_ March 31, 1987
820K87118
ORTHO-, META-, AND PARA-DICHLOROBENZENES
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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March 31, 1987
This Health Advisory (HA) is based on information presented in the Office
of Drinking Water's Health Effects Criteria Document (CD) for ortho-, meta-,
and para-dichlorobenzenes (U.S. EPA, 1987). The HA and CD formats are
similar for easy reference. Individuals desiring further information on
the toxicological data base or rationale for risk characterization should
consult the CD. The CD is available for review at each EPA Regional Office
of Drinking Water counterpart (e.g., Water Supply Branch or Drinking Water
Branch), or for a fee from the National Technical Information Service,
U.S. Department of Commerce, 5285 Port Royal Rd., Springfield, VA 22161,
PB #86-117918/AS. The toll-free number is (800) 336-4700; in the Washington,
D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No.
Structural Formula
o-DCB
95-50-1
m-DCB
541-73-1
p-DCB
106-46-7
Synonyms
0 o-DCB, m-DCB, p-DCB; 1,2-dichlorobenzene, 1,3-dichlorobenzene,
1,4-dichlorobenzene.
Uses (U.S. EPA, 1987)
0 o-DCB: Solvent, chemical intermediate, deodorizer
p-DCB: Deodorizer, insecticide
m-DCB: None documented
Properties (U.S. EPA, 1987; 1985a)
o-DCB
Molecular Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Log Olive Oil/Water Partition
Coefficient
Odor Threshold (water)
Taste Threshold
Conversion Factor (air)
C6H4C12
147.01
Colorless liquid
179°C
-17.6°C
1.3 g/mL at 20°C
1 .56 mm Hg at 25°C
145 mg/L
3.65
0.01-0.03 mg/L
1 ppm = 6.01 mg/L
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March 31, 1987
m-DCB
Molecular Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Log Olive Oil/Water Partition
Coefficient
Odor Threshold (water)
Taste Threshold
Conversion Factor
C6H4C12
147.01
Colorless liquid
172°C
-24.2°C
1.29 g/mL at 20°C
5 mm Hg at 39CC
1.23 mg/L
3.69
0.01-0.03 mg/L
Molecular Formula
Molecular Weight
Physical state
Boiling Point
Melting Point
Density
Vapor Pressure
Log Olive Oil/Water Partition
Coefficient
Water Solubility
Odor Threshold (water)
Taste Threshold
Conversion Factor (air)
Occurrence
C6H4C12
147.01
Colorless crystals
174°C
53°C
1.46 g/mL at 20°C
0.4 mm Hg at 25°C
3.65
79 mg/L
0.01-0.03 mg/L
1 ppm = 6.01 mg/m^
There are no natural sources for the three isomers of dichlorobenzene
(DCB).
Production of the DCB isomers in 1981 was 11 million Ibs for the
ortho isomer and 15 million for the para isomer. Production of the
meta isomer was not reported and is believed to be small.
Releases of the ortho and meta isomers to the environment are believed
to be small. The majority of the para isomer produced is released to
the environment during its use as a deodorant and moth repellent.
Dichlorobenzenes, while they have a low vapor pressure, are released
to the environment largely by evaporation. Dichlorobenzenes in air
are expected to degrade within a few days or weeks. Dichlorobenzenes
released to surface waters would tend to be removed either by vola-
tilization or adsorption onto soil and sediments. Dichlorobenzenes
are biodegraded poorly in the environment. When released to the
ground the compounds are expected to bind to soil and only slowly
migrate to ground water. Dichlorobenzenes have been reported to
bioaccumulate in fish, aquatic invertebrates and algae.
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The DCBs rarely occur as environmental contaminants (U.S. EPA, 1983).
Based upon Federal surveys of drinking water, it is estimated that
the ortho and para isomers occur at detectable levels in approximately
0.2 and 1.1 percent of all ground water supplies and 0.3 and 0.1 of
all surface water supplies, respectively. No levels have been detected
greater than 5 ug/L. Federal surveys of drinking waters have not
reported finding the meta isomer. No information on the occurrence
of DCB in food has been identified. Dichlorobenzenes have been
identified as contaminants of air at very low levels (< 40 ppt) in
urban and suburban areas. There are insufficient data on the DCBs to
identify the major route of environmental exposure.
III. PHARMACOKINETICS
Absorption
0 No studies have been reported which determine the percentage of a
dose of DCB absorbed following oral or inhalation exposure. However,
it will be assumed that 100% of an oral dose of any of the isomers of
DCB is absorbed and that 60% of an inhalation dose is absorbed when
exposure persists for longer than one to three hours (Astrand, 1975;
Dallas et al., 1983).
Distribution
0 The ortho- and para- isomers are lipophilic and can be expected to
bioaccumulate to some extent, particularly in tissues with high fat
content, during prolonged, continuous exposures. Para-DCB has been
detected in human adipose tissue and all three isomers have been
detected in blood (Dowty et al., 1975; Morita et al., 1975; Morita
and Ohi, 1975).
Metabolism
0 After oral administration to rabbits, the DCBs are oxidized princi-
pally to phenols. Ortho- and meta-DCB also form catechols (Azouz
et al., 1955; Williams, 1959). Although small amounts of the metabo-
lites are excreted as free phenols or catechols, the overwhelming
percentage are eliminated as conjugates of glucuronic or sulfuric
acids. Ortho- and meta-DCB form mercapturic acids as well, but p-DCB
does not (Williams, 1959). The conjugated dichlorophenols appear to
be the principal metabolic products of the DCB isomers in humans
(Hallowell, 1959; Pagnatto and Walkley, 1965).
Excretion
Hawkins et al. (1980) found that, after exposure of female CFY rats
to 14C p-DCB, more than 90% of the 14C was eliminated in urine within
five days post-treatment, with the remainder in feces and expired air.
During the first two days following treatment, 50 to 60% of the 14C was
excreted in bile, thus indicating reabsorption in the enterohepatic
circulation.
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IV. HEALTH EFFECTS
Humans
0 Cases have been reported in which individuals suffered moderate to
severe anemia following exposure to DCBs (concentrations not estimated)
(U.S. EPA, 1987). Several instances of skin lesions (e.g., pigmen-
tation and allergic dermatitis) developing after contact also have
been reported. Exposure levels were not estimated in these reports.
0 In other reported cases, patients complained of vomiting, headaches,
irritation of the eyes and upper respiratory tract and profuse rhinitis
and periorbital swelling (U.S. EPA, 1987). Anorexia, nausea, vomiting,
weight loss, yellow atrophy of the liver and blood dyscrasias also
were reported for higher exposure concentrations. Liver damage was
sometimes accompanied by porphyria (Hallowell, 1959). Exposure levels
were not estimated in these reports.
0 2apata-Gayon (1982) reported headache, dizziness, nausea, and
chromosomal breaks in blood samples from men and women exposed to o-
DCB (exposures not given) 8 hours per day for 4 days with reduced
chromosomal breaks by 6 months after exposure.
Animals
Short-term Exposure
0 The DCBs produce sedation and anesthesia in animals after acute oral
or parenteral administration (U.S. EPA, 1987). Relatively high doses
are needed to produce acute effects. Acute poisoning is characterized
by signs of disturbance of the central nervous system including
hyperexcitability, restlessness and muscle spasms or tremors. The
most frequent cause of death is respiratory depression. Acute and
subchronic exposures also may result in kidney and/or liver damage.
Liver alterations may be manifested as necrosis/degeneration, perhaps
coincident with porphyria.
0 Fourteen-day repeated dose gavage studies in mice (30 to 4,000 mg/kg)
and rats (60 to 1,000 mg/kg) were conducted with both o- and p-DCB in
the prechronic testing phase of the National Toxicology Program (NTP)
bioassay on these two substances (Battelle-Columbus, 1978a,b,d,e,f,g,h),
In addition to early deaths and lack of body weight gain at the higher
doses, animals exhibited histopathological changes indicative of
hepatic centrolobular necrosis and degeneration, occasionally with
cyto- and karyomegaly, as well as lymphoid depletion of the spleen
and thymus. The NOAEL for o-DCB in mice cannot be determined since
degeneration and necrosis in liver found at 250 and 500 mg/kg were
not assessed at lower doses. In rats given o-DCB, the NOAEL was
250 mg/kg with the LOAEL being 500 mg/kg for decreased body weights
in males. For animals given p-DCB, the LOAEL in mice was 250 mg/kg
(lowest dose tested) for tissue lesions and in rats the NOAEL was
250 mg/kg and the LOAEL 500 mg/kg (lower body weight in males).
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Long-term Exposure
0 Gavage doses of o-DCB at 250 and 500 mg/kg given to rats and mice
over a thirteen-week schedule of five days/week resulted in hepatic
necrosis as well as porphyria (Battelle-Columbus, 1978c,i). Serum GPT
levels were increased in mice exhibiting liver histopathology at the
highest dose level. Some mice also exhibited myocardial and skeletal
muscle mineralization and lymphoid depletion of the thymus and spleen
and necrosis of the spleen. Rats also showed pathological changes in
their kidneys, characterized by tubular degeneration. No treatment-
related effects were observed with doses of 30, 60 and 125 mg/kg.
0 Boilingsworth et al. (1958) gave rats a series of 138 doses of o-DCB
over a period of 192 days (18.8, 188 or 376 mg/kg/day, five days a
week) by gastric intubation. No adverse effects were noted at the
lowest dose. With the intermediate dose, slight increases in the
weights of th« liver and kidney were noted. At the highest dose,
there was a moderate increase in the weight of the spleen and
swelling and cloudy appearance of the liver.
0 Hollingsworth et al. (1958) also assessed the effects of multiple
inhalation exposures to o-DCB in rats, guinea pigs, mice, rabbits and
monkeys. The animals were exposed seven hours a day, five days a
week, for six to seven months. No adverse effects were observed in
rats, guinea pigs or mice exposed to 49 ppm (0.29 mg/L), or in rats,
guinea pigs, rabbits and monkeys exposed to 93 ppm (0.56 mg/L).
0 Twenty oral doses of 10, 100 or 500 mg/kg p-DCB given five days/week
to rats produced marked hepatic effects including cloudiness, swelling
and centrilobular necrosis at only the highest dose (Hollingsworth
et al., 1958). No adverse effects were observed at the other doses.
° Thirteen-week exposures to p-DCB by gavage resulted in histopathological
alterations in the liver similar to those observed with o-DCB, but at
somewhat higher doses (675 and 800 mg/kg in the mouse, 300 and 600
mg/kg in the rat) (Battelle-Columbus, 1978a,b, 1980a,b). Hepatic
necrosis, degeneration and porphyria were found in both species. The
spleen and thymus also exhibited histopathological changes similar to
those observed with o-DCB. In mice and rats, hematopoietic hypoplasia
of the bone marrow occurred in survivors at the highest dose (1,500
mg/kg/day). Rats at the two highest dose levels (1,000 and 1,500
mg/kg) also exhibited epithelial necrosis of the nasal turbinates and
small intestine as well as villar bridging of the mucosa of the latter
tissue. Again, the rats exhibited multifocal degeneration or necrosis
of the cortical tubular epithelium of the kidney. A NOAEL of 150
mg/kg/day for rats and 337.5 mg/kg for mice was identified.
0 Oral doses of 188 or 376 mg p-DCB/kg given five days a week, for 192
days (138 doses) to rats produced an increase in the weights of the
liver and kidneys (Hollingsworth et al., 1956). At 376 mg/kg,
increased splenic weight and slight cirrhosis and focal necrosis of
the liver were observed. No adverse effects were seen with the 18.8
mg/kg dose.
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0 inhalation studies also were carried out by Hollingsworth et al.
(1956) with p-DCB in rats, rabbits, mice and monkeys. The concentra-
tions used were 96, 158, 173, 314 and 798 ppm (0.58, 0.95, 1.04, 2.05
and 4.8 mg/L, respectively). Exposures were conducted seven hours/day,
five days/week for six to seven months. Adverse effects observed
included liver and kidney lesions with increased organ weights,
pulmonary edema and congestion, splenic weight changes and reversible,
non-specific eye changes. The NOAELs were 96 ppm in rats and 158 ppm
in the other species.
0 Because available studies with lifetime exposures were conducted to
assess carcinoqenicity, they are discussed in the Carcinogenicity
section.
Reproductive Effects
0 Data on reproductive effects were not found in available literature.
Developmental Effects
0 Several teratogenicity studies have been conducted on two of the
three isomers of DCB. Hayes et al. (1985) observed no
teratogenic or fetotoxic effects in rat or rabbit fetuses whose dams
were exposed by inhalation to doses of o-DCB at levels up to 400 ppm.
Similarly, no fetotoxic or teratogenic effects were noted in rabbits
subjected to exposures of p-DCB at levels up to 500 ppm. In addition,
the results of a study by Hodge e't al. (1977, summarized in Loeser
and Litchfield, 1983), support the conclusions of the Hayes et al.
(1985) study in showing that maternal exposure to atmospheric levels
of p-DCB up to 500 ppm on days 6 through 15 of pregnancy in the rat
does not result in any embryotoxic, fetotoxic or teratogenic effects
in the offspring.
Mutagenicity
0 Para-dichlorobenzene induces abnormal mitotic division in higher
plants. Observed effects include shortening and thickening of
chromosomes, precocious separation of chromatids, tetraploid cells,
binucleate cells and chromosome bridges (c-mitosis) (Sharma and
Battacharya, 1956; Sharma and Sarkar, 1957; Srivastava, 1966; Gupta,
1972). Ortho-DCB was shown to produce abnormal mitotic division in
the onion Allium cepa (Ostergren and Levan, 1943).
0 Ortho- and para-dichlorobenzene were not mutagenic when tested in a
culture of histidine-requiring mutants of Salmonella typhimurium or
in the E_, coli WP2 system (Anderson et al., 1972; Anderson, 1976;
Simmon et al., 1979; Shimizu et al., 1983; NTP, 1985; NTP, 1986).
However, all three isomers increased the frequency of back mutation
of the methionine-requiring locus in the fungus Aspergillus nidulans
(Prasad and Pramer, 1968; Prasad, 1970). In addition, the meta
isomer was shown to increase mitotic recombination in the Saccharomyces
cerevisiae C3 yeast system (Simmon et al., 1979). The results with
the para isomer were ambiguous. These investigators also showed that
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both o- and m-DCB interacted with and damaged bacterial DNA in the
E. coli W3110 polA+/p3478 polA" differential toxicity assay system.
Treatment with p-DCB did not induce forward mutations in mouse lymphoma
cells (NTP, 1986), sister-chromatid exchange in Chinese hamster ovary
cells (NTP, 1986), and unscheduled DMA synthesis in human lymphocytes
(Perocco et al., 1983).
0 DCB has not been found to be mutagenic in animals. Guerin et al.
(1971) showed that DCB (unspecified isomer) did not produce a sig-
nificantly different number of mitoses in rat lung cell cultures.
Cytogenetic studies with rat bone marrow cells and a dominant lethal
study in CD-1 mice following exposure to p-DCB were all negative
(Anderson and Hodge, 1976; Anderson and Richardson, 1976; NTP, 1986).
Carcinogenicity
8 Hollingsworth et al. (1956, 1958) exposed several species of animals
to various oral and inhalation exposures of ortho- and para-dichloro-
benzene for six to seven months. No evidence of carcinogenicity was
observed; however, the exposure duration was too short to allow
conclusions on carcinogenicity to be drawn.
0 An assessment of the data from an NTP bioassay using o-DCB administered
by gavage indicates that, under the conditions of the study, this
substance is not carcinogenic in Fischer 344 rats or B6C3Fi mice
(NTP, 1985). The NTP Board of Scientific Counselors added that no
non-neoplastic lesions were noted in either the mice or the rats,
suggesting that the maximum tolerated dose was not achieved. Both
rats and mice (50/sex/dose) were given o-DCB in corn oil by gavage
5 days/week for 103 weeks at doses of 0, 60 or 120 mg/kg. No effect
on survival, body weight, and pathology was noted except for lower
(p <0.001) survival in high-dose male rats and increased tubular
regeneration in kidney of high-dose male mice.
0 In an NTP (1986) bioassay on p-DCB in F344 rats and B6C3F-J mice,
treatment-related neoplastic effects include renal adenocarcinomas in
male rats (1/50, controls; 3/50, low dose, p >0.05; 7/50, high dose,
p <0.05) and carcinomas and adenomas in liver of high-dose male and
female mice (P <0.001). Rats and mice (50/sex/group) were given
p-DCB in corn oil by gavage 5 days/week for 103 weeks at 0, 150 or
300 mg/kg (male rats) and 0, 300 or 600 mg/kg (remaining groups).
Other treatment-related effects include kidney lesions in male and
female rats at both doses, kidney and liver lesions in male and
female mice at both doses, and reduced survival (p <0.05) in high-dose
male rats.
0 A long-term (76 weeks exposure, 36 weeks further observation) inhalation
study revealed no increase in tumor incidence or type after exposure
to p-DCB in Alderley Park Wistar rats (Riley et al., 1980, summarized
in Loeser and Litchfield, 1983). At the high exposure level (500 ppm),
observed effects included increases in liver, kidney, heart and lung
weights (both sexes) and an increase in urinary protein and copropor-
phyrin output (males). The low exposure level of 75 ppm was a NOAEL.
The 500 and 75 ppm levels equal 3,005 and 451 mg/m3, respectively.
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V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) X (BW) = mg/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in rag/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
o-Dichlorobenzene (and/or m-Dichlorobenzene)
One-day and Ten-day Health Advisories
No satisfactory dose-response data are available from which to derive a
One-day HA or Ten-day HA for the 10-kg child. It is recommended, that for
this duration of exposure, the Longer-term HA for the 10-kg child (8.93 mg/L)
be applied (see below).
Longer-term Health Advisory
Subchronic treatment studies with o-DCB in rats and mice were conducted
in which daily doses were administered in corn oil by gavage at dose levels
of 30, 60, 125, 250 and 500 mg/kg/day five days/week for 13 weeks (Battelle
Columbus, 1978c,i). The NOAEL in these studies was 125 mg/kg. Renal and
hepatic lesions, lower body weights and increased uro- and coproporphyrin
levels were found with higher doses.
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA = (125 mg/kg/day) (10 kg) (5) = 8i93 mg/Ij (8,930 Ug/L)
(100) (1 L/day) (7)
where:
125 mg/kg/day = NOAEL based on absence of renal and hepatic effects
in rats and mice exposed to o-DCB for 13 weeks.
10 kg = assumed body weight of a child.
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5/7 m conversion of 5 day/week dosing regimen to 7 day/week
exposure pattern.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
For a 70-kg adult consuming 2 L of water per day, the Longer-term HA is
calculated as follows:
Longer-term HA = (125 mg/kg/dav) (70 kg) (5) , 31>25 mg/L (31,250 ug/L)
(100) (2 L/day) (7)
125 mg/kg/day = NOAEL based on absence of renal and hepatic effects
in rats and mice exposed to o-DCB for 13 weeks.
70 kg = assumed body weight of an adult.
5/7 = conversion of 5 day/week dosing regimen* to 7 day/week
exposure pattern.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
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The fact that the HAs generated from the chronic studies in the KTP
bioassay with a NOAEL of 120 mg/kg/day would be larger than those derived
from the subchronic studies preceding them with a NOAEL of 125 mg/kg/day
would suggest that the extra 10-fold uncertainty factor used with the
subchronic data to estimate a Lifetime HA from subchronic data may not be
necessary for this compound. However, the chronic studies offer a narrower
evaluation of toxicity in that urinalysis, clinical chemistry and hematology
were not included in the chronic study protocols. In view of this considera-
tion, the extra 10-^old uncertainty factor may be appropriate.
The results of Hollingsworth et al. (1958) suggest a safe daily level
of 0.94 rag/day to be used in the calculation of a lifetime HA, while those of
the subchronic studies preceding the NTP bioassay suggest a level of 6.25
mg/day. Each of these levels was derived from a NOAEL (18.8 mgAg and 125
mg/kg, respectively). Since the highest NOAEL should be used to derive a
Lifetime HA, it is more appropriate to use the NOAEL established in the NTP
subchronic studies than the NOAEL from the Hollingsworth study. Furthermore,
the minimal effect dose identified in the Hollingsworth study (188 mg/kg) is
somewhat higher than the NOAEL established in the NTP subchronic studies.
The Lifetime HA is, therefore, calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (125 mg/kg/day) (5) = Q.089 mg/kg/day (89 ug/kg/day)
(1,000) (7)
where:
125 mg/kg/day = NOAEL used for Longer-term HA.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
5/7 = conversion of 5 day/week dosing to 7 day/week.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.089 mg/kg/day) (70 kg) = 3>13 mg/L (3,125 ug/L)
(2 L/day)
where:
0.089 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = 3.13 mg/L x 20% =0.62 mg/L (620 ug/L)
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where:
3.13 mg/L = DWEL.
20% = assumed relative source contribution from water.
m-Dichlorobenzene
There are no toxicity studies on jn-DCB on which to base Health Advisories;
however, because certain properties of o-DCB and m-DCB are similar, the HAs
for o-DCB are recommended for m-DCB (U.S. EPA, 1987).
p-Dichlorobenzene
One-day and Ten-day Health Advisories
No satisfactory dose-response data are available from which to derive
a One-day HA or a Ten-day HA for p-DCB for the 10-kg child. It is recommended
that for this duration of exposure, the Longer-term HA for the 10-kg child
(10.7 mg/L) be applied (see below).
Longer-term Health Advisory
The 90-day treatment study with p-DCB by Battelie-Columbus (1979a) is
selected for calculation of a Longer-term HA; results in rats were used since
they indicated a lower NOAEL compared to that in mice (Battelie-Columbus,
1979b). In addition, a 90-day study is considered to provide a stronger
evaluation of toxicity than 14-day treatment studies which preceded the
90-day studies. The rats were given p-DCB in corn oil by gavage, 5 days/week,
for 13 weeks. The NOAEL was 150 mg/kg/day since renal lesions were observed
in males at higher doses.
The Longer-term HA for the 10-kg child is calculated as follows:
Longer-term HA = (ISO mg/kg/day) (10 kg) (5) = 10.7 mg/Ii (TO,700 ug/L)
(100) (1 L/day) (7)
where:
150 mg/kg/day = NOAEL, based on absence of renal lesions.
10 kg = assumed body weight of a child.
5/7 = conversion of 5 day/week dosing regimen to 7 day/week
exposure pattern.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
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Ortho-, Meta-, and Para-Dichlorobenzenes March 31, 1987
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For a 70-kg adult, the Longer-term HA is calculated as follows:
Longer-term HA = (150 mg/kg/day) (70 kg) (5) =37.5 mg/L (37,500 ug/L)
(100) (2 L/day) (7)
where:
150 mg/kg/day = NOAEL, based on absence of renal lesions.
70 kg = assumed body weight of an adult.
5/7 = conversion of 5 day/week dosing regimen to 7 day/week
exposure pattern.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
p-Pichlorobenzene
The EPA has developed for comparison with cancer-based criteria, a
presumed safe daily intake level based on non-carcinogenic effects as indicated
in U.S. EPA (1987). For consistency, the rationale used by EPA for the
calculation of this value by U.S. EPA (1987) is used here for the DWEL
calculation. The rationale as presented in U.S. EPA (1987) is as follows:
The results of the Hollingsworth et al. (1956) study and the subchronic
studies preceding the NTP bioassay, as well as the acute toxicity studies
described earlier, indicate that the rat is somewhat more sensitive to p-DCB
toxicity than is the mouse. Therefore, when estimating potential risk to the
human, the data from the experiments in the rat should be used in deriving a
Lifetime HA.
The NOAEL derived from the Hollingsworth study was 18.8 mg/kg; the
NOAEL from the NTP subchronic study in the rat was 150 mg/kg. Since the
highest NOAEL should be used to calculate a daily level of intake, the NOAEL
established in the NTP subchronic study will be used. In addition, it should
be noted that the minimal effect level identified in the Hollingsworth study
(188 mg/kg) was somewhat higher than the NOAEL established in the NTP sub-
chronic study.
As with o-DCB (and m-DCB), any Lifetime Health Advisories derived from
the NTP chronic studies might be higher than those derived from the subchronic
studies preceding them because the 10-fold uncertainty factor applied to
accommodate for the difference in duration of exposure may be unnecessarily
large. However, as mentioned for o-DCB, the lack of certain parameters in
the chronic study (urinalysis, clinical chemistry and hematology) may make
the use of a 10-fold uncertainty factor appropriate. Also, the finding
of renal lesions with 150 mg/kg/day in the NTP (1986) chronic study in rats
further supports use of an extra 10-fold uncertainty factor.
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Ortho-, Meta-, and Para-Dichlorobenzenes March 31, 1987
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The Lifetime HA is, therefore, calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (ISO mg/kg/day) (5) = 0.-, mg/kg/day (100 ug/kg/day)
(1,000) (7)
where:
150 mg/kg/day = NOAEL used for Longer-term HA.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
5/7 = conversion of 5 day/week dosing to 7 day/week.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.1 mg/kg/day) (70 kg) =3.75 mg/L (3,750 ug/L)
(2 L/day)
where:
0.1 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (3.75 mg/L) (20%) = 0.075 mg/L (75 Ug/L)
10
where:
3.75 mg/L = DWEL.
20% = assumed relative source contribution from water.
10 = additional uncertainty factor for Group C carcinogens per
Office of Drinking Water policy.
Evaluation of Carcinogenic Potential
0 Assessment of the NTP bioassay on o-DCB suggests that it was not
carcinogenic under the conditions of the experiment.
0 No adequate data are available to assess the potential cancer risk
associated with exposure to m-DCB,
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Ortho-, Meta-, and Para-Dichlorobenzenes March 31, 1987
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0 The IARC (1982) classified both p-DCB and o-DCB as Group 3 chemicals
with inadequate evidence for carcinogenicity in animals and humans.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986a), o-DCB and m-DCB may be classified
in Group D: Not classified. This category is for agents with inade-
quate animal evidence of carcinogenicity.
0 Because of positive evidence in two animal species, p-DCB may be
placed in category B2 (sufficient animal evidence, inadequate human
evidence) by these guidelines. However, consideration of the overall
weight of evidence could suggest the alternative view that p-DCB be
placed in Group C (limited animal evidence) by these guidelines, with
respect to uncertainties with high doses and corn oil gavage and
diminished toxicological significance of the mouse liver tumor results.
The EPA has concluded that the overall weight of evidence favors
classification of p-DCB in Group C (U.S. EPA, 1987).
0 Because p-DCB is considered a Group C agent, the DWEL would be divided
by an extra uncertainty factor of 10 to yield 0.375 mg/L.
0 Provisional cancer potency estimates for p-DCB were derived using the
multistage model and the liver tumor data on male mice in the chronic
feeding study by NTP (1986).
o Tne 95% upper-limit carcinogenic potency factor for humans, q^*, is
2 x 10~2 (mg/kg/day)-1 by the multistage model (U.S. EPA, 1986b).
For a 70 kg human drinking 2 L water/day, the water concentration
should be 17.5 ug/L in order to keep the upper-limit individual
lifetime cancer risk at 10"^. Water concentrations corresponding to
excess cancer risk of 10~4 and 10~6 are, therefore, 175 and 1.8 ug/L,
respectively. Maximum likelihood estimates by the multistage model
associate risks of 10~5 and 10"^ with exposures to 20.7 and 6.3 mg/L,
respectively. There are not enough distinct data points to allow fits
to other models tried (Weibull, logit, probit). while recognized as
statistically alternative approaches, the range of risks described by
using any of these modeling approaches has little biological signifi-
cance unless data can be used to support the selection of one model
over another. In the interest of consistency of approach and in
providing an upper bound on the potential cancer risk, the EPA has
recommended use of the linearized multistage approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The OSHA standard for 1,2-dichlorobenzene is 50 ppm (300 mg/m3) (U.S.
EPA, 1985a).
0 The 1982 ACGIH TLV is 50 ppm (U.S. EPA, 1985a).
0 The OSHA standard for 1,4-dichlorobenzene is 75 ppm (450 mg/m3)
(U.S. EPA, 1985a).
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Ortho- M»t-a-, and Para-Dichlorobenzenes March 31, 1987
-16-
0 The dichlorobenzene isomers are designated as hazardous wastes under
the Resource Conservation and Recovery Act (RCRA) (U.S. EPA, 1985a).
0 Under the Federal Water Pollution Control Act, 1,2-di- and 1,4-dichloro-
benzenes are hazardous substances with reportable quantities of 100 Ibs.
0 The ambient water quality criterion for dichlorobenzenes is 400 ug/L,
using a NOAEL of 13.4 mg/kg/day and an uncertainty factor of 1,000
(U.S. EPA, 1980).
0 The WHO (1984) recommended an acceptable drinking water level of 1 ug/L
for 1,2- and 1,4-dichlorobenzenes based on odor threshold.
0 The NAS (1983) calculated a chronic SNARL of 0.3 mg/L for o-DCB,
using a NOAEL of 60 mg/kg, 20% relative source contribution, and a
1,000-fold uncertainty factor.
0 The NAS (1977) calculated a chronic SNARL of 0.094 mg/L for p-DCB,
using a NOAEL of 13.4 mg/kg/day, a relative source contribution of
20%, and an uncertainty factor of 1,000.
0 The proposed RMCL for o-DCB is 0.62 mg/L (U.S. EPA, 1985b).
0 The U.S. EPA Office of Drinking Water issued a final RMCL of 0.75 mg/L,
a proposed MCL of 0.75 mg/L, and a practical quantitation level of 5
ug/L for p-DCB (U.S. EPA, I985c). However, p-DCB is being considered
for reproposal as a result of the recent positive NTP (1986) carcino-
genicity bioassay.
VII. ANALYTICAL METHODS
0 Analysis of dichlorobenzene(s) is by a purge-and-trap gas chromato-
graphic procedure used for the determination of volatile organohalides
in drinking water (U.S. EPA, 1985d). This method calls for the
bubbling of an inert gas through the sample and trapping dichloro-
benzene(s) on an adsorbant material. The adsorbant material is
heated to drive off the dichlorobenzene(s) onto a gas chromatographic
column. The gas chromatograph is temperature programmed to separate
the method analytes which are then detected by a halogen specific
detector. This method is applicable to the measurement of dichloro-
benzene(s) over a concentration range of 0.05 to 1500 ug/L. Con-
firmatory analysis for dichlorobenzene(s) is by mass spectrometry
(U.S. EPA, 1985e). The detection limit for confirmation by mass
spectrometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Granular activated carbon (GAG) adsorption and aeration for the
removal of ortho-, meta- and para-dichlorobenzene from water are
available and have been reported to be effective. Because ortho-,
meta- and para-dichlorobenzene are chemically similar, they can be
considered together (U.S. EPA, 1985f).
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Ortho-, Meta-, and V
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Ortho-, Meta-, and Para-Dichlorobenzenes March 31, 1987
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