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Dibromochloromethane (CASRN 124-48-1)
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0222
Dibromochloromethane;
CASRN 124-48-1
Health assessment information on a chemical substance is included in IRIS
only after a comprehensive review of chronic toxicity data by U.S. EPA
health scientists from several Program Offices and the Office of Research
and Development. The summaries presented in Sections I and II represent
a consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Dibromochloromethane
File First On-Line 09/30/1987
Category (section) |
Status |
Last Revised |
|---|---|---|
| Oral RfD Assessment (I.A.) | on-line | 03/01/1991 |
| Inhalation RfC Assessment (I.B.) | no data | |
| Carcinogenicity Assessment (II.) | on-line | 01/01/1992 |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Dibromochloromethane
CASRN — 124-48-1
Last Revised — 03/01/1991
The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.
__I.A.1. Oral RfD Summary
Critical Effect |
Experimental Doses* |
UF |
MF |
RfD |
|---|---|---|---|---|
|
Hepatic lesions Rat, Subchronic NTP, 1985 |
NOEL: 30 mg/kg/day LOAEL: 60 mg/kg/day |
1000
|
1
|
2E-2
mg/kg/day |
*Conversion Factors -- Dose adjusted for gavage schedule (5\days/week).
__I.A.2. Principal and Supporting Studies (Oral RfD)
NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis
Studies of Chlorodibromomethane in F344/N Rats and B6C3F1 mice (gavage
studies). NTP TR282.
Groups of 10 F344/N rats of each sex and 10 B6C3F1 mice of each sex were
administered 0, 15, 30, 60, 125, or 250 mg DBCM/kg/day by gavage for
5\days/week for 13 weeks. At 250 mg/kg/day, male mice showed increased
incidence of vacuolar change (fatty metamorphosis) in the liver and toxic
nephrosis. Both sexes of rats showed increased incidences of liver vacuolar
change, centrilobular necrosis, toxic nephropathy, and salivary gland
inflammation and squamous metaplasia at 250 mg/kg/day. Vacuolar changes in
the livers of lower-dose male rats were also increased. A Fisher Exact test
showed that incidences of these liver lesions at doses of 60 mg/kg/day or
above were elevated relative to the vehicle controls, thus 30 mg/kg/day is the
NOEL.
In the chronic bioassay portion of the NTP (1985) study, 50 F344/N rats of
each sex were administered 0, 40, or 80 mg DBCM/kg/day by gavage for 104 weeks
and 50 B6C3F1 mice of each sex were similarly treated with 0, 50, or 100 mg
DBCM/kg/day for 105 weeks. Treatment was 5 days/week. A dose-related
increase in liver fatty changes and ground glass cytoplasmic changes in
treated rats of both sexes was reported. Treated female rats also had higher
incidences of kidney nephrosis. Treated mice of both sexes exhibited higher
incidences of hepatomegaly, fatty metamorphosis, calcification, and liver
necrosis. The incidence of nephrosis was increased in dosed males and thyroid
follicular cell hyperplasia was increased in dosed female mice. The LOAELS
for this portion of the study are 40 mg/kg/day for rats and 50 mg/kg/day for
mice.
The results in these chronic bioassays support the subchronic studies used as
a basis of the RfD. In this case, the choice of the subchronic NOAEL as the
basis of the RfD rather than the chronic LOAEL (either choice normally
requires a 1000 UF, and the resulting RfDs are similar), reflects the slightly
greater confidence in the subchronic NOAEL versus the chronic LOAEL that was
associated with several adverse effects.
__I.A.3. Uncertainty and Modifying Factors (Oral RfD)
UF — Factors of 10 each were employed for use of a subchronic assay, for
extrapolation from animal data, and for protection of sensitive human
subpopulations.
MF — None
__I.A.4. Additional Comments (Oral RfD)
No adequate data on the teratogenic or reproductive effects of trihalomethanes are available.
__I.A.5. Confidence in the Oral RfD
Study — Medium
Database — Medium
RfD — Medium
The NTP (1985) subchronic bioassays utilized adequate numbers of animals of both sexes of two species; multiple endpoints were measured, including complete histopathology; thus confidence in the chosen study is medium. NTP also published supporting chronic studies of dibromochloromethane, but without adequate reproductive or teratology bioassays, the database is given medium confidence. Medium confidence in the RfD follows.
__I.A.6. EPA Documentation and Review of the Oral RfD
Source Document — U.S. EPA, 1985
The 1985 Drinking Water Criteria Document for Trihalomethanes is currently
undergoing Agency Review.
Other EPA Documentation — None
Agency Work Group Review — 12/02/1985, 02/05/1986, 05/14/1986, 08/13/1987
Verification Date — 08/13/1987
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Dibromochloromethane conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — Dibromochloromethane
CASRN — 124-48-1
Not available at this time.
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — Dibromochloromethane
CASRN — 124-48-1
Last Revised — 01/01/1992
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
_II.A. Evidence for Human Carcinogenicity
__II.A.1. Weight-of-Evidence Characterization
Classification — C; possible human carcinogen
Basis — Based on inadequate human data and limited evidence of
carcinogenicity in animals; namely, positive carcinogenic evidence in B6C3Fl
mice (males and females), together with positive mutagenicity data, and
structural similarity to other trihalomethanes, which are known animal
carcinogens.
__II.A.2. Human Carcinogenicity Data
Inadequate. There are no epidemiologic studies of dibromochloromethane alone. Dibromochloromethane is one of several trihalomethanes (including chloroform, bromodichloromethane, and bromoform) which are formed from the interaction of chlorine with the organic materials found in water. Several ecologic studies (Cantor et al., 1978; Aldrich and Peoples, 1982; Isacson et al., 1983) and case-control studies (Young and Kanarek, 1983; Cantor et al., 1987) suggest a positive correlation between drinking chlorinated water and the incidence of several human cancers, particularly bladder, rectal and colon cancer. Although both types of studies have design limitations, which might include lack of individual information; misclassification of exposure; or no controls for diet, smoking, or alcohol consumption, the agreement of findings in several independent studies strengthens the association between drinking chlorinated water and cancer (Cantor, 1983; Crump, 1983; Crump and Guess, 1982). In all studies, the cases were exposed to a mixture of compounds, including chloroform, which is considered to be a probable human carcinogen. The data collected are inadequate for assessing the carcinogenic potential of dibromochloromethane.
__II.A.3. Animal Carcinogenicity Data
Limited. In a 2-year carcinogenicity study, 50 F344/N rats/sex/dose were
treated by gavage with dibromochloromethane (>98% pure) in corn oil at 0, 40,
or 80 mg/kg, 5 days/week for 104 weeks (NTP, 1985). Groups of B6C3F1 mice
(50/sex/dose) were similarly gavaged at doses of 0, 50, or 100 mg/kg, 5
days/week for 105 weeks. In rats, the final survival rates of all groups were
comparable (approximately 76%); mean body weights were also comparable between
dose groups in each sex, except for a decrease in the high-dose males after
week 20. No compound-related clinical signs were seen, and no evidence for
carcinogenicity was seen in rats under these study conditions.
In mice, the mean body weights of both male and female high-dose groups
were lower than those of their respective controls throughout the study.
Mean body weight of the low-dose male mice was lower than the control group
after both low-dose groups received an overdose of chemical in week 58.
Survival of low- and high-dose males was significantly lower than the control
group; the percent survival was 88, 14, and 58% in the control, low-, and
high-dose groups, respectively (70% of the low-dose males were accidentally
killed). The survival rate in females was comparable for all groups
(approximately 63%). In female mice, the incidence of hepatocellular adenomas
and the combined incidence of hepatocellular adenomas and carcinomas were
statistically significantly increased in the high-dose group. The incidence
of adenomas was 2/50, 4/49, and 11/50; the incidence of carcinomas was 4/45,
6/49, and 8/50; and the combined incidence was 6/50, 10/49, and 19/50 for
female mice in the 0, 50, and 100 mg/kg dose groups, respectively. In high-
dose male mice, there was a significantly increased incidence of
hepatocellular carcinomas; however, the combined incidence of hepatocellular
adenomas and carcinomas was only marginally increased. The incidence of
adenomas was 14/50, 5/50, and 10/50; the incidence of carcinomas was 10/50,
9/50, and 19/50; and the combined incidence of adenomas and carcinomas was
23/50, 14/50, and 27/50 for the 0, 50, and 100 mg/kg dose groups,
respectively. Under the conditions of this study, NTP (1985) determined that
there was equivocal evidence of carcinogenicity of dibromochloromethane in
male mice, and some evidence of carcinogenicity in female mice.
Voronin et al. (1987) observed no significant tumor increases in groups
of 50 CBAxC57B1/6 mice/sex treated with dibromochloromethane in the drinking
water at concentrations of 0, 0.04, 4.0, or 400 mg/L (0, 0.008, 0.76, or 76
mg/kg/day) for 104 weeks.
Preliminary results of an unpublished 2-year dietary study using groups of
40 SPF Wistar rats reported no increase in gross tumors in male rats treated
with dibromochloromethane at doses of 10, 39, or 210 mg/kg/day, or in female
rats treated at doses of 17, 66, or 350 mg/kg/day. Control groups consisted
of 70 rats/sex. Only 5 or 7 rats/sex/dose group were examined following 18 or
24 months of exposure (Tobe et al., 1982).
__II.A.4. Supporting Data for Carcinogenicity
Dibromochloromethane has been shown to produce reverse mutations in
Salmonella typhimurium strain TA100 in a vapor-phase test performed in a
desiccator (Simmon et al., 1977). Results were not positive when plate
incorporation (Simmon et al., 1977) or preincubation (NTP, 1985; Zeiger et
al., 1987) methods were used. Nestmann and Lee (1985) reported positive
results for gene conversion in Saccharomyces cerevisiae strain D4 without, but
not with, hepatic homogenates, and negative results for mutation in strain
XV185-14C both with and without hepatic homogenates. Dibromochloromethane
produces sister chromatid exchange in cultured human lymphocytes and in bone
marrow cells of mice treated orally (Morimoto and Koizumi, 1983).
Dibromochloromethane is structurally similar to known animal carcinogens
such as bromodichloromethane, bromoform, and chloroform (B2, probable human
carcinogens).
_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
__II.B.1. Summary of Risk Estimates
Oral Slope Factor — 8.4E-2 per (mg/kg)/day
Drinking Water Unit Risk — 2.4E-6 per (ug/L)
Extrapolation Method — Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level
|
Concentration
|
|---|---|
|
E-4 (1 in 10,000)
|
4E+1 ug/L
|
|
E-5 (1 in 100,000)
|
4E+0 ug/L
|
|
E-6 (1 in 1,000,000)
|
4E-1 ug/L
|
__II.B.2. Dose-Response Data (Carcinogenicity, Oral Exposure)
Tumor Type: hepatocellular adenoma or carcinoma
Test animals: mouse/B6C3F1, female
Route: gavage
Reference: NTP, 1985
|
Administered
Dose (mg/kg/day) |
Human Equivalent
Dose (mg/kg/day) |
Tumor
Incidence |
|---|---|---|
|
0
|
0
|
6/50
|
|
50
|
35.71
|
10/49
|
|
100
|
71.43
|
19/50
|
__II.B.3. Additional Comments (Carcinogenicity, Oral Exposure)
The unit risk should not be used if the water concentration exceeds 4E-3 mg/L, since above this concentration the slope factor may differ from that stated.
__II.B.4. Discussion of Confidence (Carcinogenicity, Oral Exposure)
An adequate number of animals of both sexes were treated for an adequate duration of exposure at two dose levels. Comprehensive histopathological and statistical analyses were performed. The compound was given by gavage rather than in feed or drinking water; exposure to a chemical through oral gavage is different from exposure through drinking water. Exposure could be overestimated leading to an underestimate of potency.
_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
Not available.
_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)
__II.D.1. EPA Documentation
Source Document — U.S. EPA, 1988
The 1988 Health and Environmental Effects Document for Dibromochloromethane is
an external draft for review purposes. It has received OHEA review.
__II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review — 09/07/1989
Verification Date — 09/07/1989
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Dibromochloromethane conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__II.D.3. EPA Contacts (Carcinogenicity Assessment)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI. Bibliography
Substance Name — Dibromochloromethane
CASRN — 124-48-1
Last Revised — 11/01/1990
_VI.A. Oral RfD References
NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis
Studies of Chlorodibromomethane in F344/N Rats and B6C3F1 mice (gavage
studies). NTP TR282.
U.S. EPA. 1985. Drinking Water Criteria Document for Trihalomethanes.
Office of Drinking Water, Washington, DC. External Review Draft.
_VI.B. Inhalation RfD References
None
_VI.C. Carcinogenicity Assessment References
Aldrich, T.E. and A.J. Peoples. 1982. Malignant melanoma and drinking water
contamination. Bull. Environ. Contam. Toxicol. 28(5): 519-523.
Cantor, K.P. 1983. Epidemiologic studies of chlorination by-products in
drinking water: An overview. In: Water Chlorination, Environmental Impact
and Health Effects, Vol. 4, Part 2. Environment, Health and Risk, R.L.
Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs,
Ed. Proceed. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor
Science Publ., Inc., Ann Arbor, MI. p. 1381-1398.
Cantor, K.P., R. Hoover, T.J. Masso and L.J. McCabe. 1978. Associations of
cancer mortality with halomethanes in drinking water. J. Natl. Cancer Inst.
61: 979-985.
Cantor K.P., R. Hoover, P. Hartge et al. 1987. Bladder cancer, drinking
water source, and tap water consumption: A case-control study. J. Natl.
Cancer Inst. 79(6): 1269-1279.
Crump, K.S. 1983. Chlorinated drinking water and cancer: The strength of the
epidemiologic evidence. In: Water Chlorination, Environmental Impact and
Health Effects, Vol. 4, Part 2. Environment, Health and Risk, R.L. Jolley,
W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed.
Proceed. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science
Publ., Inc., Ann Arbor, MI. p. 1481-1491.
Crump, K.S. and H.A. Guess. 1982. Cancer: Review of recent epidemiological
findings and assessment of risks. Ann. Rev. Public Health. 3: 339-357.
Isacson, P., J.A. Bean and C. Lynch. 1983. Relationship of cancer incidence
rates in Iowa USA municipalities to chlorination status of drinking water.
In: Water Chlorination, Environmental Impact and Health Effects, Vol. 4,
Part 2. Environment, Health and Risk, R.L. Jolley, W.A. Brungs, R.B. Cumming,
J.S. Mattice and V.A. Jacobs, Ed. Proceed. 4th Conference, Pacific Grove, CA.
October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. p. 1353-1364.
Morimoto, K. and A. Koizumi. 1983. Trihalomethanes induce sister chromatid
exchanges in human lymphocytes in vitro and mouse bone marrow cells in vivo.
Environ. Res. 32(1): 72-79.
Nestmann, E.R. and E.G.H. Lee. 1985. Genetic activity in Saccharomyces
cerevisiae of compounds found in effluents of pulp and paper mills. Mutat.
Res. 155(1-2): 53-60.
NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis
studies of chlorodibromomethane (CAS No. 124-48-1) in F344/N rats and B6C3F1
mice (gavage studies). NTP Tech. Report Series No. 282. NTIS PB 86-166675.
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.
Tobe, M., Y. Suzuki, K. Aida et al. 1982. Studies on the chronic oral
toxicity of tribromomethane, dibromochloromethane and bromodichloromethane.
Unpublished intraagency report to the National Institute of Hygienic
Sciences. Tokyo Medical and Dental University, Tokyo, Japan. p. 8-43.
U.S. EPA. 1988. Health and Environmental Effects Document for
Dibromochloromethane. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste and Emergency Response, Washington, DC. ECAO-CIN-
GO40.
Voronin, V.M., A.I. Donchenko and A.A. Korolev. 1987. An experimental study
of the carcinogenicity of dichlorobromomethane and dibromochloromethane
released during the water chlorination process. Gig. Sanit. 0(1): 19-21.
Young, T.B. and M.S. Kanarek. 1983. Matched pair case control study of
drinking water chlorination and cancer mortality. In: Water Chlorination,
Environmental Impact and Heath Effects, Vol. 4, Part 2. Environment Health
and Risk, R.L. Jolley, W.A. Brungs, R.B. Cumming, J.S. Mattice and V.A.
Jacobs, Ed. Proceed. 4th Conference, Pacific Grove, CA, October 18-23. Ann
Arbor Science Publ., Ann Arbor, MI. p. 1365-1380.
Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Mortelmans and W. Speck.
1987. Salmonella mutagenicity tests: III. Results from the testing of 255
chemicals. Environ. Mutagen. 9(Suppl. 9): 1-4, 12-18, 20, 43.
_VII. Revision History
Substance Name — Dibromochloromethane
CASRN — 124-48-1
|
Date |
Section |
Description |
|---|---|---|
| 06/30/1988 | I.A.7. | Primary contact changed |
| 08/01/1989 | VI. | Bibliography on-line |
| 10/01/1989 | II. | Carcinogen assessment now under review |
| 11/01/1990 | I.A. | Text edited |
| 11/01/1990 | II. | Carcinogen assessment on-line |
| 11/01/1990 | IV.F.1. | EPA contact changed |
| 11/01/1990 | VI.C. | Carcinogen references added |
| 03/01/1991 | I.A.7. | Primary contact changed |
| 08/01/1991 | II.B.1. | Concentration levels corrected |
| 01/01/1992 | II.B.2. | Doses: Add transformed animal; human equivalent change |
| 01/01/1992 | II.B.4. | Last sentence of paragraph added |
| 01/01/1992 | IV. | Regulatory actions updated |
| 04/01/1997 | III.,IV.,V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
| 12/03/2002 | I.A.6., II.D.2. | Screening-Level Literature Review Findings message has been added. |
| 02/05/2003 | I., II. | This chemical is being reassessed under the IRIS Program. |
_VIII. Synonyms
Substance Name — Dibromochloromethane
CASRN — 124-48-1
Last Revised — 09/30/1987
- 124-48-1
- Chlorodibromomethane
- Dibromochloromethane
- Dibromomonochloromethane
- Methane, dibromochloro-
- Monochlorodibromomethane