United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/014F
Final
9-30-2009
Provisional Peer-Reviewed Toxicity Values for
Dibromochloromethane
(CASRN 124-48-1)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICTY VALUES FOR
DIBROMOCHLOROMETHANE (CASRN 124-48-1)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	U.S. EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal review by
two U.S. EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all U.S. EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Dibromochloromethane is a trihalomethane found in drinking water that has been
extensively studied in laboratory animals but not humans. IRIS provides a chronic oral RfD of
2 x 10~2 mg/kg-day (U.S. EPA, 1991). The critical study used by IRIS (NTP, 1985) is based on a
subchronic rat gavage bioassay with a NOAEL of 30 mg/kg-day converted to a 21.4 mg/kg-day
human equivalent concentration (HEC) and a LOAEL of 60 mg/kg-day converted to
42.9 mg/g-day for rat hepatic lesions with a composite uncertainty factor (UF) of 1000. The
composite UF is composed of 10 for subchronic assay, 10 for extrapolation from animal data,
and 10 for sensitive human populations. The value is of medium confidence (study and
database). IRIS also examined a chronic NTP study (NTP, 1985) that gave LOAELs of
40 mg/kg-day for rats and 50 mg/kg-day for mice. IRIS concluded that the subchronic NOAEL
was a better basis for the RfD than the chronic LOAEL because of greater confidence in the
subchronic NOAEL since the chronic LOAEL was associated with several effects. Due to a lack
of inhalation toxicity information, an inhalation RfC is not derived (U.S. EPA, 2009).
HEAST provides a subchronic oral RfD of 2 x 10"1 mg/kg-day (HEAST, 1997) based on
a NOAEL of 21.4 mg/kg-day for liver lesions based on the same study used for IRIS (NTP,
1985). ATSDR (2005) provides acute and chronic oral MRLs of 1 x 10"1 and 9 x 10"2 mg/kg-day
based on the same NTP study (NTP, 1985). Health advisories include an MCLG of 0.06 mg/L
and an MCL of 0.08 mg/L (Final Rule for Disinfectants and Disinfection by-products). IRIS
provides a carcinogenicity assessment (U.S. EPA, 1992) of Group C (possible human
carcinogen) based on inadequate human data and limited evidence of carcinogenicity in animals;
namely, positive carcinogenic evidence in B6C3F1 mice (males and females), positive
mutagenicity data, and structural similarity to other trihalomethanes (which are known animal
carcinogens). IRIS provides an oral slope factor (OSF) of 8.4 x 10" per mg/kg-day based on a
gavage female mouse (B6C3F1) study (NTP, 1985). Drinking water Unit Risks are provided as
2.4 x 10"6 per (J,g/L. A linearized multistage procedure, extra risk model was utilized in the
determination. IARC indicated that no epidemiological data relevant to the carcinogenicity of
chlorodibromomethane were available and that limited evidence exists in experimental animals
for the carcinogenicity of chlorodibromomethane. IARC's overall evaluation is that
chlorodibromomethane is not classifiable as to its carcinogenicity to humans (Group 3).
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Metabolism studies indicate that the oxidation of dibromochloromethane to bromide and
carbon monoxide is mediated primarily by cytochrome P450 2E1, 2B1 and 2B2. Excretion of
unmetabolized parent compound and carbon monoxide was observed in expired air of both rats
and mice.
Several animal bioassays have been reported for dibromochloromethane using oral
gavage, drinking water administration, or dietary exposure as the routes of exposure. No studies
of the inhalation route of exposure have been reported in the literature. The primary target
tissues in these oral studies are the liver and kidney. NTP (1985) conducted 13 week and 2 year
oral gavage studies that found noncancer effects such as hepatic fatty metamorphosis,
hepatocellular centrilobular necrosis, and toxic nephropathy. Rats failed to demonstrate
dibromochloromethane carcinogenicity in this study. Male mice exhibited hepatocellular
carcinomas, while female mice displayed hepatocellular adenomas and carcinomas, and thyroid
follicular cell hyperplasia. A 90-day drinking water study of dibromochloromethane in rats
resulted in hepatotoxicity and nephrotoxicity. Significant increases in the incidence, multiplicity
and size of preneoplastic colon lesions known as aberrant crypt foci (ACF) were found in two
subchronic drinking water studies of dibromochloromethane. Shorter-duration studies support
the findings of liver and kidney toxicity in rats and mice. Only one two-generation reproduction
study has been reported for dibromochloromethane. This study reports hepatotoxicity and
reduced fertility.
Computer searches were initially conducted through March 2007 but have since been
updated to include information published through May 2009. The databases include health
effects and toxicity information available from the U.S. EPA (IRIS), ATSDR, and other relevant
federal, state, or international governmental or quasi-governmental agencies: ACGIH, NIOSH,
OSHA, NTP, IARC and WHO. Additional sources include CURRENT CONTENTS,
TOXLINE, MEDLINE, CANCERLIT, RTECS, HSDB, TSCATS, CCRIS, GENETOX, EMIC,
EMICBACK, DART, CalEPA and ETICBACK. Unpublished potentially relevant information
from industry or academic laboratories was also sought.
REVIEW OF PERTINENT LITERATURE
Human Studies
There are no epidemiologic data directly relevant to dibromochloromethane in humans
(IARC, 1999; 1991).
Animal Studies
NTP (1985) conducted gavage studies with a corn oil vehicle (vehicle corn oil) of
dibromochloromethane in F344/N rats and B6C3F1 mice. The exposure durations evaluated in
this study included a single exposure, 14-day exposure, 13-week subchronic exposure, and
2-year chronic exposure. The single and 14-day exposure durations were range finding studies
that are not relevant to the derivation of subchronic and chronic noncancer toxicity values and
cancer slope factors. U.S. EPA (1997) derived an oral RfD from the subchronic exposure study
of rats (NTP, 1985). Rats and mice (10/sex/dose) were administered 0, 15, 30, 60, 125 or
250 mg/kg dibromochloromethane by gavage (5 days/week) for 13 weeks. In rats, the
250-mg/kg group (the high-dose group) exhibited high mortality in both sexes (9/10) prior to
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study termination. Body weight (bw) was depressed by 47% for males and 25% for females.
Fatty metamorphosis of the liver, characterized by intracytoplasmic clear vacuoles in
hepatocytes, was observed in all of the high-dose males and females (Table 1). Control and
lower dose male rats also had high incidences of this effect; however, a Fisher Exact test
concluded that only liver lesions in the dose groups 60 mg/kg or higher were statistically
significantly elevated (Table 1). The LOAEL was 60 mg/kg and the NOAEL was 30 mg/kg.
This NOAEL was converted to a daily dose of 21.4 mg/kg-day (5/7 days of dosing), which was
used by U.S. EPA to derive the chronic oral RfD. Fatty metamorphosis of the liver was observed
in 1/10 female control rats, 0/10 in the 125-mg/kg dose group, and 9/9 in the 250 mg/kg-day
dose group; the other female dose groups were not evaluated for this endpoint. Hepatocellular
centrilobular necrosis was observed in high-dose male rats (8/10) and high-dose female rats (7/9)
but not in the other lower dose groups examined. Toxic nephropathy was observed in high-dose
male rats (8/10) and high-dose female rats (9/9) but not in the other lower-dose groups examined.
Acute inflammation and squamous metaplasia of the salivary gland were observed only in the
high-dose groups of both sexes.
Table 1. Incidences of Noncancer Effects in Male and Female Rats


in the 13-Week Study




Control
15 mg/kg
30 mg/kg
60 mg/kg
125 mg/kg
250 mg/kg
Male rats
Liver
Fatty metamorphosis
4/10
7/10
8/10
10/10
10/10
10/10
Centrilobular necrosis
0/10
1/10
0/10
0/10
0/10
8/10
Kidney
Toxic nephropathy
0/10
NE
NE
NE
0/10
8/10
Salivary gland
Inflammation
0/10
NE
NE
NE
0/10
5/10
Squamous metaplasia
0/10
NE
NE
NE
0/10
9/10
Female rats
Liver
Fatty metamorphosis
1/10
NE
NE
NE
0/10
9/9
Bile duct hyperplasia
1/10
NE
NE
NE
0/10
6/9
Centrilobular necrosis
0/10
NE
NE
NE
0/10
7/9
Kidney
Toxic nephropathy
0/10
NE
NE
NE
0/10
9/9
Salivary gland
Inflammation
0/10
NE
NE
NE
0/10
5/8
Squamous metaplasia
0/10
NE
NE
NE
0/10
6/8
NE, not evaluated.
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In mice, fatty metamorphosis (necrosis and vacuolar change) was observed only in the
250-mg/kg dose group of male mice (5/10). Toxic nephropathy, characterized by tubular
degeneration or mineralization of the kidney, was exhibited by 5/10 male mice in the high-dose
group. The 125-mg/kg dose group did not exhibit these endpoints. The lower dose groups (15,
30 and 60 mg/kg) were not evaluated for liver or kidney effects. Female mice did not exhibit
these lesions.
In the 2-year gavage studies (NTP, 1985), F344/N rats were administered 0, 40 mg/kg
(low dose) or 80 mg/kg (high dose) dibromochloromethane (50/sex/dose) for 5 days/week. At
study termination, mean body weights of males were decreased by 7.7% in the high-dose group.
Mean bw of females were not different between treated and control groups. No statistically
significant differences in survival were observed between groups; survival of males was 34/50 in
controls, 38/50 in the low-dose group, and 43/50 in the high-dose group. Survival of females
was 39/50 in controls, 37/50 in the low-dose group, and 41/50 in the high-dose group.
Incidences of neoplastic lesions were not statistically significantly elevated at any site in either
male or female rats. Statistically significant negative trends were observed for the incidences of
thyroid gland follicular cell carcinomas in male rats, follicular cell adenomas or carcinomas
(combined) in male rats, thyroid gland C-cell carcinomas in female rats, C-cell adenomas or
carcinomas (combined) in female rats, mononuclear cell leukemia in male rats, mammary gland
fibroadenomas in female rats, endometrial stromal polyps in female rats, and testis interstitial
cell tumors in male rats. Negative trends in the thyroid gland, the hematopoietic system, and
testis were not considered to be chemical-related since incidences in the dosed groups were not
different from historical rates at this laboratory.
Noncancer effects in dibromochloromethane-treated rats include fatty metamorphosis in
the liver, ground-glass cytoplasmic changes of the liver, and nephrosis (Table 2). In male rats,
fatty metamorphosis incidences were 27/50 in controls, 47/50 in the low-dose group, and 49/50
in the high-dose group. Female rats had fatty metamorphosis incidences of 12/50 in controls,
23/50 in the low-dose group, and 50/50 in the high-dose group. The incidences of ground-glass
cytoplasmic changes in male rats were 8/50 in controls, 22/50 in the low-dose group, and 34/50
in the high-dose group; female rats had incidences of 0/50 in controls, 1/50 in the low-dose
group, and 12/50 in the high-dose group. Kidney nephrosis in male rats was comparable in
control, low-dose and high-dose groups (42/50, 44/50 and 41/50, respectively). Female rats
exhibited a dose-related increase in the incidence of nephrosis: 7/50 in controls, 11/50 in the
low-dose group, and 14/50 in the high-dose group.
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Table 2. Incidences of Noncancer Effects in Male and Female Rats in the Chronic
Exposure Study

Male rats
Female rats
Controls
40 mg/kg
(low dose)
80 mg/kg
(high dose)
Controls
40 mg/kg
(low dose)
80 mg/kg
(high dose)
Liver fatty
metamorphosis
27/50
47/50
49/50
12/50
23/50
50/50
Liver group-glass
cytoplasmic changes
8/50
22/50
34/50
0/50
1/50
12/50
Kidney nephrosis
42/50
44/50
41/50
7/50
11/50
14/50
In the chronic study, B6C3F1 mice were administered by gavage 0, 50 mg/kg (low dose)
or 100 mg/kg (high dose) dibromochloromethane (50/sex/dose) for 2 years (5 days/week). Mean
body weights of the high-dose mice of both sexes were lower than controls for most of the study.
Mean bw of low-dose mice were lower than controls beginning in week 60. Survival of the
low-dose and high-dose mice was significantly lower than the controls. An accidental overdose
caused the death of 35 low-dose male mice during weeks 58-59, rendered the analysis
inadequate for analysis. Female low-dose mice also received this overdose, however, no adverse
effects were observed. Nine high-dose males died at week 82 due to unknown causes. Survival
rates for the female mice at study termination were 32/50 in controls, 27/50 in the low-dose
group, and 36/50 in the high-dose group.
Table 3 presents the effects observed in male mice, including those accidentally killed.
The incidence of hepatocellular carcinomas was significantly increased in the high-dose male
mice compared to the controls. Liver effects were observed in the low-dose male mice that died
at weeks 58-59 including centrilobular necrosis and fatty metamorphosis. The incidence of
malignant lymphomas in male mice was significantly lower in the high-dose mice compared to
the control: 9/50 in control and 0/50 in high-dose male mice.
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Table 3. Chronic Effects of Male Mice Administered Dibromochloromethane


50 mg/kg (low dose)


Control
Animals
killed
weeks 58-59
Animals
surviving to
terminal kill
100 mg/kg (high dose)
Liver
Necrosis
2/50
28/35
1/15
9/50
Fatty metamorphosis
13/50
32/35
0/15
20/50
Hepatocytomegaly
0/50
0/35
0/15
12/50
Adenoma
14/50
3/35
2/15
10/50
Carcinoma
10/50
2/35
7/15
19/50
Adenoma/carcinoma
23/50
5/35
9/15
27/50
Kidney
Nephrosis
0/50
35/35
10/15
37/50
Tubular calcification
0/50
12/35
1/15
0/50
Female mice exhibited significant positive trends for hepatocellular adenomas,
hepatocellular adenomas, and carcinomas combined (Table 4). Incidences of follicular cell
hyperplasia of the thyroid also occurred with a dose-response relationship. U.S. EPA (1992)
derived an oral cancer slope factor (OSF) from the incidences of hepatocellular adenoma or
carcinoma (combined) in female mice.
Table 4. Chronic Effects in Female Mice Administered Dibromochloromethane

Control
50 mg/kg (low dose)
100 mg/kg (high dose)
Liver
Adenoma
2/50
4/49
11/50
Carcinoma
4/50
6/49
8/50
Adenoma/carcinoma
6/50
10/49
19/50
Thyroid
Follicular cell hyperplasia
1/49
13/46
31/50
NTP (1985) concluded that "Under the conditions of these gavage studies, there was no
evidence of carcinogenicity in male or female F344/N rats receiving dibromochloromethane at
doses of 40 or 80 mg/kg five times per week for 104 weeks. Fatty metamorphosis and
ground-glass cytoplasmic changes of the liver in male and female F344/N rats were related to
administration of dibromochloromethane. There was equivocal evidence of carcinogenicity for
male B6C3F1 mice; dibromochloromethane caused an increased incidence of hepatocellular
carcinomas, whereas the combined incidence of hepatocellular adenomas or carcinomas was
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only marginally increased. Some evidence of carcinogenicity was observed for female B6C3F1
mice, since dibromochloromethane caused an increased incidence of hepatocellular adenomas
and an increased combined incidence of hepatocellular adenomas or carcinomas."
Daniel et al. (1990) investigated the effects of dibromochloromethane in male and female
Sprague-Dawley rats (10/sex/dose) exposed by daily oral gavage for 90 days, at the following
doses: 0, 50, 100 and 200 mg/kg. Survival rates were unaffected in both sexes. Body weight
was significantly reduced in males (31.5%) and females (13.3%) exposed to the highest dose,
200 mg/kg, compared to control groups (corn oil). Food intake was also significantly depressed
in males exposed to the 200-mg/kg dose. In males, the following organ weights were
significantly decreased at 200-mg/kg dose relative to controls (approximate percentages): brain
(5.9%>), heart (25%), liver (16.5%>), and thymus (34%>). At 200 mg/kg, the following organ
weight/bw ratios were significantly increased: brain, spleen, and testes. At 50 and 100 mg/kg,
kidney and lung weight/bw were also significantly increased. Liver lesions, including
vacuolization, necrosis and inflammation exhibited a dose-dependent increase in severity. At the
200-mg/kg dose, the kidneys exhibited significant degeneration of proximal tubular cells,
granularization and microvacuolization.
No significant hematological alterations in males were noted. Biochemistry profiles in
males were significantly altered as follows (approximate percentages): (1) creatinine was
increased by 17%> at 100 mg/kg and by 33.3% at 200 mg/kg, (2) alkaline phosphatase was
increased by 72.8%> at 200 mg/kg, and (3) alanine transferase was increased by 37%> at
100 mg/kg and 157% at 200 mg/kg. Elevated alanine transferase and alkaline phosphatase
activities are indicative of hepatotoxicity. Increased serum creatinine and decreased potassium
are suggestive of nephrotoxicity.
In females, the following organ weights showed significant differences relative to control
organ weights (approximate percentages): (1) brain (-5.3% at 100 mg/kg and 200 mg/kg),
(2) kidney (+16.0%) at 100 mg/kg and +24.7% at 200 mg/kg), (3) liver (+31.1%> at 200 mg/kg),
and (4) thymus (-23.7%) at 100 mg/kg and -39.5%> at 200 mg/kg). Organ weight/bw ratios were
significantly increased in females, too, at 200 mg/kg for the brain and spleen, but decreased for
the thymus. Kidney and liver weights/bw ratios were also increased at 50 mg/kg and 100 mg/kg.
Liver and kidney lesions were significant only at the highest dose, exhibiting characterizations
noted in male liver and kidney lesions (above). Significant biochemical changes include the
following: (1) creatinine (+17.0% at 100 mg/kg), (2) alkaline phosphatase (+96.6%> at
200 mg/kg), (3) calcium (+5.2% at 100 mg/kg), (4) total protein (+7.5% at 100 mg/kg) and
(5) albumin (+10.2%) at 50 mg/kg and 100 mg/kg).
The hepatotoxicity and nephrotoxicity indicated by the serum biochemistry profiles are
supported by the histopathological evaluation of liver and kidney. Table 5 presents the
incidences of noncancer liver and kidney effects. Male rats exhibited liver centrilobular lipidosis
in all dose groups. Liver centrilobular necrosis and kidney cortex tubular degeneration were
observed only in the 100- or 200-mg/kg-day dose groups of males. Female rats exhibited liver
centrilobular lipidosis and necrosis only in the 100- and 200-mg/kg-day groups. Based on the
observation of liver centrilobular lipidosis in all dose groups of male rats, a LOAEL of
50 mg/kg-day is provided.
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Table 5. Incidences of Noncancer Liver and Kidney Effects in Rats
Treated for 90 Days

0
mg/kg-day
50
mg/kg-day
100
mg/kg-day
200
mg/kg-day
Males
Liver
Chronic focal inflammation
10/10
9/10
7/10
5/10
Centrilobular lipidosis
0/10
9/10
9/10
10/10
Centrilobular necrosis
0/10
0/10
1/10
9/10
Chronic centrilobular necrosis
0/10
0/10
0/10
4/10
Kidney
Tubular degeneration, cortex
0/10
0/10
4/10
10/10
Tubular mineralization, cortex
4/10
2/10
3/10
0/10
Tubular mineralization, medulla
4/10
0/10
2/10
4/10
Progressive nephropathy, chronic
3/10
4/10
1/10
0/10
Females
Liver
Chronic focal inflammation
9/10
7/10
5/10
5/10
Centrilobular lipidosis
0/10
0/10
1/10
9/10
Centrilobular necrosis
0/10
0/10
1/10
9/10
Chronic centrilobular necrosis
0/10
0/10
0/10
2/10
Kidney
Tubular degeneration, cortex
1/10
5/10
9/10
10/10
Tubular mineralization, cortex
3/10
4/10
3/10
0/10
Tubular mineralization, medulla
3/10
1/10
3/10
3/10
Progressive nephropathy, chronic
1/10
0/10
0/10
0/10
Chu et al. (1982) exposed male and female Sprague Dawley rats to
dibromochloromethane in drinking water (20/sex/group) at 0, 5, 500 or 2500 ppm for 90 days.
Two control groups were established for this study: (1) tap water only and (2) 1% emulphor in
tap water. At completion, 10 rats/sex/group were sacrificed and liver and kidney histologies
were assessed. The remaining 10 rats/sex/group were retained on drinking water only, for an
additional 90 days, to evaluate the potential recovery of toxicities induced by the initial
exposures. Table 6 shows the intake estimates of dibromochloromethane based on
measurements of daily water intake and known levels of dibromochloromethane in the drinking
water. Survival rates of males were significantly reduced at 2500 ppm (data not provided) while
female rats were not affected. There was no significant change in body weight relative to the
control groups. Food intake was significantly depressed at 2500 ppm/day among male rats
during both the initial and recovery 90-day periods; females showed a significant reduction in
food intake at exposure of 2500 ppm/day and only during the recovery phase. There was a
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general dose-dependent increase in the severity of liver lesions in both males and females, which
were negligible at the end of the recovery phase. Males showed a significant increase in
lymphocyte count (4.1-4.5%) relative to both controls at 500 ppm/daily during initial 90-day
exposure period. At the end of the 90-day recovery period, lymphocyte counts returned to levels
comparable to controls.
Table 6. Approximate Daily Intake of Dibromochloromethane
Dose
Daily intake in mg/rat/day
0 ppm
5 ppm
50 ppm
500 ppm
2500 ppm
Male
-
0.14 mg/rat/day
1.6 mg/rat/day
13 mg/rat/day
49 mg/rat/day
Female
-
0.13 mg/rat/day
1.2 mg/rat/day
9.8 mg/rat/day
32 mg/rat/day
Aida et al. (1992) evaluated the toxicity of microencapsulated dibromochloromethane
administered to Wistar rats in the diet. Groups of 7 male rats/dose were provided a diet
containing 0.020%, 0.062% and 0.185%) dibromochloromethane; groups of 7 female rats/dose
were provided a diet containing 0.038%>, 0.113% and 0.338%) dibromochloromethane.
Microencapsulation of dibromochloroethane was selected as the vehicle of exposure because
(1) this chemical is sparingly soluble in drinking water and (2) the authors desired to evaluate its
oral toxicity. Hepatic lesions, such as vacuolization and liver cell swelling, were observed in
both sexes of the middle- and high-dose groups. Single-cell necrosis was observed in both sexes.
Relative and absolute liver weights were statistically significantly increased in the high-dose
male rats and in the mid- and high-dose female rats. Female rats also exhibited significantly
decreased body weight in the high-dose group. The NOAEL in this study was determined as
18.3 mg/kg dibromochloromethane based on the absence of effects in the low-dose (0.020%>)
group of male rats. This study demonstrates that the liver is the target organ in rats.
Munson et al. (1982) studied the subchronic toxicity of selected halomethanes that are
drinking water contaminants—including dibromochloromethane at doses of 50 and
250 mg/kg-day for 14 days in CD-I male and female mice that were performed using doses of
1/10th the LD50 for the compounds. Observations include a reduction in body weight in males
at the high dose. Liver weights were increased at 125 and 250 mg/kg-day when expressed as
percent of body weight. Spleen and thymus values decreased significantly at the high dose.
Only fibrinogen was affected with a decrease occurring at the high-dose only. Clinical chemistry
alterations were increases in SGPT and SGOT and a decrease in serum glucose—all in the high
dose group. Both humeral and cell-mediated immunity were affected. The number of AFC was
significantly reduced when expressed as total cells or as AFC/106 spleen cells. This was noted
at the high dose, as was a reduction in hemagglutination titer. Cell-mediated immunity, as
measured by the popliteal lymph node stimulation index, was depressed at the high dose. It
should be noted that even though the changes were significant only at the 250-mg/kg-day level,
the decreasing trend can be observed with the lower doses. No significant body weight change
was observed in females. The major organ weight change in females was an increase in liver
size in the intermediate- and high-dose groups. The ability of the liver to metabolize
hexobarbital was impaired at the intermediate and high dose as evidenced by increased
hexobarbital sleeping times. The only hematological change was a slight decrease in fibrinogen
at the high dose. Altered clinical chemistry parameters were increases in SGPT and SGOT and a
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decrease in serum glucose, all occurring at 250 mg/kg-day. A decrease in AFC/spleen and
AFC/106 spleen cells was noted in the intermediate- and high-dose groups, whereas a reduction
of hemagglutination titer occurred only at the high dose. With regard to exposure to
trichloromethane (assumed to have similar mode of action), the authors observed that a 90-day
exposure did not exacerbate the changes seen to occur as a result of 14-day administration, and
were, in fact, less severe. The observation was supported by a tolerance experiment that revealed
compensatory mechanisms being activated during the subchronic 90-day exposure.
Since these doses were considerably higher than the NTP (1985) study, they are not
considered further for use in risk assessment or in the derivation of provisional toxicity values.
Da Silva et al. (2000) evaluated the blood kinetics of simultaneous dosing of binary
mixtures of trihalomethanes (chloroform, bromoform, bromodichloromethane and
dibromochloromethane at 0.25 nmol/kg) by gavage to male Sprague-Dawley rats. The authors
concluded that at the dose level investigated, every binary combination, when orally
administered, resulted in a significant modulation of their pharmacokinetics. The authors
suggested that this is probably the consequence of a mutual metabolic inhibition between the
trihalmethanes. Because these compounds may occur together in the environment, some
consideration should be given to the interactive effects on toxicity.
Potential short term exposure effects of dibromochloromethane on mutagenicity,
nephrotoxicity and serum testosterone levels were investigated by Potter et al. (1996). Male
F344/N rats (4 rats/dose) were administered 0.75 mmol/kg or 1.5 mmol/kg of
dibromochloromethane (purity not indicated, in 4% emulphor) by oral gavage for 7 consecutive
days. Rats were sacrificed at 1, 3 and 7 days. Rats were infused with 5'-bromodeoxyuridine
3 days prior to sacrifice—except those sacrificed on days 1 and 3. The kidney/body weight ratio
(day 7) was significantly increased (17.2%) in rats exposed to 1.5 mmol/kg bw
dibromochloromethane. Hyaline droplets in the kidney were significantly reduced at both doses
and on days 3 and 7 of sacrifice. DNA strand break rates were not affected by
"3
dibromochloromethane exposures. Based on wide variability, cell proliferation based on [ H]
incorporation in renal cells did not show statistically significant differences between exposed and
control groups. There is a general dose-dependent decrease in mean testosterone levels, which is
significant at the high dose of 1.5 mmol/kg (approximately 2.5-fold). Decreased serum
testosterone was hypothesized to account for the decreased hyaline droplet formation.
Coffin et al. (2000) administered dibromochloromethane to female B6C3F1 mice
(6-10/dose) by oral gavage, for 11 days (2 days off between days 5-8) at 100 and 300 mg/kg
(doses of 0.48 and 1.44 mmol/kg, respectively), or for 11 consecutive days at 790 mg/L in
drinking water (0.82 mmol/kg dose). There was a dose-dependent increase in liver/body weight
ratios in mice that were administered dibromochloromethane by oral gavage but not in drinking
water. Liver toxicity was based on a grading system of 1-4 by degree of
severity/characterization. The 100-mg/kg gavage dose caused mid-1 obular ballooning of
hepatocytes (Grade 1); the 300 mg/kg gavage dose caused mid-lobular ballooning hepatocytes
extending to the central vein (Grade 2) Liver toxicity of dibromochloromethane administered in
drinking water was similar to that observed with the 10-mg/kg gavage dose. Proliferating cell
nuclear antigen-labeling index (PCNA-LI) was increased in a dose-response manner when mice
were treated by gavage. When administered in drinking water, PCNA-LI was increased
similarly to the 100-mg/kg gavage dose. There was also a dose-dependent decrease in DNA
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methylation in the promoter region of the c-myc gene when mice were treated by gavage;
dibromochloromethane treatment by drinking water produced similar results on DNA
methylation as the gavage route of exposure. The authors concluded that
(1) dibromochloromethane, administered by gavage, enhanced cell proliferation, and decreased
methylation of the c-myc gene and that (2) this conclusion was consistent with its carcinogenic
activity. The authors also speculate that the more modest effects caused by drinking water
administration is evidence that the carcinogenic activity of dibromochloromethane is dependent
on the rate of delivery (i.e. rapid delivery by oral gavage being more efficacious than slower
delivery via drinking water).
A two-generational murine reproduction on the effects of dibromochloromethane
commissioned by U.S. EPA was conducted by Borzelleca and Carchman (1982). Doses of 0.1,
1.0 and 4.0 mg/mL (approximately 685 mg/kg) dibromochloromethane in drinking water were
administered to ICR Swiss Albino mice beginning at 7 weeks of age and continued for two
generations. There were 9-10 males/dose in the F0 generation, 30 females/dose in the F0
generation, and 4 males in the 4 mg/mL dose in the Fib generation. Body weights were
significantly reduced in both the F0 and Fi generations of males and females exposed to
4.0 mg/mL dose. Survival was significantly reduced among females in the Fib generation
(48.3%). In both generations, all treated animals showed a dose-dependent increase in liver size
and severity of hepatotoxic morphology (characterizations not indicated). Significant decreases
were observed in litter size in all generations at the highest dose of dibromochloromethane.
Fertility was reduced in the Fic and F2a generations at the 4.0 mg/mL dose of
dibromochloromethane. The gestational index was reduced at the 4.0 mg/mL dose in the Fia, F^
and Fic generations.
Hewitt et al. (1983) investigated the effects of acetone potentiation of hepatotoxicity and
nephrotoxicity by dibromochloroethane using adult male Sprague-Dawley rats. Rats (6/dose)
were administered by oral gavage the following doses: 0, 0.10, 0.20, 0.25, 0.50, 0.75, 1.00, 2.00
or 2.50 mL/kg (concentration not provided). An LD50 post 24 hours of exposure was determined
to be 1.08 mL/kg. Liver injury was observed at 1.0 mL/kg dose based on significantly elevated
levels of glutamic-pyruvic transaminase (GPT) activity (5.0-fold) and ornithine carbamoyl
transferase (OCT) activity (17.8-fold). No nephrotoxicity was observed. In a second series of
experiments, rats were pretreated orally with 15 mmol/kg acetone (<99% purity, diluted in H20).
After 18 hours of pretreatment, the rats were given 0.25, 0.50 or 1.00 mL/kg
dibromochloromethane (in corn oil) or corn oil (10 mL/kg). Acetone-pretreatment induced
significant potentiation of dibromochloromethane effects at 0.50 mL/kg and 1.00 mL/kg doses
on (1) GPT activity (5-fold and 7-fold higher, respectively) and (2) OCT activity (14-fold higher
at 0.50 mL/kg). Pretreatment with acetone significantly increased (1) liver/body weight ratio at
0.50 and 1.00 mL/kg doses (29.3% and 19.3%, respectively), (2) GPT activity at 0.25, 0.50 and
1.00 mL/kg doses (33.4-fold, 11.6-fold and 33.6-fold increases, respectively), and (3) OCT
activity at 0.25 and 1.00 mL/kg doses (59.0-fold and 30.7-fold increases, respectively). No
potentiation of nephrotoxicity was observed.
Other Studies
Dibromochloromethane is positive in mutagenicity and genotoxicity studies. Although
NTP (1985) reported that dibromochloromethane was negative in Ames mutagenicity assays,
another report (Simmon et al., 1977) using a dessicator method to address the volatility of
dibromochloromethane described positive results. Some assays of sister chromatid exchange and
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chromosome aberration assays are positive while others report negative results. Mouse
lymphoma forward mutation assays are positive in two studies. However, unscheduled DNA
synthesis in rat liver using thymidine incorporation is negative. Because IRIS already provides a
detailed discussion on these, no further information is presented here.
Mink et al. (1986) performed toxicokinetic metabolic studies of dibromochloromethane
intake using male Sprague-Dawley rats (n = 6) and B6C3Fi mice (n = 20).
14C-dibromochloromethane was given by oral gavage at doses of 100 mg/kg or 150 mg/kg to rats
and mice, respectively. The rats and mice were kept in glass chambers connected to a series of
chamber traps containing xylene/2-methoyethanol and ethanolamine/2-methoxyethanol to collect
expired 14C-dibromochloromethane or 14C-carbon monoxide (CO). Expired air, urine samples
and feces were collected over intervals during an 8-hour period. In a second experiment, urine
samples were taken at intervals throughout a period of 36 hours for mice and 48 hours for rats.
At 8 hours, the total recovery of 14C was 70.3% and 91.63% for rats and mice, respectively,
based on detection of 14C radiolabel in expired CO2, parent dibromochloromethane, urine, and in
all organs. The majority of dichloromethane was eliminated through expiration. In rats, 18.2%
was expired as 14C-CO, -48.1% was expired as unmetabolized dibromochloromethane, 1.1%
was expelled in urine (14C), and 1.4% was found retained in organs (14C). In mice, 71.58%) was
expired as 14C-CO, 12.31% was expired as the parent compound, 1.90% was expelled in urine
(14C), and 5.02% was found retained in organs (14C). The half-life of dibromochloromethane is
1.2 hours and 2.5 hours in rats and mice, respectively. The urine contained <10% of total
radioactivity at 36 or 48 hours postexposure.
The data suggest that clearance of dichloromethane is predominantly through expired air
in both species. Species comparisons demonstrate that mice clear dichloromethane in expired air
as CO ~3.8-fold more and as parent compound 4-fold less, as compared to rats. Mice retain
nearly 5-fold more dichloromethane in organs, while both species excrete (14C detection) the
putative parent compound at similar levels. Mink et al (1986) authors suggest that mice clear
dibromochloromethane faster than rats. The high recovery of unmetabolized parent compound
suggests limited metabolism of dibromochloromethane.
Pankow et al. (1997) investigated the metabolism of dibromochloromethane to its
oxidized metabolites, bromide and carbon monoxide in male Wistar Unilever rats.
Dibromochloromethane was given either acutely (30/dose) or for 7 days (3/dose) by oral gavage
at the following doses: 0.4, 0.8, 1.6 and 3.1 mmol/kg. Physiological saline was given to control
groups. Table 7 provides detection of dibromochloromethane in the blood postacute exposures.
No significant differences in the dibromochloromethane levels were seen between 1.6 and
3.1 mmol/kg bw doses after 1.5 hours. There was a significant dose-dependent increase in
bromide detection following acute exposure to dibromochloromethane (Table 8). Accumulation
of bromide levels in the blood post-7-day exposure was significantly greater than in acute
exposures, with a peak ~5-fold difference at 12 hours (blood collection: 0, 3, 6, 12, 24, 48 and
72 hours). Carbon monoxide retention was also significantly higher between 0-3 hours for
repeated exposure of dibromochloromethane compared to acute exposures.
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Table 7. Detection of Dibromochloromethane in Blood after Various Acute Dose
Exposures to Dibromochloromethane
Time postexposure
(hours)
Dibromochloromethane (mmol/L) in blood
0.4 mmol/kg
0.8 mmol/kg
1.6 mmol/kg
3.1 mmol/kg
1.5
-
0.16 ±0.12
0.65 ± 0.40
0.43 ± 0.09
3
03 ±0.1
0.16 ±0.04
0.49 ±0.27
0.65 ± 0.06
6
Not detected
0.06 ± 0.04
0.43 ± 0.27
-
9
Not detected
Not detected
0.29 ±0.18
-
Table 8. Detection of Bromide Levels 24 hours Post Acute Exposure to

Dibromochloromethane



Dibromochloromethane (mmol/L) in blood

0.0 mmol/kg
0.4 mmol/kg
0.8 mmol/kg
1.6 mmol/kg
3.1 mmol/kg
Bromide (mmol/L)
0.0
2.04 ±0.16
3.57 ±0.43
5.14 ± 1.22
-7.0 ± 0.9
GSH activity in the liver of rats acutely exposed to 0.8 mmol/kg of
dibromochloromethane was decreased by buthionine sulphoximine pretreatment
(i.p. administration of 4 mmol/kg) which depletes GSH. GSH levels were decreased by 30% by
buthionine sulphoximine, but formation of carbon monoxide and bromide were not significantly
affected. Pretreatment with butylated hydroxyanisole (5x5.5 mmol/kg, administered
daily/5 days by oral gavage) resulted in increased GSH levels (31%) and significantly higher
rates of carbon monoxide and bromide formation (approximately 1-2-fold). Enhancement of
cytochrome P450 enzymes, as measured by levels of liver /;-nitrophenyl hydroxylase activity
was significantly increased in rats pre-treated by i.p. for 4 days with phenobarbitol, isoniazid
(360 (j,mol/kg), or w-xylene, followed by an acute treatment with 0.8 mmol/kg
dibromochloromethane. Blood levels of carbon monoxide and bromide were significantly
increased initially, over a 24-hour period. Conversely, carbon monoxide and bromide levels
were significantly reduced throughout the 24 hour assessment period, in rats dually treated with
the cytochrome P450 inhibitor, diethyldithiocarbamate (i.p. daily/4 days/64 (j,mol/kg) and
0.8 mmol/kg dibromochloromethane.
Pankow et al (1997) concluded that oxidation of dibromochloromethane to bromide and
carbon monoxide is mediated primarily by cytochrome P450 enzymes (CYP2E1, CYP2B1 and
CYP2B2). Repeated exposures to dibromochloromethane result in an accumulation of bromide.
DERIVATION OF A PROVISIONAL SUBCHRONIC RfD FOR
DIBROMOCHLOROMETHANE
IRIS (U.S. EPA, 1991) derived a chronic oral RfD for dibromochloromethane based on
hepatic lesions observed in male rats in a 13-week NTP (1985) study.
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The subchronic study (NTP, 1985) was utilized by IRIS to develop a chronic oral RfD of
2 x 10~2 mg/kg-day. IRIS considered the 60-mg/kg-day dose as a LOAEL (10/10 responding vs.
a control of 4/10 \p = .005, Fisher Exact Test]) and selected the next lowest level (30 mg/kg-day)
as a NOAEL (8/10 responding). IRIS corrected the time duration of gavage (5 days/7days) to
get a POD of 21.4 mg/kg-day. The application of a composite UF of 1000 (10 intrahuman,
10 interhuman, 10 extrapolation to chronic period) obtains an RfD of 2 x 10"2 mg/kg-day.
The NOAEL of 30 mg/kg-day is selected as the POD for the derivation of the subchronic
p-RfD. This value was duration adjusted for continuous exposure resulting in a PODAdj of
21.4 mg/kg-day. Applying a composite uncertainty factor of 300 (10 for intraspecies, 10 for
interspecies, 3 for database correction since a developmental study is not available) is calculated
below:
Subchronic p-RfD = POD adj/UF
= 21.4/300 = 0.071 mg/kg-day (rounded to)
= 7 x 10"2 mg/kg-day
The NTP (1985) subchronic bioassays utilized standards for numbers of animals of both
sexes and two species; multiple endpoints, including complete histopathology. Confidence in the
chosen study is medium. The database is given medium confidence. Medium confidence in the
p-RfD follows.
FEASIBILITY OF PROVISIONAL SUBCHRONIC AND CHRONIC RfCs FOR
DIBROMOCHLOROMETHANE
Subchronic and chronic p-RfCs cannot be derived for dibromochloromethane because no
toxicology information from the inhalation route of exposure is available. A route-to-route
extrapolation could not be performed because of the lack of information on the absorption,
metabolism and distribution of pentachloroethane following inhalation exposure.
FEASIBILITY CARCINOGENICITY ASSESSMENT FOR
DIBROMOCHLOROMETHANE
IRIS (U.S. EPA, 1992) classified dibromochloromethane as a possible human carcinogen
(group C). U.S. EPA derived an oral cancer slope factor for dibromochloromethane from the
NTP (1985) cancer bioassay of female mice. Female mice exhibited dose-related increases in
hepatocellular adenoma and carcinoma (combined). Using a linearized multi-stage procedure of
extra risk, an OSF of 8.4 x 10" per mg/kg-day was derived. No IUR is developed because of
lack of useful inhalation data.
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REFERENCES
Aida, Y, K. Takada, O. Uchida et al. 1992. Toxicities of microencapsulated tribromomethane,
dibromochloromethane and bromodichloromethane administered in the diet to Wistar rats for
one month. J. Toxicol. Sci. 17(3): 119—133.
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological profile for
bromoform and dibromochloromethane; Public Health Service, U.S. Department of Health and
Human Services, Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxprofiles.
Borzelleca, J.F. and R.A. Carchman. 1982. Effects of selected organic drinking water
contaminants on male reproduction. Office of Research and Development, U.S. Environmental
Protection Agency, Research Triangle Park, NC; EPA600/1-82-009. Available from: National
Technical Information Service, Springfield, VA; PB82-259847.
Chu, I., D.C. Villeneuve, V.E. Secours et al. 1982. Trihalomethanes: 2. Reversibility of
toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane
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Coffin, J.C., R. Ge, S. Yang et al. 2000. Effect of trihalomethanes on cell proliferation and
DNA methylation in female B6C3F1 mouse liver. Toxicol. Sci. 58(2):243-252.
Daniel, F.B., M. Robinson, L.W. Condie et al. 1990. Ninety-day oral toxicity study of
dibromochloromethane in Sprague-Dawley rats. Drug Chem. Toxicol. 13(2-3): 135-154.
Da Silva, M.L., et al. 2000. Evaluation of the Pharmocokinetic Interactions between Orally
Administered Trihalomethanes in the Rat. J. Toxicol. Environ. Health. Part A, 60:343-353.
Hewitt, W.R., E.M. Brown and G.L. Plaa. 1983. Acetone-induced potentiation of
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Mink, F.L., T.J. Brown and J. Rickabaugh. 1986. Absorption distribution and excretion of
carbon-14 trihalomethanes in mice and rats. Bull. Environ. Contam. Toxicol. 37(5):752-758.
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Trichloromethane, Bromodichloromethane, Dibromochloromethand and Tribromomethane.
Environ. Health Perspect. Vol. 46, p. 117-126.
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NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of
chlorodibromomethane in F344/N rats and B6C3F1 mice (gavage studies). National Institute of
Environmental Health Sciences, Public Health Service, U.S. Department of Health and Human
Services, Research Triangle Park, NC; NTP TR 282. Online, http://ntp-server.niehs.nih.eov.
Pankow, D., B. Damme, U. Wunscher et al. 1997. Chlorodibromomethane metabolism to
bromide and carbon monoxide in rats. Arch. Toxicol. 71(4):203-210.
Potter, C.L., L.W. Chang, A.B. DeAngelo et al. 1996. Effects of four trihalomethanes on DNA
strand breaks, renal hyaline droplet formation and serum testosterone in male F-344 rats. Cancer
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Simmon, V.F., K. Kauhanen and R.G. Tardiff 1977. Mutagenic activity of chemicals identified
in drinking water. Dev. Toxicol. Environ. Sci. 2:249-258.
U.S. EPA. 1991. Integrated Risk Information System (IRIS). National Center for
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http://www.epa.gov/iris. Accessed June 2009.
U.S. EPA. 1992. Integrated Risk Information System (IRIS). National Center for
Environmental Assessment, Office of Research and Development, Washington, DC. Online.
http://www.epa.eov/iris. Accessed June 2009.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
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