 or 24 mg/L), have not resulted in any adverse
effects reported in human subjects. Following human exposure,
the subject's physical condition, u'rinalysis, hematology and
clinical chemistry were evaluated. No adverse clinical effects
were noted in any of the studies.
In another, study, acute nemolytic anemia, characterized by
. oxidation of hemoglobin to methemoglobin and denaturation of
hemoglobin, was reported in .hemodialysis patients when tap water
-------
23
containing chloramines was used for dialysis baths
were reported to produce oxidant damage II ?ed blSod
inhabits the metabolic pathway used by red blood cSllSto
and repair such damage. Many dialysii centers havT installd
C?Upled *it* charcoal la± or the
of ascorbic acid to prevent hemolytic anemia.
Animal studies indicate varying sensitivity and c
amona ™am°ng di«erent . ^i»al secies . Toxic ejects
Bo?hgmonkL=r; °ha"geS ln bl°°d 9lutathione arid methemogobin .
Both monkeys and mice were unaffected during short-term assays
with doses up to 200 mg/L chloramines. Based on studies
S
to
more sensitetamic and
^^
the rat, chloramines are metabolized to chloride ion and
"
+-h» *™adSi*ion' chlorainine »ay induce immunotoxicity in rats in
the form of increased prostaglandin E, synthesis reduced
ab0d^ svn*:hesis an<* spleen weight at levels as low as 9 to 19
chloramines for 90 days. Because these finding have not
-------
24
and 17 2 mg/kg/day for female mice. There was a dose-related
lecrease in the amount of water consumed by both sexes; this
demise was noted during the first ..week and continued throughout
the study. Dosed male and female mice had similar food
consumptions- as controls except for females^- in the 200 ppm dose
group that exhibited slightly. lower consumption than controls.
Study results indicated that there was a do|e~related^
decrease in mean body weights of dosee male and female mice
?h?ougSou£ t£e Study . Mean body weights of high-dose male mice^
we?e 10-22% lower than their control group after week 37 and the
bod? weights of high-dose female mic
-------
25
in mononuclear cell leukemia. There was no
. The
was substantially lesJ thai tS S^J***1* contro1 9ro«PS (16%) .
historical controls (25%? SSiXSf ^ rep°rted in ^treated
lukemia in test animals'reachel a Mgh of ST^^fX1-
in
the
HOAEL derived trom an
^
appropriate for «=e of .
RfD = 9.5
100
= 0.095 mg/kg/day
(rounded to O.lmg/kg/day)
DWEr _
DWEL ~
nor /Ica/dav
llters
= 3.5 mg/L
(rounded
to 4 mg/L)
MCLG
4.0 mg/L x 0.8 = 3.2 mg/L (rounded to 3 rng/L)
tjt.i'SSrSirs^i^.^'s1?^,,, t,e MCLG-in-r—
sss^Ts'cSiHs?'*^ Hi?m*? sSrSiS-T:of a
•Cl, and NH2C1. ' c^/iiter, based on the molecular weights of
-------
26
3 mg NH2ci/L -x -5l°£ g gjfel = 4.13 mg C12/L
2 (rounded to 4 mg C12/L)
EPA is considering proposing an MCLG of 4 mg C12/liter.
Issues . _ - , .
1. The proposed MCLG-for chloramines based on RSC of 8-0%.
2 The significance of the findings of immunotoxicity for setting
the RfD instead of the NTPstudy. . , . •
3. The finding of mononuclear cell leukemia in female F344 rats.
4. The finding of tubular cell neoplasms in high-dose exposed
mice.
5 Whether the adjusted MCLG, which takes into account the
measurement of monochloramine as total chlorine, is appropriate?
chloroform ...
Chloroform [trichloromethane, CAS No. 67-66-3] is a
ammable colorless liquid with a sweet odor and high vapor
surT<200 SS Hg at 250?). It is moderately soluble in water (8
at 20°C) and soluble in organic solvents (log octanol/water
partition coefficient of 1.97). Chloroform is used primarily to
manufacture fluorocarbon-22 (chlorodifluoromethane) which in tar
is used for refrigerants and fluoropolymer synthesis. A smal
percentage of the manufactured chloroform is used as an extra
Solvent for various products (e.g. resins, gums). In the past,
chloroform was used in anesthesia and medicinal preparations -IT
rgrain fumigant ingredient. Chloroform can,be released to tr.c
environment from direct (manufacturing) and indirect
(processing/use) sources and chloroform is a prevalent chlor ....i. .on
disinfection by-product. Volatilization is the principle necr..»r.:sm
for removal of chloroform from lakes and rivers. Chloroform
bioconcentrates slightly in aquatic organisms and adsorbs pcor./ -o
sediments and soil. Chloroform can be biodegraded in.water ir.J
soil (half-life of weeks to months) and ground water (half-li.*? >.
months to years), and photo-oxidized in air (half-life of ncr.tr.s. .
in turn
smal 1
ct: on
.vp.d as
Human Exposure
Chloroform is a prevalent chlorinatibn by-product in dri--
water. The principle source of chloroform in drinking water
chemical interaction of chlorine with commonly present natura.
humic and fulvic substances and other precursors produced by *
normal organic decomposition or by the metabolism of aquatic o
Because humic and fulvic material are generally found at nucn
higher concentrations in surface water sources than in grour.-t
-. e
-------
27.
sources, surface water systems have higher freauencies of
•
-------
CO
V.
M
.5
.|
Q
'l
u
ence of Chloro!
t
|
2"
.3
13
"5
<3
1
O
e
a
H
2
e
i
1
C3
ee
e
pie Informatto
o. of Samples)
c Z
« •— '
M
Location
—
I?
V} &
M
s
? •» ~
•1°""
"w
£
•
^3 *K
10 v
•
Water (1,100):
Surface Water
Ground Water
•8
fVt
u.
l/l
E
o
450 Water Supply Sysl
, CO
o\
°o ~1
Ei "«
ll
£ S
CJ CO
(A
^
111
O
"^1
"w
<£
r- o
10 V
tn
S oo'
Water from:
Surface Water
Ground Water
en
a
Q
> 600 Rural Systems
(> 2,000 Households)
0
CO
•7
™ CO
so a"
^ 2
en m
_o
'•§ t- °°,
b«
8.
^5
§
s °
0 O
O fl
tn v
x ><
a o
F-" oo"
cs —
G- S.
§§
^. °-
cT 2
A V
CO CJJ
c c
'E 'E
o- u
co to
E a o
**~^ 00
3 Os
6 *«
g a
SI
0^
>n
P**
o
CO.
'e
a
a,
I
i
"a
.«
CO-
ri
« . 3
.Unregulated ConUtmin
Data Base - Treatment
Facilities from 19 Stat
^^
.» ^ ,.
ii
H C-
CA
C
o
s
y \O oo
(•J Ov ^N
.^
.•J
tn
<£
S 9
r^ Fpr
0 O
TT TT
H C.
«
« "3j
« a.
Q S
° 5
feS O
cy^ •««
JC eo
Tn
°^
o
a
1 S
s «
0 C/
S *
M *••
.l|
'co'S
35 Water Utilities
Nationwide
r>4
CO o\
X co
8 -
"^ S\" "s
S S 1!
lei g
S » g
oS 2 2
pj >*^ *nj
. .§
8
i
•o §
o •»
o g
g-J:
o
!2
o
ra
§•
•8
11
o E .2
5, Si -o
so 3
-------
29
OKI sjveral studies have assessed inhalation exposure to
chloroform. The major source of this data is from the USEPA's
Total Exposure Assessment Methodology (TEAM) Studies which
measured chloroform exposure to approximately 750 Arsons in
eight geographic areas from 1980 to 1987. Personal exposure to
chloroform from air was measured over a 12-hour p^riSd^Scluli
showers) for individuals in three areas. The Le?ag2 exposures
B^rP VVa!!ge from 4 to 9 W™3 in »ew Jersey an*
W^SS^'iS?!^0?* ^5 t0 4 Mg/m3 in calif°«ia cities
(Wallace, 1991 , In the 1987 Los Angeles TEAM Studies
St^°r? in-indoor a!r was measured in the living Joom and
*i^he? °£.Pri^te residences. Observed mean indoor
concentrations ranged from 0.9 to 1.5 ug/m3 fPellizzari *+ ai
1989 and Wallace et al., 1990 in Wallacl, 1992) . P« ^ '
h- - outdoor conctratins meared in
the California and New Jersey TEAM Studies ranged from of! to
0.6 /zg/m3 and 0.1 to 1.5 ng/m3, respectively
99nd WallaCe St al" 199° and ?EI ^ a
can i
--- personal air
higher average inhalation exposure
10 to iso Mg/d.
Two studies analyzed some foods for chloroform.
? o™ .'^sg. s-srs - ,
butter, 670 ppb; cheddar cheese, 80 ppb; plain
chocola^ chifcooklSs?
9 PPb; and high meat dinner if ppb
the food product ion/ food processing area
H L^£- ^^^^
air exposures are issues currently under review. EPA requests
-------
30
any additional data on known concentrations of chloroform in
drinking water, food, and air.
Health Effects • .
The health effects information is summarized from the draft
Drinking Water Criteria Document for Trihalomethanes (USEPA,
1992d). Studies cited in this'section are summarized in the
criteria document.
Chloroform has been shown to be rapidly absorbed .upon oral,
inhalation and peritoneal administration and subsequently
metabolized. The reported mean human lethal dose, from clinical
observations of overdoses, was around 630 mg/kg. The LD5Q values
in mice and rats have been reported in the range of 908-1400
mg/kg. Several reactive metabolic intermediates (e.g. phosgene,
carbene, dichloromethyl radicals) can be produced via oxidation
•(major pathway) or reduction (minor pathway) by microsomal
preparations. Experimental studies suggested that these active
metabolic intermediates are responsible for the hepatic and renal
toxicity, and possibly/ carcinogenicity, of the parent compound;'
Animal studies suggest that the-extent of chloroform metabolism
varies with species and sex. The retention of chloroform in
organs after dosing was small. Due to the lipophilic nature of
the compound, the residual concentration is in tissues with
higher fatty content. In humans, the majority of the tested oral
intake doses' (0.1 to 1 gm) were excreted through the lungs in the
form of a metabolite CO2 or as-the unchanged compound. Urinary
excretion levels were below 1% .
Mammalian bioeffects following exposure to chloroform
include effects on the central nervous system (CNS) , ,.
hepatotoxicity, nephrotoxicity, reproductive toxicity and .
carcinogenicity. Chloroform caused CNS depression and affected
liver and kidney,, function in humans in both accidental and long.-
term occupational exposure situations. In experimental animals,
chloroform caused changes in kidney, thyroid, liver, and serum
enzyme levels. These responses are discernible in mamiitals from
exposure to levels of chloroform ranging from 15 to 2900 mg/kg;
the intensity of response was dependent upon the dose and the
duration of the exposure. Atoxia and sedation were noted in mice
receiving a single dose of 500 mg/kg chloroform. Short-term
exposure to the low levels of chloroform typically found in air,
food/ and water are not known to manifest acute toxic effects.
The potential for human effects from chronic lifetime exposure is
the basis for this regulation.
Developmental, toxicity and .reproductive toxicity have been
investigated in animals. One developmental study reported
maternal toxicity in rabbits administered with chloroform by the
oral route. Decreased weight gain and mild fatty chancfes in
-------
31
evidence of developmenal effects. ay* ere ^ no
by
S^'S
enzyme levels, ii
J--.fit
1985). . ' ' KP- et.al-/ 1979; Jorgenson et al.,
was
n
female B6C3F, mice at doses of 0 200 fo'n^nV11*1"1*1 ra€s and
19, 38, 81 or 160 mg/kg/day in rats and n ' £°° «r 1'8°° ppm f
ing/kg/day in mice) for 2 vearS chlo^^, -' 65' 13° or 263
incidence of kidney tumors ?£ m,i J f?rm increased the
The combined ' '
ra l
-------
32
Since hepatic changes appeared to. be dependent on the corn
oil vehicle, the interaction 'of corn oil and chloroform could
account for the enhanced hepatic toxicity and thus for the
difference in the NCI and Jorgenson studies. Because the
drinking water study did not replicate hepatic tumors in female
Sice and the potential role .of corn oil in enhancing toxicity
the NAS Subcommittee on the Health Effects of Disinfectants, and
Disinfection By-Products 'recommended that male rat .kidney tumor
data obtained from Jorgenson 's study be used to estimate the
carcinogenic potency of chloroform. Until future studies can _
provide a better understanding of the corn oil effect on hepatic
carcinogenicity, EPA agrees to adopt 'the aforementioned
recommendation by the NAS Subcommittee.
Based on all kidney tumor data in male Osborne-Mendel rats
reported by Jorgenson et al. (1985) , EPA used a linearized
multistage model and derived a carcinogenic potency factor for
chloroform of 6.1 x 10'3 (mg/kg/day)*1. Assuming a daily
consumption of two liters of drinking water and an average human
body weight of 70 kg, the 95% upper bound limit lifetime cancer
risk levels of ICr6, 10'5, and icr4 are associated with
concentrations of chloroform in drinking water of 6, SO and .
600 Aig/L, respectively.
EPA has classified chloroform in Group B2, probable human
carcinogen, based on sufficient evidence of carcinogenicity in
animals and inadequate evidence in humans (IRIS, 1985) . Jhe
International Agency for Research on Cancer (IARC) hals> classified
chloroform as a Group 2B carcinogen, agent possibly carcinogenic
to humans. (IARC, 1982).
According to EPA's three-category approach for establishing
'MCLGs., chloroform . would -be placed in Category I since there is
sufficient evidence of carcinogenicity via ingestion considering
weight of evidence, potency, pharmacdkinetics, and exposure.
Thus, EPA is considering proposing an MCLG of zero for this
contaminant.
Issues
1. The basis for the proposed MCLG for chloroform.
Bromodichloromethane YBDCM)
Bromodichloromethane [CAS No. -75-27-4] is a nonflammable,.
colorless liquid with a relatively high vapor pressure (50 mmHg
at 20°C). BDCM is moderately, soluble in water (3.3 gm/L at 30°C)
and soluble in organic solvents (log octanol/water partition
coefficient of 1.88). Only a small amount .. of BDCM. is .currently
produced commercially in the United States. The chemical is used
• as an intermediate for organic synthesis and as a laboratory
-------
33
reagent. The principal source of BDCM in drinking water is
.
studies reported that BDCM adsorbed poorly to sedSeits ™
^^^^^
within days) under
Occurrence and Humar.
s-
-a
bromodichloromethane in drinking water.
.assKpSStf s asLs^^H&
Drinking Water , •' USEPA, August 1992 ?he tlb?^?' J} X" Pub^
-------
•
c
to
M
.c
0
a
l_
O
Occurrence
•
la
«5-
-2
1
J
1
c
«
1
S
i
s
00
Q
If
u 9
1*
Location
r U *^^
i 3
C/D ^**
C
_o
!**
o
"55
«2
" fn
C*l ^^
III
Finished Water (1
Surface '
Ground
450 Systems
< ^K
OO
OS
So""
t** T
V* *^
I!
u m
i
S *0 "a
Q vo n
o
1
-2
1
r- P":
w u
Drinking Water ft
Surface
Ground
> 600 Rural Systems
(> 2,000 households)
C?
CO
OV
"^
CO *~*
r2 oo
c^ o^
^ s"
fti a
c • •
4> O\ *O
a
i
^.
o ,_
« f^
g a
«5 5
I— 00
. ss
2* 2*
A V
. If
u o
in t/v
945 GW Systems:
(466 Random and
479 Nonrandom)
*"" ao!
00 *
1?. —
o "™
CO _
O, u
*~ "
v^
a£
PI
_!»
"w
£ .
— ir>
-
n t-
gg
—S i
^B
^^
1
u
Finished Water:
At Ihe Plant (73)
Distribution Syst
«
Disinfection By-Produi
Field Studies
S? S\
OV C7\
- pi-
Q °°
t2c.
to
rt
c« • ao
C5 •*•
Q 2
O £
JC «
VO
vd •
0
1
i— 1
S
.
«J
!l
s «
p 5-
35 Water Utilities
Nationwide
X S
Q &*
u "1
^ sr* *3
J^ CO «j
*S Z*4
<:.| f
""•^
-------
35
asr?
Health Effiar^e
-------
36
response), hepatotoxicity, nephrotoxicity, reproductive toxicity
and carcinogenicity. in experimental mice and rats, BDCM caused
changes in kidney, liver, and serum enzyme levels, and decrease
of body weight. These responses were discernible in rodents from
exposure-to levels-of BDCM: that ranged from 25 to 300 ,mg/kg; the
intensity of response was dependent upon the dose and the
duration of the exposure. Ataxia and sedation were observed in
mice receiving a • single dose of. 50.0. mg/kg BDCM.
One study investigated developmental and reproductive
toxicity of BDCM in rodents. Ruddick et al. (1983) administered
BDCM in corn oil to groups of pregnant rats by gavage at doses of
0, 50, 100 or 200 mg/kg/day on days 6 to 15 of gestation..' At
200 mg/kg/day, BDCM significantly (p <0.05) decreased maternal
weight (25%) and increased relative kidney weights. There were
no increases in the incidence of fetotoxicity or external/
visceral malformations, but sternebral anomalies were more
prevalent at 100 and 200 mg/kg than at 50 mg/kg. 'The sternebral
anomalies were not considered by the authors to be evidence of a
teratogenic effect, but of the maternal toxicity.
Data from a National Toxicology Program (NTP) chronic oral
study in B6C3F! mice (NTP, 1987) was used to calculate the RfD
and DWEL. BDCM in corn oil was given to mice by gavage 5 days/
week for 102 weeks. Male mice (50/dose) were administered doses
of 0, 25 or 50 mg/kg/day while female mice (50/dose) received
doses of 0, 75 or 150 mg/kg/day. Following treatment, mortality,
body weight and histopathology were observed. Renal cytomegaly
and fatty metamorphosis of the liver was observed in male mice
(£25 mg/kg/day). Compound-related follicular cell hyperplasia of
the thyroid gland was observed in both males and females. The
survival rate decreased i-n females and decreases in mean body
weights were observed in both m.ales and females at high doses.
Based on the observed renal, liver and thyroid effects in sale
mice, a LOAEL of 25 mg/kg/day was identified. A RfD of 0.02
mg/kg/day has been derived from the LOAEL of 25 mg/kg/day in T..ce
by the application of an uncertainty factor of 1,000, in
accordance with EPA guidelines for use of a LOAEL derived frcrn i
chronic animal study. From this RfD, a DWEL of 0.7 mg/L has cecn
calculated for a 70-kg adult consuming 2 liters of drinking war or
per day.
In vitro genotoxicity studies reported mixed results in
bacteria Salmonella strains and yeasts. BDCM was not jinutageni:
in mouse lymphoma cells without metabolic activation; but induce!
mutation with activation. An increase in frequency of sister
chromatid exchange was reported in cultured human lymphocytes,
rat .liver cells, and mouse bone marrow cells (in vivo); but ro*
in Chinese hamster ovary cells. Overall, more studies yielded
positive results and evidence of mutagenicity for BDCM is
considered adequate. • .
-------
37
There are no
exposure. A
asas
for 102 weeks (NTP, 1987). Male B6C3?, mice (%/dose) w^ '
.SMS '
-------
38
EPA considers carcinogenic risk quantification for BDCM based on
kidney or large intestine tumor data to be more appropriate.
According to the Risk Assessment Guidelines of 1986 (USEPA,
1986), where two or more significantly elevated tumor sites or
types are observed in the same study, the slope factor of the
greatest sensitivity preferably should be used for carcinogenic
risk estimation. 'Based on the potency factor of 6.2 x 10"
(rag/kg/day)'* derived from the kidney tumor incidence in male
mice, the estimated concentrations of BDCM in drinking water
associated with excess cancer risks of 10^, 10'5 and ICT6 are 60, 6
and 0.6 jag/L, respectively.
EPA has classified BDCM in Group B2, probable human
carcinogen, based on the sufficient evidence of carcinogenicity
in animals and inadequate evidence in humans. The International
Agency for Research on Cancer (IARC) has recently classified BDCM
as a Group 2B carcinogen, agent probably carcinogenic to humans
(IARC, 1991).
Following EPA's three-category approach for establishing- ....
MCLGs, BDCM would be placed in Category I since there is
sufficient evidence for carcinogenicity via ingestion considering
weight of evidence, potency, pharmacokinetics, and exposure.
Thus, EPA is considering proposing an MCLG of zero for this
contaminant.
Issues
1. Basis of the proposed MCLG for BDCM.
2. The use of tumor data of large intestine and kidney, but not
liver, in quantitative estimation of carcinogenic risk of BDCM
from oral exposure. •
Dibrbmochloromethane fDBCM)
Dibromochloromethane [CAS No. 124-48-1] is a nonflammable,
colorless liquid with a relatively high vapor pressure (76 mmHg
at 20°C). DBCM is moderately soluble in water (4 gm/1 at 20°C)
and soluble in organic solvents (log octanol/water partition
coefficient of 2.09). Currently DBCM is not produced
commercially in the United States. The chemical has only limited
uses
-------
39
sediments.
aoh
under anaerobic conditions? Condition and more extensive
vcro »ater
source waters through natural iJ5 and. bromine. that can enter
water quality factors can a?fec? tS2 ^£2£?*nlc means- Several
Total Organic carbon (TOC) 2 b«£iJ ^ °f DBCM' including
Different treatment orac? AoS A= ide/ and temperature . *
drinking ^t^.^LlflnoIuL ^L^se^f^r f°rmation of DBCM in
technologies such as coagulation/?*???,?? Precursor removal
carbon (GAG) , membrane fixation and EJOIV granular activated
dioxide, chloramination and SzonatiSn ^ USS °f
^^
conducted by Federal/ as will aa nrivaS . ? llStS Six su^v«ys
concentrations of dibromochloro»JS£ ® agencies. Median
to range from 0.6 to^TS/S^S^SJaS d^nkin9 wa*er appear
for ground-water supplies surface water supplies and
-------
o
b
i
t
•2
a
1
'ss
0 v
*C*l "os
oo' os
«_
iking Water from:
Surface Watei
Ground Watci
•p
"
>600 Rural Systems
(> 2,000 households)
S
CO
•^
fS oo
J^ ^
g'jf
al a
_o
'•§ rl so
g ^ ^
•)
S
Ov
'5«
^N f^ "
>r> \O
S S
S S
P" e;?
rving > 10,000 (32
rving < 10,000 (61
U U
945 GW Systems:
(466 Random and •
479 Nonrandom)
? °o
00 OS
o "3
oo —
Os U
»r*
•£ 3
O ?
s
o
pi
OS*
en
~*w
u
"a
1
o.
E
€9
t/J
1 ..B
Unregulated Contamin
Data Base - Treatment
Facilities from 19 Stati
O> Os
Os OS
Q S
t"* ' d-
in
C
y
ij o
V V
so"
_
«*
Hi
"S « .2
jjj * Q
B.
S
Disinfection By-Prodm
Field Studies
If
^M W*
Q «
12s
trt
' ^ "eb
Ir
<__ CTv
O J
JC flQ
e^i
c4
VO
5
1 S
S3
II
CJ O1
E •«
^^
41
S""
— . .
• co u
35 Water Utilities
.Nationwide
£2 os
8 2.
^ «**» w
ll «
5 j, o
5 s? S
S £ 2
U3 *-*" yf
S § g g Q
o o b os &
S
= 9
•S I
I li
s .1
•gj
£"«
S g
t« .:..
a r-
I
••g 's
II
« £
S o
•!•»
••E S
a
,|
>
'•3
III
HI
•a s E
I S-8 ^
" o
•^ M
O at
-------
41
Administration (FDA) does not analyze for DBOT in fold,
^
°f "ater at soda and beer bottlinf 1-laSts
^I^^^^^
Based on information obtained through a literature
.
s "Sa! eXP°Sure ™* >» as 1* as O-lTg/daor as high
Although some uses of chlorine have been identif i»rt '•!« ^-K«
food production/food processing area, nonitSlSg datf Jre not
witA I Jf?f?' iS pr°P°sln9 to regulate DBCM in drinkinSwater
le^^or^^^ne0^ r^es^y 35^^^ £0?
concentrations of DBCM in drinking water? ISod, and air
Health Effects
Se
-------
42 '
suggest that these active metabolic intermediates are responsible
for the hepatic and renal toxicity, and possibly carcinogenicity,
of the parent compound. Animal studies suggest that the extent
of DBCM metabolism,varies with species and sex. The retention of
DBCM in organs'after* dosing was small and'relatively higher
concentrations were found in stomach, liver and kidneys. Urinary
excretion levels were below 2% .
Mammalian bioetTects following exposure to DBCM include
effects on the central nervous system (decreased operant
response), hepatotexicity, nephrotoxicity, reproductive toxicity
and carcinogenicity. In experimental mice and rats, DBCM caused
changes in kidney, liver, and serum enzyme levels.,, and decreased
body weight. These responses are discernible in mammals from
exposure to levels of DBCM ranging from 39 to 250 nig/kg; the
intensity of response was dependent upon the dose and the
duration of the exposure. Ataxia and sedation were observed in
mice receiving a single dose-of 500 mg/kg DBCM.
Developmental and reproductive toxicity of DBCM was,
investigated in rodents. A multi-generation reproductive study
of rtiice treated with'DBCM in drinking water showed maternal
toxicity (weight loss, liver pathological changes) and fetal
toxicity (decreased pup weight & viability). The study
identified a NOAEL of 17 mg/kg/day and a LOAEL of 171 mg/kg/day.
The National Toxicity Program (NTP, 1985) evaluated the
subchronic and chronic toxicity of DBCM in F344/N rats and B6C3F1
mice. In this study corn oil is used as the gavage vehicle. The
chronic data indicated that doses of 40 and 50 mg/kg/day produced
histopathological lesions in the liver of rats and mice,
respectively. However, the chronic studies did not identify a
reliable NOAEL. The subchronic study identified both a LOAEL and
a NOAEL for hepatotoxicity, and was used to calculate the RfD and
DWEL.
In the NTP subchronic study, DBCM in corn oil was
administered to Fischer 344/N rats and B6C3Fi mice via gavage at
dose levels of 0, 15, 30, 60, 125 or 250 mg/kg/day, 5 days a week
for 13 weeks. Following treatment, survival, body weight,
clinical signs, histopathology and gross pathology were
evaluated. Final body weights of rats that received 250
rag/kg/day were depressed 47% for males and 25% for females.
Kidney and liver toxicity was observed in male and female rats
and male mice at 250 mg/kg/day. A dose-dependent increase in
hepatic vacuolation was observed in male rats. Based on this
hepatic effect, the NOAEL and LOAEL in rats were 30 and
60 mg/kg/day, respectively.
Several studies on the mutagenicity potential of DBCM have
reported inconclusive results. Studies on the. in vitro
-------
43
genotoxicity of DBCM reported mixed results in bacteria
Salmonella typhimurium strains and yeasts. DBCM produced sister
chromatid exchange uncultured human lymphocytes and Chinese
hamster ovary cells (without activation). An increased frequency
of sister chromatid exchange was observed in., mouse bone marrow
cells from mice dosed orally,, but not via the intraperitoneal
route. . ......
No epidemiologic studies isolate DBCM exposure. A number of
ecological studies and case-control studies reported positive
association between the ingestion of chlorihated drinking water
and cancer mortality rates for the stomach,"large intestine,
rectum and bladder. One study reported a strong correlation
between bladder cancer and brominated trihalomethanes. In all
studies, people were exposed to a mixture of compounds. Thus,
these data are inadequate for assessing the carcinogenic
potential of DBCM.
The carcinogenicity of DBCM was investigated by a NTP (1985)
chronic animal study, in this study DBCM in corn oil was
administered via gavage to groups of male and female F344/N rats
at doses of 0, 40 or 80 mg/kg/day, 5 days/week for 104 weeks;
and groups of male and female mice at 0, 50 or 100 mg/kg/dav 5
days/week for 105 weeks. Administration of DBCM showed a
significant increase in the incidence of hepatocellular adenomas
in high-dose female mice (vehicle control, 2/50; low dose, 4/49-
high dose, 11/50) and combined incidence of hepatocellular '
adenomas or carcinomas (6/50; 10/49; 19/50). In high-dose male
mice, administration of DBCM showed a significant increase in the
incidence of hepatocellular carcinomas (10/50; 9/50; 19/50) •
however, the combined incidence of hepatocellular adenomas or
carcinomas was only marginally increased (23/50; 14/50; 27/50)
DBCM did not result in increased incidence of tumors in treated
rats. ' ... ,
Using the linearized multistage model, EPA derived a cancer
potency, factor of 8.4 x 10"2 (mg/kg/day)-' (IRIS, 1990). The
derivation was based on the tumor incidence of the hepatocellular
fr^n°mas °r carcinoaas in the female mice reported in the 1985
NTP study. Due to the possible role of the corn oil vehicle in
induction of hepatic tumors as reported in studies on chloroform,
some uncertainty exists regarding the relevance of this derived
cancer potency factor to exposure via drinking water. However
the only tumor data currently available on DBCM are for liver '
tumors in mice. Until future studies can provide additional
data, EPA considers this cancer potency factor valid for
potential carcinogenic risk quantification for DBCM.
EPA has classified DBCM in Group c, possible human
carcinogen, based on the limited evidence of carcinogenicity in
animals (only in one species) and inadequate evidence of
-------
44
carcinogenicity in humans. The International- Agency for Research
on Cancer (IARC) has classified DBCM as a Group 3 carcinogen:
agent not classifiable as to its carcinogenicity to humans.
Using EPA's three-category approach for establishing MCLG,
DBCM would be placed in Category II since there is limited
evidence for carcinogenicity via drinking water considering
weight of evidence, potency, pharmacokinetics , .and exposure. As
a. Category II chemical, EPA would follow the first option and set
the MCLG for DBCM on noncarcinogeni.c endpoints (the RfD) with the
application of an additional safety factor to account for
possible carcinogenicity. A RfD o£-o.02 mg/kg/day has been
derived from the NOAEL of 30 mg/kcj/d, adjusted for dosing 5 days
per week and divided by an uncertainty factor of 1,000. This
factor is appropriate for use of -a NOAEL derived from a
subchronic animal study. EPA is .considering proposing an MCLG of
0,06 mg/L for DBCM based on the DWEL of 0.7 mg/L, ah additional
safety factor of 10 for possible carcinogenicity, and an assumed
drinking water contribution of 80 percent of total exposure.
- 30 mcr/kg/d x 70 k
- 1/000 X 2 L/d = °'7
MCLG = .
Issue
1. The basis for the proposed MCLG for DBCM.
2. The RSC of 80% for DBCM.
Bromoform
Bromoform [tribromqmethane, CAS No. 75-25^2] is a
nonflammable, colorless liquid with a sweet odor and a relative1-
high vapor pressure (5.6 mmHg at 25°C) . Bromoform is'moderately
soluble in water (3.2 gm/L at 30°C) and soluble in organic
solvents (log octanol/water partition coefficient of 2 38)
Bromoform is not currently produced commercially in the United
States. The _ chemical has only limited uses as a laboratory agent
and as a fluid for mineral ore separation. The principal source
of bromoform in drinking water is the chemical interaction of
chlorine with commonly present organic matter and bromide ion
Degradation of bromoform is not well studied, but probably
involves photooxidation. The estimated atmospheric half -life of
bromoform is one to two months. Volatilization is the principle
mechanism for removal of bromoform from rivers and streams fhalf-
iiS:10f+.hOUr;!.t0 weeks>- Studies reported that bromoform adsorbs
poorly to sediments and soils. No experimental studies were
located regarding the bioconcentration of bro.moform. . Based on
the data from, a few .'structurally similar chemicals, the potent ia<
for bromoforra to be bioconcentrated by aquatic organisms* is low
-------
,45
. . - ,:-M^' ' W,:
Biodegradation of bromoform Is limited under aerobic condition
but more extensive under anaerobic conditions.
Occurrence and Human Exposure
Bromoform occurs in public water systems that chlorinate
water containing humic and fulvic acids and bromine that can
enter source waters through natural and anthropogenic means.
Several water quality factors affect the formation .of bromoform
including Total Organic Cairbon (TOC) , pH, and temperature.
Different treatment practices can reduce the level of bromoform.
These include the use of chloride dioxide, chloramination, and
ozonation prior to chloramination.
The following table presents the most recent and
comprehensive occurrence information available for bromoform in
drinking water. Descriptions of these surveys and other data are
detailed in "Occurrence Assessment for Disinfectants and
Disinfection By-Products (Phase 6a) in Public Drinking Water,"
USEPA, August 1992. The table lists six surveys conducted by
Federal, as well as private agencies. Median concentrations of
bromoform in drinking water appear to range from <0.2 to
0.57 ng/L for surface water supplies and <0.5 jug/L for ground- •
water supplies.
-------
Q« 2
£ 89 69
— 0
0 O
V V
— •>
V V
'Scs
OO *"*
in
CM
o -o
V V
t^ O
o «
w »ri
?n O
en
o
«« i2 ,2 C-
ST o o SJ o
* ~
s|
en so
1 rJl CN
o
i
I 0 <=>
V V
,_^
S
1
=3 v
< o a o «
W
§gQ
?* &• ^1
O a* £
o -a
o o
- SL
o
> CO U
|
;» to O
I
1 .
t/» VI
/\ V
11
CO CO
'
^^J
a
•5
"H.
§ _ 8
•= s «
Ja. fS tfj
"S' « .i
.f f °
U)
ts
3
O fc-
•'41
is
-5- I 1
« c
•8
« e "
I 32
£ =
CO
- a
3 «S
5? m S
n
D Q l2
fr
S g
I-a i
£-3
Q 2
'S £ . o
ifi1
Sir «
O OS
Q «
•a: m
Q oo
=• F
-------
47
No information is available concerning the occurrence of
bromoform in food in the United States. The Food and Drug
Administration (FDA) does not analyze for bromoform in foods.
However, there are several uses of chlorine in food production;
for example, disinfection of chicken in poultry plants and the
superchlorination of water at soda and beer bottling plants
(Borum, 1991). Therefore, the possibility exists for dietary
exposure from the by-products of chlorination in food products. .
Bromoform is usually found in ambient air at low
concentrations. One study reported ambient air concentrations
from several, urban locations across the U.S.. The overall mean
concentration of positive samples was found to be 4 . 15 ng/m3 and
the maximum level was .71 ng/m3 (Brodzinsky and Singh., 19.83 in
USEPA, 1991) . i Although the data are limited for bromoform, an
inhalation intake could be estimated using the mean and maximum
values from the Brodzinsky and Singh (1983) study, indicating a
possible range of 0.08 to 1.4
Based on the limited number of food groups that are believed
to contain bromoform and that significant levels are not expected
in ambient or indoor air, EPA is assuming that drinking water is
the predominant source of bromoform intake. Characterization of
food and air exposures are issues currently under review. The
EPA requests any additional data on known concentrations of
bromoform in drinking water, food, and air.
Health Effects
The health effects information in this section is summarized
from the Drinking Water Health Criteria Document for
Trihalomethanes (USEPA, I992d) . Studies mentioned in this
section are summarized in the criteria document.
Studies have indicated that -gastrointestinal absorption ;-t
bromoform is high in humans and animals. No studies were located
regarding bromoform in humans or animals following inhalation cr
dermal exposure. Based on the physical-chemical properties of
bromoform, and by analogy with the structurally-related
halomethanes such as chloroform, it is expected that both
inhalation and dermal absorption could be significant for
bromoform.
Bromoform was used as a sedative for children with whoop inq
cough. Based on clinical observations of accidental overdose
cases, the estimated lethal dose for 'a 10- to 20-Ocg child is
about 300 mg/kg. The clinical signs in fatal cases were centra.
nervous system (CNS) depression followed by respiratory failure.
The LD50 values in mice and rats have been reported in the
range of 1,147-1550 mg/kg. Under both in vivo and in vitro
-------
48
conditions, several active metabolic intermediates (e.g.,
dibromocarbonyl, dibromomethyl radicals) are produced via
oxidation or reduction by microsomal preparations. Experimental
rap^i5?r?£^
carcinogenicity, of the parent compound. Animal studi«ae!/c:1irrrr«<=.-t-
that the extent of bromoform metabolism variS wi?h sPt5iJs9Kf
sex. The retention of bromoform in organs- after closing was
below 5%.
, — f -* ~ — ———•»••*-• vm *v.fe *— ^ S^ W1A iWL 11^ "CIS SUSS
lipophilic content. Urinary excretion levels were
bl°ef£ects following exposure to bromoform include
« central nervous system (CNS)', hepatotoxicity,
nephrotoxicity, and carcinogenicity. Bromoform causes CNS
f5!refS:i0n *? humans. The reported LOAEL which results in mild
f™at£ in humanVS 54 mg/kg- In experimental mice and rats? '
bromoform caused changes in kidney, liver, and serum enzyme
levels, decrease of body weight, and decreased oper ant response.
S3 ? re;P°nses,are discernible- in mammals from exposure to
levels of bromoform ranging from 50 to 250 mg/kg; the intensity
of response was dependent upon the dose and the duration of the
exposure. Ataxia and sedation were noted in mice receiving a
single dose of 1,000 mg/kg bromoform or 600 mg/kg for 14 days.
sjud.ies 5ave !nvestigated developmental and reproductive
°J ^r?mofo:f\in rodents. A developmental study in ratl
?et*i varia^ons in a group fed with 50 mg/kq/day: An
« nn ^n°^dence °f minor anomalies was noted at doses of 100
and 200 mg/kg/day No maternal toxicity in rats was observed
??^dftaile? reproductive toxicity study reported no apparent
effects on fertility and reproduction when Sale and female rats
e via .«vag. in corn '
EPA used subchronic data from an oral study (NTP 1989) to
calculate the RfD and DWEL, In -this study, bromoform was
administered to rats in corn oil via gavage at SoJe levels of o
10 °r 2°
R« A« ^ 102 °r 2f° mg/kg/day 5 days a week for 13 weeks
Based on the observation of hepatocellular vacuolization in
treated male rats a NOAEL of 25 mg/kg/day was established A Rfri
?f»?,'°2^g/kg^day hSS been ^rived f?om this HS!S bj the'
Sf ™?2i?? r uncertaintv fa^or of 1,000, in accor ance with
fu^ Adelines for use of a NOAEL from a subchronic stu dv Pro™
SSf^' a ?WEL °f °'7 mg/L has been calculated rora^kg
adult consuming 2 liters of drinking water per day? g
A number of studies . investigated the
sss s
-------
-49
;• . .i- -
i.n vivo condition bromoform' induced sister chromatid exchange,
and chromosomal aberration and micronucleus in mouse bone marrow
cells. Overall, most studies yielded positive results and
evidence of mutagenicity for bromoform is considered adequate.
There are no epidemiologic studies which isolate bromoform
exposure. A number of ecological studies and case-control
studies reported positive association between the ihgestion of
chlorinated drinking water and canqer mortality rates for the
stomach, large intestine, rectum and bladder. One study reported
a strong correlation between bladder cancer and brominated
trihalomethanas. In all studies, the cases were exposed to a
mixture of compounds. Thus, EPA believes these data are
inadequate for assessing the carcinogenic potential of bromoform.
The NTP (1989) conducted a chronic animal study to
investigate the carcinogenicity of bromoform. In this study
bromoform was administered in corn oil via gavage to F344/N rats
(50/sex/group) at doses of 0, 100 or 200 mg/kg/day, 5 days/week
for 105 weeks. An evaluation of the study results showed
adenomatous polyps or adenocarcinoma (combined) of the large
intestine (colon or rectum) were induced in three male rats
(vehicle control, 0/50; low dose,. 0/50; high dose, 3/50) and in
nine female rats (0/50; 1/50; 8/50). The increase was considered
to be significant since these tumors are rare in control animals.
Neoplastic lesions in the large intestine in female rats reported
was used to estimate carcinogenic potency of bromoform. EPA
derived a cancer potency factor of 7.9 x 10'3 (mg/kg/day)-1 using
the linearized multistage model (IRIS, 1990). Assuming a daily
consumption of two liters of drinking water and an average human
body weight of 70 kg, the 95% upper bound limit lifetime cancer
risks of 10"°, 10'5 and 10"* are associated with concentrations of
bromoform in drinking water of 4, 40 and 400 jug/L, respectively.
EPA classified bromoform in Group B2, probable human
carcinogen, based on the sufficient evidence of carcinogenicity
in animals and inadequate evidence of carcinogenicity in humans.
The International Agency for Research on Cancer (IARC) has
recently classified bromoform in Group 3: agent not classifiable
as to it carcinogenicity to humans (IARC, 1991).
Using EPA's three-category approach for establishing MCLG,
bromoform would be placed in Category I since there is sufficient
evidence for carcinogenicity from drinking water considering
weight of evidence, potency, pharmacokinetics, and exposure.
Thus, EPA is considering proposing an MCLG of zero for this
contaminant.
Issues
The basis for the proposed MCLG for bromoform.
-------
• 50
Dichloroacetic Acid
Chlorination of water containing organic material (humic,
fulvic acids) results in the generation of many organic
compounds, including dichloroacetic acid (DCA) (CAS. Ho.
79-43-6), a nonvolatile compound.
Though DCA is generally a concern due to its occurrence in
chlorinated drinking water, dichloroacetic acid is used as a
chemical intermediate, and an ingredient in Pharmaceuticals and
medxcine. Previously, DCA was used experimentally to treat
diaoetes and hypercholesterolemia in human patients. In
addition, DCA was used as an agricultural fungicide arid topical
astringent. It has also been extensively investigated for
potential therapeutic use as a hypoglycemic, hypolactemic and
hypolipidemic agent.
Occurrence and Human Exposure •
DCA has been found to occur as a disinfection by-product in
public water systems that chlorinate water containing humic and
fulvic acids.
The following table presents the most recent and
comprehensive^occurrence information available for dichloroacetic
acid in drinking water. Descriptions of these surveys and other
data are. detailed in "Occurrence Assessment for Disinfectants and
Disinfection By-Products (Phase 6a) in Public Drinking Water,"
USEPA, August 1992. Median concentrations of dichlorpacetic acid
in drinking water were found to range from 6.4 to 17 /*g/L.
-------
H
in
-------
52
Based on the above data, a range of exposure to DCA from
drinking water can be calculated using a consumption rate of 2
liters per day. The expected median exposure from drinking water
would range from 13 to 34 /ig/day, using these data sets.
No information is available .concerning the occurrence of DCA
in food and ambient or indoor air in the United States. The Food
and Drug Administration (FDA) does not analyze for DCA in foods.
•However, there are several uses of chlorine in food production;
for example, disinfection of chicken in poultry plants and the
superchlorination of water at soda and beer bottling plants.
Therefore, the possibility-exists for dietary.exposure from the
by-products of chlorination in food products. However,
monitoring data are not available to characterize adequately the
magnitude or frequency of potential DCA exposure from diet.
Additionally, • preliminary discussions with FDA suggest that there
are not approved uses for chlorine in most foods consumed in the
typical diet. Similarly, the Air Division of EPA's Office of Air
.and Radiation is not currently, sampling for DCA in air (Borum,
1991). Little exposure to DCA from air is expected since DCA is
nonvolatile.
Since only a limited number .of food groups are expected to
contain chlorinated chemicals and no significant DCA levels are
expected in ambient or indoor air, EPA believes that drinking
water is the predominant source of DCA intake. Characterization
of the potential exposures from food and air are issues currently
under review. The EPA requests any additional data on known
concentrations of DCA in drinking water, food, and air..
Health Effects , .
The health effects information in. this section is summarized
from the.Drinking Water Health Criteria Document for Chlorinated
Acetic Acids, Alcohols, Aldehydes and Ketbhes (USEPA, 199la). '
Studies mentioned in this section are summarized in the criteria
document. .
Humans treated with DCA for 6 to 7 days at 43 to.
57 mg/kg/day have experienced mild sedation, reduced blood
glucose, reduced plasma lactate, reduced plasma cholesterol
levels and reduced triglyceride levels. At the same time, the
DCA treatment depressed uric acid excretion, resulting in
elevated serum uric acid levels.
A longer term study in two young men receiving 50 mg/kg for
5 weeks up to 16 weeks, indicated that DCA significantly reduces
serum cholesterol levels, and blood glucose, and causes
peripheral neuropathy in the facial, finger, leg and foot
muscles.
-------
53 .
Estimates of acute oral LD50 values range from 2800 to
4500 mg/kg in rats and up to 5500 mg/kg in mice. Short term
studies in dogs and rats indicate an effect on intermediary
metabolism, as demonstrated by decreases in blood lactate and
pyruvate. Exposures to ,DCA up to 3 months in dogs and rats
result in a variety of adverse effects including effects to the
neurological and reproductive systems. These effects are seen
above 100 mg/kg/day in dogs and rats.
Studies on the toxicokinetics of DCA indicate that
absorption is rapid and that DCA is quickly^distributed to the
liver and muscles in the rat. DCA is metabolized to glyoxylate
which in turn is metabolized to oxalate. Although there are few
studies regarding the excretion of DCA, studies in which rats,
dogs and humans received intravenous injections of DCA indicated
that the half-life of DCA in human blood plasma is much shorter
than in rats or dogs. Urinary excretion of DCA was negligible
after 8 hours. Total excretion of DCA was less than 1% of total
. dose. .
EPA considered two studies for the derivation of a DWEL. A
drinking water study by Bull, et al. (1990) reported a dose-
related increase in hepatic effects in mice that received DCA at
270 mg/kg/day for 37 weeks and at 300 mg/kg/day for 52 weeks.
Adverse effects included enlarged livers, marked cytomegaly with
massive accumulation of glycogen in hepatocyte and focal
necrosis. The NOAEL for this study was 137 mg/kg./day for
52 weeks.
The second study is a drinking water study by DeAngelo
et al. (1991) in which mice received DCA at levels of 7.6, 77,
410, and 486 mg/kg/day for 60 or 75 weeks. While this study was
intended as an assessment of carcinogenicity, other systemic
effects were measured. This study concluded that levels at .
77 mg/kg/day and above caused an extreme increase of relative
liver weights and a significant increase in Neoplasia at levels
of 410 mg/kg/day and above. This study indicates a NOAEL of
7.6 mg/kg/day for noncancer liver effects.
Based on the available data, DCA does not appear to be a
potent mutagen. Studies in bacteria have indicated that DCA did
not induce mutation or activate repair activity. Two studies
have shown some potential for mutagenicity but these results have
not been reproducible. .
DCA appears to induce both reproductive and developmental
toxicity. Damage and atrophy to sexual organs has been reported
in male rats and dogs exposed to levels from 50 mg/kg/day to 2000
mg/kg/day for up 3 months. Malformation of the cardiovascular
system has been observed in rats exposed to DCA, 140 mg/kg/day
from.day 6 to 16 of pregnancy.
-------
54
Several studies indicate that DCA is a carcinogen in both
mice and rats exposed via drinking water lifetime studies. These
studies indicate that DCA induces liver tumors. In one study
with male B6F3F1 mice, exposure to DCA at 0.5 g/L and 3.5 g/L for
104 weeks resulted in tumor formation in exposed animals at 75%
C18y.24) and 100% (24/24) respectively. .In female mice exposed.
for 104 weeks to DCA at the same levels, tumor prevalence.was 20%
and 100%,, respectively. In male rats exposed to 0..05, 0.5 or 5
g/L DCA for 104 weeks, tumor prevalence increased to 22% in the
highest dose. No tumors were seen -it the lower doses. However,
at 0.5 g/L, there was an increase ih the prevalence of
proliferation of liver lesions. S
-------
• '• 5.5 • '
Trichloroacetic Acid u? fe
Trichloroacetic acid (TCA) (CAS. No. 76-03-9) is also a
major by-product of chlorinated drinking water. Chlorination of
source waters containing organic materials (humic, fulvic acids)
results in the generation of organic compounds such as TCA.
. TCA is also sold as a pre-emergence herbicide. It is used
in the laboratory to precipitate proteins and as a reagent for
synthetic medicinal products. It is applied medically as a
peeling agent for damaged skin, cervical dysplasia and removal of
tatoos. ' _ ,
Occurrence and Human Exposure
* '
Trichloroacetic acid (TCA) occurs in public water systems
that chlorinate water containing humic and fulvic acids.
The following table presents the most recent and
comprehensive occurrence information available for
trichloroacetic acid in drinking water. Descriptions of these
surveys and other data are detailed in "Occurrence Assessment for
Disinfectants and Disinfection By-Products (Phase 6a) in Public
Drinking Water," USEPA, August 1992. Median concentrations of
trichloroacetic acid in drinking water were found to range from
5.5 to 15 Mg/L. Based on the available data sets, and assuming a
drinking water consumption rate of 2 L/day, median exposures from
drinking water would range from 11 to 30 jig/day.
-------
vo
to
-------
57
No information is available concerning the occurrence of TCA
in food and ambient or indoor air in the United States. The Food
and Drug Administration (FDA) does not analyze for TCA in foods.
However, there are several uses of chlorine in food production;
for example, disinfection of chicken in poultry plants arid the
superchlorination of. water at soda and beer bottling plants.
Therefore, the possibility exists for dietary exposure from the
- by-products of chlorination in food products. Also, TCA has
limited use as a herbicide. However, monitoring data are not
available to characterize adequately the magnitude or frequency
of potential TCA exposure from diet. Similarly, the Air Division
of EPA's Office of Air and Radiation is not currently measuring
for TCA in air (Borum, 1991). The exposure from air for TCA is
probably not a large source since TCA is nonvolatile.
Since only a limited number of food groups are expected to
contain chlorinated chemicals and no significant TCA levels are
expected in ambient or indoor air, EPA assumes that drinking
water is the predominant source of TCA intake. Characterization
of potential exposures from food and air are issues currently
under review. The EPA is, therefore, proposing to regulate TCA
in drinking water with a relative source contribution (RSC) value
at the ceiling level of 80%. The EPA requests any additional
data on known concentrations of TCA in drinking water, food, and
air.
Health Effects
The health effects information in this section is summarized-
from the Drinking Water Health Criteria Document for Chlorinated
Acetic Acids/Alcohols, Aldehydes and Ketones (USEPA, 1991a) .
Studies mentioned in this section are summarized in the criteria
document. -.....'
No studies were located on short- or long-term exposure of
humans to TCA. •
Estimates of acute and LD50 values for TCA range from 3.3 to
5 g/kg in rats to 4.97 g/kg in mice. Short-term studies, up tD
30 days, in rats demonstrate few effects other than decreased
weight gain after administration of 240-312 mg/kg/day.
Few studies on toxicokinetics of TCA were located; however
a human study and a dog study show TCA to respond
pharmacokinetically similar to DCA. The response indicates a
rapid absorption, distribution to the liver and predominant
excretion through the urine. The two studies indicate that f~A
is readily absorbed from all sections of the intestine and that
the urinary bladder may be significant in the absorption of TCA
TCA is also a major.metabolite of trichloroethylene. -
-------
58
Longer-term studies in animals indicate that TCA affects the
liver, kidney and spleen by altering weights, focal
hepatocellular enlargement, intracellular swelling, glycogen
t accumulation, focal necrosis, an accumulation of lipofuscin and
ultimately tumor generation.in. mice. '
EPA is considering three chronic studies for the'derivation
of the MCLG for TCA. The first study by.Mather et al. (1990) ' '
involves male rats receiving TCA in their drinking water at 0,
4.1, 36.5 or 355 mg/kg/day. The high dose resulted in spleen
weight reduction and increased relative liver and kidney weights.
Hepatic peroxisomal ^-oxidation activity was increased. Liver
effects at the high dose included focal hepatocellular
enlargement, intracellular swelling and glycogen accumulation.
The NOAEL for this study was 36.5 mg/kg/day.
In the second study, Parnell et al. (1988) exposed male rats
to TCA in their drinking water at 2.89, 29.6 or 277 mg/kg/day for
up to one year. No significant changes were detected in body
weight, organ, weight or histopathology over the study duration.
This study identified a NOAEL as the highest dose tested,
277 mg/kg/day.
The third study, Bull et al. (1990) investigated the effects
of TCA on liver lesions and tumor induction in male and female
B6C3Fj mice. Mice received TCA in their drinking water at 0, 1
or 2 g/L (164 or 329 mg/kg/day) for 37 or 52 weeks. Dose-related
increases in relative and absolute liver weights were seen in
females and males exposed to l and 2 g/L for 52 weeks. Small
increases in liver cell size, accumulation of lipofuscin and
focal necrosis were also seen. A LOAEL of. 164 mg/kg/day (1 q/Li
was identified. . '
Several studies show that TCA can produce developmental
malformations in fetal Long Evans rats, particularly in the '
cardiovascular system.- Teratogenic effects were observed at the
lowest-dose tested, 330 mg/kg/day.
With_regard to mutagenicity tests, TCA was negative in Ames
mutagenicity tests using Salmonella strain TA100, but was
positive for bone marrow chromosomal aberrations and sperm
abnormalities in mice. It also induced single-strand DNA breaks
in rats and mice exposed by gavage.
TCA has induced hepatocellular carcinomas in two tests with
B6C3F! mice, one of 52 weeks and another of 104 weeks, in the
Bull et al. (1990) study, a dose-related increase in th-p
incidence of hepatoproliferative lesions was observed in male
B6C3F, mice exposed to 1 or 2 g/L for 52 weeks. An increase in
hepatocellular carcinomas was observed in males at both dose
levels. Carcinomas were not found in females.
-------
59
- "r-jjisy &.;••, .
DeAngelo et al. (1991) administered mice and rats with TCA
over their lifetime. Male and female B6C3F1 mice were exposed to
4.5 g/L TCA for 104 weeks. Male mice at 4.5 g/L TCA had a tumor
prevalence of 86.7%. Female mice appeared to be less sensitive
to TCA than males: 60% prevalence over a 104-week exposure to
4.5 g/L. At 104 weeks, 0.5 g/L TCA did .not result in a
significant increase in tumors. In a preliminary study of 60
weeks exposure to 0.05, 0.5 and 5 g/L, no significant additional.
increase .in tumors was.seen at 0.05 g/L> but tumor prevalence was
37;9% and 55,2% at 0.5 and 5 g/L, respectively.
F344 mr.le rats administered TCA over a lifetime at 0.05 to
5 g/L did not produce a significant increase in carcinogenicity.
EPA bslieves that the 90-day study by Mather et-al. (1990)
is the most suitable to calculate the MCLG for TCA because a
NOAEL exists which is lower than any of the other NOAELs or
Z? »S4.£r0m iess than lifetime studies. Using the rat NOAEL from
the Mather et al. (1990) study, a DWEL of 0.128 mg/L can be
.derived for the 70-kg adult consuming 2 liters of water per day
by applying an uncertainty factor of 1,000 (which is in
accordance with NAS/EPA guidelines to use an uncertainty factor
of 1,000 with a NOAEL.derived from a less than lifetime study).
Given the overall data base on TCA and carcinogenicity, EPA
is considering placing TCA in Group C: possible carcinogen in
humans. Group C is normally given to a chemical which shows
carcinogenicity in only one species, as in this case the mouse.
However, since tumor generation occurred in both sexes at a high
rate of prevalence, it may be classified in Group B2. EPA
requests comment on the appropriate cancer classification for
JL \->A • , * ' .
EPA is considering following a Category II approach for
?S 5V? MCv? £°r TCA- This aPProach would yield an MCLG for
TCA of 0.1 mg/L based on the DWEL of 1.28 mg/L, an additional
safety factor of 10 for Category II contaminants to accSSt for
possible carcinogenicity, and assuming a drinkina water
contribution of 80 percent.
DWEL = 36.5 mg/ka/dav x 7fi
U EL (1,000) x 2 I/day = 1'28 m
-------
60
2. Should TCA be regulated on the basis of its carcinogenicity
With an MCLG of zero (Category I) , or should the MCLG for TCA be
cased on noncarcinogenic endpoints?
Trichloroacetaldehvde rchloral Hvdrate)
^^£h*~?;in?ti0n ?£ "*ter containing organic materials (humic,
fulvic acids) results in the generation of .organic compounds such
as, tnchloroacetaldehyde . monohydrate or chloral hydrate (CH)
(CA«a. No. 302-17-0) .
Trichloroacetaldehyde monohydrate (chloral hydrate, CH) is
usad as a hypnotic or sedative drug (i.e., knockout drops), in
^' inClUd:Lng neonat®s. CH is also used in the manufacture
Occurrence and Human
^H has been found to occur as a disinfection by-product in
public water systems that chlorinate water containing humic and-
iUivic acids . .
•The following table presents -the most recent and
comprehensive ^ occurrence information available for chloral
2?££ !Lin drin51^.waSer- Descriptions of these surveys and
other data are detailed in "Occurrence Assessment for
Disinfectants and Disinfection By-Products (Phase 6a) in Public
hvSe?'"-UT^'^UgUSt ""•' Median concen?raSons of
hydrate in drinking water were found to range from 2.1 to
-------
H
\O
-------
62 •
Based on the available- data sets, median exposures from CH
due to drinking water would range from 3.4 to 8.8 jug/clay, based
on the consumption of 2 liters per day.
No information is available concerning the occurrence of CH
in food and ambient or indoor air in the United States. The Food
and .Drug Administration (FDA) does. not analyze for CH in foods
since the analytical methods for such an evaluation have not been
developed (Borum, 1991). .However, the FDA is considering
research in this area. CH has been used as a sedative of
hypnotic drug (see Health Effects Section). There are several
?hlorine. W food production; for example, disinfection of
£ P°uitry Pl^ts and the superchlorination of water at
beer bottl^g plants. Therefore, the possibility exists
* f tary exposure from the by-products of chlorination in food
products. However, monitoring data are not available to
adequately characterize the magnitude or frequency of potential
S«S°S?r;-fr01a^tSe-^ie^- Similarly< ^ Air Division of EPA"'S
Office of Air and Radiation is not currently measuring for CH in
air (Borum, 1991) . But, CH from indoor air may conteibutS to
exposure due to the volatilization from tap water. riDUi:e to
^^ f iimited number of food groups are expected to
contain chlorinated chemicals and no significant levels are
SS?!S ? iJ ambient or indoor air, EPA believes that drinking
water is the predominant source of CH intake. Characterization
of potential food and a.Vr exposures are issues current y unde?
review. The EPA is, therefore, proposing to regulate CH in
tKn.i??'nat?r W^V rflative source contribution (RSC) value at
the ceiling level of 80%. The EPA requests any additional data
on known concentrations of CH in drinking water, food, and air?
Health
r^ £eal?;h effects information in this section is summarized
from the Drinking Water Health Criteria Document for Chlorinated
Acetic Acids/Alcohols, Aldehydes and Ketones (USEPA, 199 la)"
ment in 'the criteria
In its use as a sedative or hypnotic drug in humans a
history of adverse effects related to CH exposure have been
??S°ma/v^ The ^CUte and tOXic d°Se to huma"s ^ aSSul ^g (or
140 mg/kg) causing severe respiratory depression and l .
Advfrse reactions such as central nervous system
n gastr°intestinal disturbances are seen between 0 5
A01' Cardiac arrhythmias are seen when pa?ien "s Deceive
levels between 10 and 20 g (167-333 mg/kg). Chronic use of CH
of tolerant ?hysical°SipenS Jncf and
-------
63
acute oral LDJ0s in mice range from 1,265 to
, ^ou ,
i*°° *?—?<£ ?en1?*1 nervous system depression and inhibition
of respiration being the cause of death. Rats may be more
sensitive tnan "iice With acute oral LD5o values ranging from
285 mg/kg in newborn to 500 mg/kg in adults,
Short -term studies in mice indicate that the liver is the
JS2K 0fMoLrOX1CityvWith chan
-------
64
exposure to the high dose (160 mg/kg/day) resulted in decreased
humoral immune function (p <0.05), but no effects on
cell-mediated immunity were noted. Based on this stxidy, a NOAEL
of 16 mg/kg/day and a LOAEL of 160 mg/kg/day were identified.
CH is weakly mutagenic in Salmonella, yeast and mold. it
has also caused chromosomal aberration in yeast and
: nondisjunction of chromosomes during spermato.genesis. .
One study has observed neurcbehavioral effects on mice pups
from female'mice receiving CH at 205 mg/kg/day for three weeks
prior to breeding. Exposure of cemales continued until pups were
weaned at 21 days of age. Pups from the high dose group (205
mg/kg/day) showed impaired retention in passive avoidance
learning tasks. This can be construed as a developmental effect
of CH.
Two studies on the carcinogenicity of CH indicate that CH
• produces mouse, liver tumors. ' In one study, Rijhsinghani et al.
(1986), B6C3F1 mice given a single oral-dose of CH at 5 or
10 mg/kg developed a significant increase in liver tumors after
92 weeks.
In the second study, Daniel et al. (1991), male mice
receiving 166 mg/kg/day CH for 104 weeks showed a total liver
tumor prevalence of 71 percent (17/24;. Proliferative liver
lesions recognized and tabulated in this study included
hyperplastic nodules, .hepatocellular adenomas and hepatocellular
carcinomas. No other studies were located on the carcinogenicity
of CH in other test species.
Based on the limited, evidence of carcinogenicity in these
two studies.and -the extensive mutagenicity of CH, the Agency is
considering classifying CH in Group C: possible human carcinogen.
EPA believes the 90-day study by Sanders et al. (1982) is
most appropriate to calculate the MCLG for CH because the effects
observed in this study (change to hepatic microsomal pcirameters
and hepatomegaly) appear to be more severe than the other studies
have indicated at similar dose levels. From the mouse LOAEL,
-------
65
16 ma/kq/d x 70
DWEL - i ' = 56
1,000 X 2 L/d
56 fig/Ij x 0.8
MCLG - - =5
10
Issues
1. Is it appropriate to set the MCLG following a Category II
approach and applying an extra^uncertainty factor of 10.
2. Is the endpoint of liver weight increase and hepatomegaly a
LOAEL or should it be considered a NOAEL given the lack of
histopathology?
Bromate
Bromate (CAS #7789-38-0 as sodium salt) is a white crystal
that is very soluble in water. Bromate may be formed by the
reaction of bromine with sodium carbonate. Sodium bromate can be
used with sodium bromide to extract gold from gold ores. Bromatp
is also used to clean boilers and in the oxidation of sulfur and
vat dyes. It is formed in.water following disinfection via
ozonation of water containing bromide ion. In laboratory studies
the rate and extent of bromate formation depends on the ozone
concentration used in disinfection, pH and contact time.
Occurrence and Human Exposure
_.• . Bromide and organobromine compounds occur in raw waters from
both natural and anthropogenic sources. Bromide can be oxidized
to bromate or hypobromous acid; however, in the presence of
excess ozone, bromate is the principal product.
The following table presents the most recent occurrence
information available for bromate in drinking water
Descriptions of this data are detailed in "Occurrence Assessment
for Disinfectants and Disinfection By-Products (Phase 6a) in
Public Drinking water," USEPA, August 1992. Significant bromate
concentrations may occur in ozonated water with bromide.
-------
I
o
60
e ^
I's
1:1
o -i
M
J
I
S3
'•3
u
O
5
I
00
i
Q
P
o o
o
V
fC
u
ll
P B.
fi <»
I-N e
JO
"S. o
52
a
I
BUi
c e
o S
•2 QO
a w
a
o
I
1
a
2
en
1
cu
«
£
w *^J
S E
c\ o\
Q oo
I
I
J) «
f-s
.
0 3
"I -
.S o
-------
67
'" " - ''f- '•
Although bromate is used as a maturing agent in malted
beverages, as a dough conditioner, and in confectionery products
(Borum, 1991), monitoring data are not available to adequately
characterize the magnitude or frequency of potential bromate
exposure from the diet. Currently, the Food and Drug
Administration does not have available data' for bromate in foods,
as bromate is not a part of their Total Diet Study program.
.Similarly, the Air Division of EPA's Office of Air and. Radiation
is not currently measuring for. bromate in air (Borum 1991) .
Since only a limited number of food groups are expected to
contain bromate and no significant bromate levels are expected in
ambient or indoor air, EPA believes that drinking water is the
predominant source of intake for bromate, and contributions from
air and food would be small. Characterization of potential
exposures from food and air are issues currently under review.
The EPA requests any additional data on known concentrations of
bromate in drinking water, food, and air.
Health Effects
The health effects information in this section is summarized
from the Drinking Water Health Criteria Document for Ozone and
By-Products (USEPA, 1991b). Studies mentioned in this section
are summarized in the criteria document.
The noncancer effects of ingested bromate have not been well
studied. Bromate is rapidly absorbed, in part unchanged, from the
gastrointestinal tract following ingestion. It is distributed
throughout the body, appearing in plasma and urine as bromate and
in other tissues as bromide. Following exposure to bromate,
bromide concentrations were significantly increased in kidney,
pancreas, stomach, small intestine, red blood cells and plasna.
Bromate is reduced in tissues probably by glutathione or "by.-ether
sulfhydryl-containing compounds. Excretion occurs via urine and
to a lesser extent feces.
Acute oral LD50 values range from 222 to 360 mg bromate/kq
for mice and 500 mg/kg for rats. Acute symptoms of toxicity
include decreased locomotion and ataxia, tachypnea, hypotherm:*,
hyperemia of the stomach mucosa, kidney damage and lung
congestion. In subchronic drinking water studies, decreased body
weight gain and marked kidney damage were observed in treated
rodents. These effects were observed at the lowest doses tested
(30 mg/kg/d). . .
Bromate was positive in a rat bone marrow assay to determine
chromosomal aberrations. Positive findings for bromate were also
reported in a mouse micronucleus assay. Bromate has also been
found to be carcinogenic to rodents following long-term oral
-------
68
administration. In these studies, an increased incidence in
Jcidney tumors was reported for male and female rats. Other tumors
observed include .thyroid follicular cell tumor and peritoneal
mesothelioma. No carcinogenic effects have been seen in mice.
Dose and time studies indicate that the minimum exposure'time to
produce tumors in,rats-is 13 weeks. ...
The available data are considered insufficient to calculate
an RfD or DWEL. Only one noncarcinogenic toxicity study (Nakano
et al. 1989. Renal changes induced by chronic oral administration:
of potassium bromate or ferric nitrilotriacetate in Wistar rats.
Jpn. Arch, of Internal Med. 36:41-47) was located in .the
literature. The study failed to provide dose response data and
did not identify a NOAEL. Histopathological lesions in, kidney
tubules that coincided with decreased renal function were noted -
in rats exposed to 30 mg bromate/kg/d for 15 months.
Kurokawa et al. (I986a) supplied groups of about 50 male and
50 female F344 rats (4-6 weeks old) with drinking water
containing 0, 250 or 500 mg/L (the maximum tolerated dose) of
KBrOj. The high dose (500 mg/L) caused a marked inhibition of
weight gain in males, and so at week 60 this dose was reduced to
400 mg/L. Exposure was continued, through week 110. The authors
stated the average doses for low dose and high dose groups were
12.5 or 27.5 mg KBrO3/kg/day in males (equivalent to 9.6 and
21.3 mg Br03/kg/day) and 12.5 or 25.5 mg KBrO3 in females
(equivalent to 9.6 and 21.3 mg BrO3) . The incidence of renal
tumors in the three groups (control, low dose, high dose) was 6%,
60% and 88% in males and 0%, 56% and 80% in females. The effects
were_statistically significant (p <0.001) in all exposed groups.
The incidence of peritoneal mesotheliomas in males at three doses
was 11% (control), 33% (250 mg/L, p
-------
69
,a.iC=''-: " ' -Y--
The International Agehby for Research on Cancer place
bromate in Group 2B, for agents that are probably carcinogenic to
humans. EPA has not officially classified bromate as to its
carcinogenic potential to humans. However, the EPA is currently
performing a cancer weight of evidence evaluation, and is
considering placing bromate in group B2:. probable human
carcinogen based on the following evidence. Bromate has.been
shown to produce several types of tumors in both sexes of rats
following drinking .water exposures. In addition, positive
mutagenicity studies have been reported include indications of
DNA interactions with bromate. As a result of bromate formation
following disinfection, particularly with ozone, there is a
potential for considerable exposure in drinking water. Thus, EPA
. is considering establishing an MCLG based on a Category I
approach. The resulting MCLG would be zero.
The EPA is also interested in examining the mechanism of
toxicity of bromate in rats in terms of whether renal tumor
formation is due to direct action of bromate or indirectly
through formation of specific adduct in kidney DNA of rats
treated with bromate.
Issues . . . ,
1. MCLG of zero based on carcinogenic weight of evidence.
2. Mechanism of action related to DNA adduct.
Other Disinfection Bv-products
EPA has also considered establishing MCLGs for other by-
products of disinfection including cyanogen chloride,
chloropicrin, chlorophenols, haloacetonitriles, formaldehyde and
other aldehydes, and hydrogen peroxide. At this time, it is not
likely that EPA will propose MCLGs for these compounds due to
lack of health or exposure information. .
Cyanogen chloride (CAS No. 506-77-4) usually occurs as a gas
and has been produced as a chemical warfare agent, for use in
tear gas and as a fumigant. It has also been formed as a by-
product of chlorination and chloramination.
Tn humans, exposure to cyanogen chloride following
inhalation results in eye and lung irritation. Death results
after .ten minutes exposure to 400 mg/m3. No information is
available on the health risks following ingestion of cyanogen
chloride. EPA believes that the available data are insufficient
to calculate an MCLG for cyanogen chloride. EPA considered using
the data base for hydrogen cyanide. However, given the
uncertainty in using this data to predict the risk for cyanogen
chloride, EPA.will follow the recommendations of the Science
-------
70
Advisory Board and pursue additional research to better
characterize the toxicity of the ingested compound.
Chloropicrin (CAS ,No. 76-06-2) is a colorless liquid that is
formed from the reaction of chlorine with humic acids, amino
acids and. ni.tr.opheno.ls:... Typical concentrations appear to be less
than .10.58,Aig/L in finished water. Like cyanogen chloride,
chloropicrin has also been used as a chemical warfare:agent. It
has also been, used as a grain fumigant, insecticide and :
fungicide. Chloropicrin is acutely toxic following ingestion and
inhalation. The oral LDSO in rats is 250 mg/kg. Chronic oral data
ara not available to calculate an MCLG at this time. EPA will
pursue additional research to determine the potential risks from
chronic low level exposure to chloropicrin.
Mono- (CAS No. 95-57-8), di- (CAS No. 120-83-2) and
trichlorophenol (CAS No. 88-06-2) are also potential by-products
of disinfection. Recent surveys, however, have not detected the
presence of the chlorophenols following disinfection. As a result
of the apparent low exposure from drinking water, EPA is not
planning to set an MCLG but has developed a Health Advisory for
chlorophenols. The Health Advisory provides information on the
health effects, analytical methods, treatment technologies and
quantitative risk assessments for these compounds in the event
that they are found in drinking water.
c >
Health Advisories rather than MCLGs have also been developed
for the haloacetonitriles and formaldehyde as a result of low
exposure from drinking water. Many of these by-products are
associated with chlorination. By-products of other disinfection
methods including ozonation are currently being evaluated for
their health effects, available analytical methods and treatment
technologies. These compounds include MX, brominated acetic
acids and other halogenated aldehydes that may be formed. .These
compounds will likely be addressed -in a' later rulemakihg for
disinfection by-products.
-------
71
"REFERENCES . . .
Abdel-Rahman, M.S. 1990. J, Appl. Toxicol.; Vol. 2; pp. 165-6;
1982. Cited in Howard, 1990.
Atlas, E.; Schauffler, S. 1991. "Analysis of Alkyl Nitrates and
Selected Halocarbons in the Ambient Atmosphere Using a Charcoal
Preconcentration Technique," Environ. Sci. Technol., Vol. 25, No.
1, pp. 61-7. .
AWWA. 1991. American Water Works Association Disinfection^
Survey. Data Base. , "
Bercz J.P., L. Jones, L. Murray et al. 1982. Subchronic
toxicity of chlorine dioxide and related compounds.in drinking
water in nonhuman primates. Environ. Health Persp. 46:47-55.
Boland, P.A. 1981. "National Screening Program for Organics in
Drinking Water Part II: Data"; SRI International. Prepared for
U.S. Environmental Protection Agency under Contract No. 68-01-
4666; March, 1981. ,.
Borum, D. 1991. OGWDW, U.S. Environmental Protection Agency,
Washington, D.C. Phone Conversation with Greg Diachenko, Food
and Drug Administration, Washington, D.C.; December 17, 1991.
Brass, H.J. 1981. "Rural Water Surveys Organics Data"; Drinking
Water Quality Assessment Branch, Technical Support Division,
Office of Drinking Water, U.S. Environmental Protection Agency.
Memo to Hugh Hanson, Science and Technology Branch, CSD, ODW
U.S. Environmental Protection Agency.
Brass, H.J.; Weisner, M.J.; Kingsley, B.A. 1981. "Community
Water Supply Survey: Sampling and Analysis for Purgeable
Organics and Total Organic Carbon (Draft) '<; American Water "Works
Assoc, Annual Meeting, Water Quality Division; June B, 1981.
Brodzinsky, R.; Singh, H.B. 1990. "Volatile Organic Chemicals
in the Atmosphere; An Assessment of Available Data"; U.S.
Environmental Protection Agency, Office of Research and
Development, Research Triangle Park, North Carolina; 1983. Cited
in Howard, 1990.
Bull, R.J.., I.M. Sanchez, M.A. Larson and A.J. Lansing. 1990.
Liver tumor induction in B6C3F1 mice by dichloroacetate and
trichloroacetate. Toxicol. 63:341-359.
Bull, R.J.; Kopfler, F.C. 1991. "Health Effects of
Disinfectants and Disinfectant By-Products." Prepared for: AWWA
Research Foundation; August, 1991.
-------
•72 ' .
Coleman, W.E. et al. 1990. "Analysis and Identification of
Organic Substances in Water"; L. Keith Ed., Ann Arbor Michigan;
Ann Arbor Press; 1976; pp. 305-27. Cited in Howard, 1990.
Daft, J.L. 1987. "Determining Multifumigants in Whole Grains
and Legumes,• Milled and Low-Fat-Grain Products, Spices, Citrus
Fruits, and Beverages," J". Assoc. Off. Anal. Chem.,. Vol. 70,
No. 4, pp. 734-739. . .
Daft, J.L. 1988. "Rapid Determination of Fumigant and
Industrial Chemical Residues in Food," J. Assoc. Off. Anal.
Chem., Vol. 71, Fo. 4, pp. 748-760.
Daft, J.L. 198?. "Determination of Fumigants in Fatty and
Nonfatty Foods", J. Agric. Food Chem., Vol. 37, No. 2, pp. 560-4.
Daniel, F.B., A.B. DeAngeio, J.A. Stober, G. R. Olson, and N.P.
Page. 1991. Hepatocarcinogenicity of Chloral Hydrates, 2-
Chloroacetaldehyde, and Dichloroacetic Acid in the B6C3F1 Mouse.
Submitted to Fundam. Appl. Toxicol. Aug. 15, 1991.
DeAngeio, A.B., F.B. Daniel, J.A. Stober and G.R. Olson. 1991.
The carcinogenicity of dichloroacetic acid in the male B6C3F1
mouse. Fundam. Appl. Toxicol. 16:337-347.
Entz, R.C.; Thomas, K,W.; Diachenko, G.W. 1982. "Residues of
Volatile Halocarbons .In Foods Using Headspace Gas
Chromatography," J. Agric. Food Chem., Vol. 30, No. 5, 1982, pp.
846-9.
Hartwell, T.D.; Pellizzari, E.D.; Perritt, R.L.; Whitmore, R.W.;
Zelon, H.S.; Sheldon, L.S.; Sparacino, C.M.; Wallace, L. 1987.
"Results from the Total Exposure Assessment Methodology (TEAM)
Study in Selected Communities in Northern and Southern
California," Atmbs; Environ.r Vol. 21, No. 9, pp. 1995-2004.
Heffernan W. P., C. Guion and R.J. Bull. 1979. Oxidative damage
to the erythrocyte induced by sodium chlorite in vivo.
J. EnvironI Pathol. and Tox. 2:1487-1499.
Heikes, D.L. 1987. "Purge and Trap Method for' Determination of
Volatile Halocarbons and Carbon Disulfide in Table-Ready Foods";
J. Assoc. Off. Anal. Chem', Vol. 70; No. 2; 1987; pp. 215-26.
Heikes, D.L.; Hopper, M.L. 1990. J. Assoc. Off. Anal. Chem.;
Vol. 69; 1986; pp. 990-8. Cited in Howard, 1990.
Heywood R, Sortwell RJ, Noel PRB, Street AE, Prentice DE, Roe
FJC, Wadsworth PF, Worden AN, Van Abbe NJ. 1979. Safety
evaluation of toothpaste containing chloroform. III. Long-term
study in beagle dogs. J. Environ. Pathol. Toxicol. 2:835-851
-------
73
Ho et al. 1983. Cited in USEPA, 'l985. .
Howard, P.H. 1990. "Handbook of Environmental Fate and Exposure
Data for Organic Chemicals"; Lewis Publishers, Chelsea, MI; Vol.
2; 1990; pp. 40-47.
Jorgenson TA, Meierhenry EF, Rushbrook CJ. Bull RJ, Robinson M.
1985. Carcinogenicity of chloroform in drinking water to male
Osborne-Mendel rats and.female B6C3Fj mice,! Fundam. Appl.
Toxicol. 5:760-769.
Kallman, M.J., G.L. Kaempf and R.L. Balster. 1984. Behavioral
toxicity of chloral in mice: an approach to evaluation.
Neurobehav. Toxicol. Teratol. 6(2):137-146. *
Kauffman, B.M., K.L. White, V.M. Sanders, K.A. Douglas, L.E.
Sain, J.F. Borzelleca and A.E. Munson. 1982. Humoral and cell-.
mediated immune status in mice exposed to chloral hydrate.
Environ. Health Perspect. 44:147-151.
Kelley, R.D. 1989. "Synthetic Organic Compounds Sampling Survey
of Public Water Supplies," NTIS PB85-214427, 1985, p. 1-32.
Cited in USEPA, 1989.
Krasner, S.W.; Barrett, S.E.; Dale, M.S.; Hwang, C.J. 1989.
"Free Chlorine Versus Monochloramine for Controlling Off-Tastes
and Off-Odors"; Journal AWWA; February, 1989; pp. 86-93.
Krasner, S.W.; McGuire, M.J.; Jacangelo, J.G.; Patania, N.L.;
Reagan, K.M.; Aieta, E.M. 1989. "The Occurrence of Disinfection
By-Products in U.S. Drinking Water"; Journal AWA; August, 1989;
pp. 41-53.
Kurokawa et al. I986a. Long-term in vitro carcinogenicity tests
-of potassium bromate, sodium hypochlorite and sodium chlorite
conducted in Japan. Environ. Health Perspect. 69:221-236.
Kurokawa et al. 1986b. Kose-response studies on the
carcinogenicity of potassium bromate in F344 rats after long-term
oral administration. J. Natl. Cancer Inst. 77:977-982.
Lykins, B.W.; Griese, M.H. 1990. "Using Chlorine Dioxide for
Trihalomethane Control," Jour. Am. Water Works Assoc*-, Vol. 78,
1986, pp. 88-93. Cited in Bull and Kopfler, 1990.
Masschelein, W.J. 1990. "Historic and Current Overview of
Chlorine Dioxide." In: Chlorine Dioxide: Scientific,
Regulatory and Application Issues, Chemical Manufacturers Assoc,.
2501.M St., NW, Washington, D.C., 20037; 1989; pp. 4-40. Cited
in Bull and Kopfler, 1990. . .
-------
74 •
Mather, G.G., J.H. Exon and .L.D. Roller. 1991. subchronic 90-
day toxicity of dichloroacetic acid and trichloroacetic acid in
rats. Toxicol. 64:71-80.
McGuire, M.J.; Miller, R.E.; Randtke, S.J.; Hathaway, L.R.;
Denne, J.E-. 1990. "Organic Carbon and THM" Formation Potential
in Kansas Groundwaters"; Journal JWWA; March, 1990; pp. 49-62.
McGuire> -M. J.;. Krasrier, S.W.; Reagan, k.-M; Aieta, E.M.;
Jacangelo, J.G. Patania, N.L.; Gra>nith, K.M. 1990. "Final
Report for Disinfection By-Products in United States Drinking
Waters, Vol. 1," U.S. Environmenttil Protection Agency and
California Dept. of Health Servicss, 1989. Cited in Bull and
Kopfler, 1990.
McGuire, M.J.; Krasner, S.W.; Gramith, J.T. 1990. "Comments on
Bromide Levels in State Project Water and Impacts on .Control of
Disinfection By-Products"; Metropolitan Water District of
Southern California, Los Angeles, California; September, 1990.
Cited in Bull and Kopfler, 1990.
McGuire, M.J.; Meadow, R.G. 1988. "AWWARF Trihalomethane"
Survey"; Journal .AWWA; January, 1988; pp. 61-68.
National Cancer Institute (NCI). 1976. Report on carcinogenesis
bioassay of chloroform. NTIS PB-264013 .
NTP. 1987. Toxicity and carcinogenesis studies of bromo-
dichloromethane in F344/N rats and B6C3F, mice (gavage studies).
Technical Report Series No. 321.
NTP.^ 1985. National Toxicology Program. Toxicology and
carcinogenesis studies of chlorodibromomethane in F344/N 'rats and
B6C3F, mice (gavage studies). Tech. Rep. Ser. No. 350.
NTP.^ 1989. National Toxicology Program. Toxicology and
carcinogenesis studies of bromoform in F344/N rats and B6C3F,
-------
75
-•$'• >- " ' '
'*&'. ' " 4 ""
Pellizzari ED, Michael LC, Serritt R, Smith DJ, Hartwell TD and
Sebestik J. 1989. Comparison of indoor and outdoor toxic air
pollutant levels in several southern California communtities.
Final Report, EPA Contract # 68-02-4544. USEPA, Research
Tirianlge Park, NC. . .
Peto, R. 1987. Why do we need systematic overviews of
randomized trials? Stat. /fed. 6:233-240.
Rijhsinghani, K.S., M.A. Swerdlow, T. Ghose, C. Abrahams arid
K.V.N. Rao. 1986. Induction of neoplastic lesions in the. liver
of C57BL x C3HF1 male in chloral hydrate. Cancer Detection and
Prevention. 9:279-288.
Sanders, V.M., B.M. Kauffman, K.L. White, K.A. Douglas, D.W.
Barnes, L.E. Sain, T.J. Bradshaw, J.F. Borzelleca and A.E.
Munson. 1982. Toxicology of chloral hydrate in the mouse.
Environ. Health Perspect. 44:137-146.
Shaw, R.W.; Binkowski, F.S.; Courtney, W.J. 1982. "Aerosols of
High Chlorine Concentration Transported Into Central and Eastern
United States," Nature, Vol. 296, No. 5854,pp. 229-31.
Shikiya, J.; Tsou, G.; Kowalski, J.; Leh, F. 1984. "Ambient
Monitoring of Selected Halogenated Hydrocarbons and Benzene in
the California South Coast Air Basin," Proc-APCA 77th Annual Mtg,
Vol. 1, pp. 84-1.1. ?
Singh et al. 1983. Cited in Wallace, 1991.
Singh, H.B.; Salas, L.J.; Smith, A.J.; Shigeishi, H. 1981.
"Measurements of Some Potentially Hazardous Chemicals in Urban
Environments," Atmos. Environ., Vol. 15, No. 4, pp. 601-12. .
Spitzer, W.O. 1991. Editorial. Meta-meta-analysis: Unanswered
questions about aggregating data. J. din. Epidemiol. 44:103-
107.
Stevens, A.A. 1981. "Reaction Products of Chlorine Dioxide";
Env. Health Persp.; Vol. 46; December, pp. 101-110.
Symons, J.M.; Bellar, T.A.; Carswell, J.K.; DeMarco, J.; Kropp,
K.L.; Robeck, G.G.; Seeger, D.R.; Slocum, C.J.; Smith, B.L.;
Stevens, A.A. 1975. "National Organics Reconnaissance Survey
for Halogenated Organics"; Journal' AWWA; Vol. 67; No. 11;
November, pp. 634-647.
Taylor D., and R. Pfohl. 1985. Effects of chlorine dioxide on
neurobehavioral development in rats. Water Chlorination. Vol 5
pp. 355-364.
-------
76
Toth G. , R. Long, T. Mills and M.K. Smith. 1990. Effects of
chlorine dioxide on developing rat brain. J. Tox. and Environ
Health. 31:29-44.
TSD. 1991. Technical Support Division Unregulated Contaminant.
Database1. Technical-Support Division (TSD)", Office of Ground
Water and Drinking Water, U.S. Environmental Protection Agency
1991. . .
TSD. 1992. Technical Support Division Disinfect ion By-Products
Field Study Data Base. Technical Support Division (TSD), Office
of Ground Water and Drinking Water, U.S. Environmental Protection
Agency. Communication with Patricia Fair, TSD, Cincinnati,
February 14, 1992.
Uden, P.C.; Miller, J.W. 1983. "Chlorinated Acids and Chloral
in Drinking Water"; J. Amer. Water Works Assoc.; Vol. 75; No. 10;
October, pp. 524-527.
Uhler, A.D.; Diachenko, G.W. 1987. "Volatile Halocarbons in
Process Water and Processed Foods"; Bull. Environ. Cont. Toxic.;
Vol. 39; No. 4; October, pp. 601-607.
USEPA.
87/045
1986. U.S. Environmental Protection Agency. EPA/6CO/3-
USEPA. 1980.' U.S. Environmental Protection Agency. - "Ambient
Water Quality Criteria Document for Halomethanes". O'ffice of
Health and Environmental Assessment, Environmental Criteria
Office, Cincinnati, OH; 1980. Cited in USEPA, 1989. (Bromoforn).
USEPA. 1991. U.S. Environmental Protection Agency. "'Drinking
Water Health Advisory for'Brominated Trihalomethanes: Bromoform,
Dibrompchloromethane, Bromodichloromethane"; Office of Water;
'September, 1991. (Bromoform). • •
USEPA. 1985. U.S. Environmental Protection Agency. "Health ' ini
Environmental Effects Profile for Bromodichloromethaness".
Environmental Criteria and Assessment Office, Office of Health
and Environmental Assessment, Cincinnati, Ohio; June, 3985
p. 25. (BDCM) . '•"'..
USEPA. 1989. U.S. Environmental Protection Agency. '"Health .in 1
Environmental Effects-Document for Bromoform". Criteria and
Assessment Office, Cincinnati, OH; September, 1989. (Bromoform .
USEPA. 199la. U.S. Environmental Protection Agency. Draft
Drinking Water Health Criteria Document for Chlorinated Acet: -
Acids/Alcohols/Aldehydes and Ketones. Office of Science and
Technology, Office of Water. .
-------
77 .
USEPA. 1991b. U.S. Environmental Protection Agency.. Draft
Drinking Water Health criteria Document for Ozone and
By-Products.. Office of Science and Technology, Office of Water.
USEPA. 1992. U.S. Environmental Protection Agency. "Occurrence
Assessment for Disinfectants and Disinfection By-Products (Phase
6a) in Public Drinking Water", August 1992.
USEPA. 1992a. U.S. Environmental Protection Agency. Draft.
Drinking Water Health Criteria Document for Chlorine, .
Hypochlorous Acid and Hypochlorite Ion. Office of Science and
Technology, .Office of Water.
t. •'•'.-••
USEPA. 1992b. U.S. Environmental Protection Agency. Draft
Drinking Water Health Criteria Document for Chlorine Dioxide,
Chlorite and Chlorate. Office of Science and Technology, office
of Water.
USEPA. 1992c. U.S. Environmental Protection Agency. Draft
Drinking Water Health Criteria Document for Chloramines. office
of Science and Technology, Office of Water.
USEPA. 1992d. U.S. Environmental Protection Agency. Draft
Drinking Water Health Criteria Document for Trihalomethanes.
Office of Science and Technology, Office of Water.
Wallace, L. 1992. "Human Exposure, Body Burden, and Exposure-
Body Burden Relationships for Chloroform and Other
Trihalomethanes: Sections for Inclusion in Chapter IV of the ODW
Criteria Document on Trihalomethanes"; U.S. Environmental
Protection Agency, Office of Research and Development, Warrenton,
Virginia; April 14, 1992.
Wallace L. .1988. "Chloroform Available on Tap," Health
Environ., Vol. 2, No. 5, .pp. 3-4. .
.Wallace, L.; Zweidinger, R.; Erickson, M.; Copper, S.; Whita'ker,
D.; Pellizzari, E. 1982. "Monitoring Individual Exposure.
Measurements of Volatile Organic Compounds in Breathing-Zone A:r,
Drinking Water, and Exhaled Breath," Environ. Int., Vol. 8,
No. 1-6, 1982, pp. 269-82.
Wallace, L.A. 1986. "Personal Exposure, Indoor and Outdoor A:r
Concentrations, and Exhaled Breath Concentrations of Selected
Volatile Organic Compounds Measured for 600 Residents of New
Jersey, North Dakota, North Carolina, and California," Toxicol:-j\-
and Environmental Chemistry TXECBP, Vol. 12, No. 3/4, pp. 215-
236.
-------
78
Wallace, L.A.; Pellizzari, E.D.; Hartwell, T.D.; Whitmore, R. ;
Zelon, H.; Perritt, R.; Sheldon, L. 1988. "The California TEAM
Study: Breath Concentrations and Personal Exposures to 26
Volatile Compounds in Air and Drinking Water of 188 Residents of
Los Angeles, Antioch, and Pittsburgh, .CA," Atmos. Environ.,
Vol. 22, No. 10, pp. 2141-63..
Wallace, L.A.; Pellizzari, E.D.; Hartwell, T.D.; Whitmore, R.;
Sparacino, C.; Zelon, H. 1986a. "Total Exposure Assessment
Methodology (TEAM) study: Personal Exposures, Indoor-Outdoor Ai.v
Relationships, and Breath Levels of Volatile Organic Compounds ii
New Jersey," Environ. Int., Vol. 12, No. 1-4, pp. 369-r87.
Wallace, L.A.; Pellizzari, E.D.; Hartwell, T.D.; Sparadno, C. ;r
Whitmore, R.; Sheldon, L.; Zelon, H.; Perritt, R. 1987. "The
TEAM Study: Personal Exposures to Toxic Substances in Air,
Drinking Water, and Breath of 400 Residents of New Jersey, North
Carolina, and North Dakota,'? Environ. Res., Vol. 43, No. 2,
pp. 290-307.
Wallace, L.A.; Pellizzari, E.; Sheldon, L.; Hartwell, T.; .
Sparacino, C.; Zelon, H. 1986b. "The Total Exposure Assessment
Methodology (TEAM) Study: Direct Measurement of Personal
Exposures Through Air and Water for 600 Residents of Several U.S.
Cities," Pollut. Multimedia Environ. (Proc. Workshop Pollut,
Transp. Accumulation Multimedia Environ.), pp. 289r-315,,
Westrick, J.J.; Mello, J.W.; Thomas, R.F. 1983. "The Ground
Water Supply Survey Summary of- Volatile Organic Contaminant
Occurrence Data"; Technical Support Division, Office of Drinking
Water and Office of Water, U.S. Environmental Protection Agency,
Cincinnati, Ohio; January, 1983.
WIDE'. 1990. Water Industry Data'Base, American Water Works
Association. Database. ' .
Wie, C.I.; Cook,"D.L.; Kirk; J.R. • 1985. "Use of Chlorine
Compounds in the Food Industry," Food Technology, Vol. 39, No. 1,
pp. 107-115.
------- |