Hexachloroethane (CASRN 67-72-1) | IRIS
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0167
Hexachloroethane; CASRN 67-72-1
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 Hexachloroethane
File First On-Line 03/31/1987
Category (section) |
Status |
Last Revised |
---|---|---|
Oral RfD Assessment (I.A.) | on-line | 04/01/1991 |
Inhalation RfC Assessment (I.B.) | no data | 12/01/1992 |
Carcinogenicity Assessment (II.) | on-line | 02/01/1994 |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Hexachloroethane
CASRN — 67-72-1
Last Revised — 04/01/1991
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
|
---|---|---|---|---|
Atrophy and Rat Subchronic Gorzinski et al., 1985 |
NOAEL: 1 mg/kg/day LOAEL: 15 mg/kg/day |
1000
|
1
|
1E-3
mg/kg/day |
*Conversion Factors: The doses were estimated by the investigators from body weights, food consumption and diet analysis data.
__I.A.2. Principal and Supporting Studies (Oral RfD)
Gorzinski, S.J., R.J. Nolan, S.B. McCollister, R.J. Kociba and J.L. Mattsson. 1985. Subchronic oral toxicity, tissue distribution and clearance of hexachloroethane in the rat. Drug Chem. Toxicol. 8(3): 155-169.
Groups of 10 male and 10 female Fischer 344 rats were treated with diets containing hexachloroethane for 16 weeks. Dosages were 0, 1, 15, or 62 mg/kg/day, as determined by the investigators. The rats were evaluated for overt signs of toxicity; body weight gain; food consumption; urinalysis, hematological, and clinical chemistry parameters; organ weights; and gross pathology. Comprehensive histologic examination was performed on the control and 62-mg/kg/day groups, while histologic examination of the 1- and 15- mg/kg/day groups was limited to the liver and kidney. At 15 and 62 mg/kg/day, male rats had dose-related increased incidences of renal lesions, including renal atrophy, degeneration, hypertrophy, and dilation. At 62 mg/kg/day, males had increased absolute and relative kidney weights and peritubular fibrosis; females had slight renal tubular atrophy and increased liver weights. No other effects were observed. Thus, 15 mg/kg/day is the LOAEL and 1 mg/kg/day is the NOAEL.
__I.A.3. Uncertainty and Modifying Factors (Oral RfD)
UF — An uncertainty factor of 1000 was used: 10 to account for interspecies extrapolation, 10 for the range of sensitivity within the human population to xenobiotics and 10 for the use of a subchronic study.
MF — None
__I.A.4. Additional Studies/Comments (Oral RfD)
The quality assessment of another chronic gavage bioassay in rats is in progress (NTP, 1986), but a draft report of results of the preliminary subchronic gavage study is available (NTP, 1983). In this study, rats were treated by gavage with 0, 47, 94, 188, 375, or 750 mg/kg/day, 5 days/week for 13 weeks. Body weight gain was reduced at 750 mg/kg/day, behavioral signs of toxicity were seen at 94 mg/kg/day, and increased relative liver and kidney weights occurred at 375 mg/kg/day. Dose-related increased incidences of renal tubular regeneration occurred at 47 mg/kg/day.
In a 6-week inhalation study, rats, dogs, and guinea pigs were exposed to hexachloroethane 6 hours/day, 5 days/week for 6 weeks at 0, 145, 465, or 2520 mg/cu.m (Weeks et al., 1979). Neurobehavioral effects occurred in rats and dogs, and reduced body weights, increased relative liver weights, and deaths occurred in guinea pigs at 2520 mg/cu.m. No effects were observed at 465 mg/cu.m. Based on this inhalation NOAEL in rats, an RfD of 0.03 mg/kg/day could be calculated using an uncertainty factor of 1000. However, the more recent 16-week oral study by Gorzinski et al. (1985) is a better basis for the RfD.
Hexachloroethane has been tested for teratogenicity by oral and inhalation administration to rats. At gavage doses of 500 mg/kg/day during gestation there was maternal toxicity, a reduced gestation index, and reduction in the numbers of fetuses/dam, and increased fetal resorption rates (Weeks et al., 1979). No effects occurred at 50 or 100 mg/kg/day. Weeks et al. (1979) administered hexachloroethane to rats by inhalation at 145, 465, or 2520 mg/cu.m, 6 hours/day during gestation. At the two highest doses, maternal toxicity was observed but there was no evidence of fetoxicity or teratogenicity.
__I.A.5. Confidence in the Oral RfD
Study — Medium
Database — Medium
RfD — Medium
Medium to high confidence is placed in the Gorzinski et al. (1985) study because, although it defined a NOAEL and a LOAEL, the study used small groups of animals. Confidence in the database is medium because, although hexachloroethane has been tested for carcinogenicity and teratogenicity, a NOAEL for chronic toxicity has not been defined. Confidence in the RfD is therefore medium.
__I.A.6. EPA Documentation and Review of the Oral RfD
Source Document — This assessment is not presented in any existing U.S. EPA document.
Other EPA Documentation — None
Agency Work Group Review — 12/18/1985, 04/16/1987
Verification Date — 04/16/1987
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 Hexachloroethane conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to 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 — Hexachloroethane
CASRN — 67-72-1
Not available at this time.
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — Hexachloroethane
CASRN — 67-72-1
Last Revised — 02/01/1994
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 — Observation of carcinomas in one mouse strain after oral exposure
__II.A.2. Human Carcinogenicity Data
None.
__II.A.3. Animal Carcinogenicity Data
Limited. Technical grade hexachloroethane (98% pure) was administered by gavage to Osborne-Mendel rats and B6C3F1 mice (50 each male and female) (NCI, 1978). Rats were treated with either 250 or 500 mg hexachloroethane/kg/day, 5 days/week for 23 weeks. After this time animals were rested 1 week and gavaged for 4 succeeding weeks up to week 78; an observation period of 33-34 weeks followed. Final TWA treatment doses were 212 and 432 mg/kg/day. There was no evidence of hexachloroethane-induced neoplastic growth in rats. Mice were administered 500 or 1000 mg/kg/day, 5 days/week, continuously. At week 9 the doses were increased to 600 and 1200 mg/kg/day, and this dosage was maintained until week 78. Mice were observed for 12-13 weeks after cessation of treatment. The TWA doses were 590 and 1179 mg/kg/day. Mice of both sexes showed a significant increase in the incidence of hepatocellular carcinoma.
__II.A.4. Supporting Data for Carcinogenicity
None. Hexachloroethane was not mutagenic for any of 5 Salmonella typhimurium strains (TA1535, TA1537, TA1538 TA98 or TA100) or for Saccharomyces cerevisiae D4 in the absence or presence of rat liver homogenates (Weeks et al., 1979).
_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
__II.B.1. Summary of Risk Estimates
Oral Slope Factor — 1.4E-2 per (mg/kg)/day
Drinking Water Unit Risk — 4.0E-7 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)
|
3E+2 ug/L
|
E-5 (1 in 100,000)
|
3E+1 ug/L
|
E-6 (1 in 1,000,000)
|
3E+0 ug/L
|
__II.B.2. Dose-Response Data (Carcinogenicity, Oral Exposure)
Tumor Type — hepatocelluar carcinomas
Test animals — mouse/B6C3F1, male
Route — gavage
Reference — NCI, 1978
Administered
Dose (mg/kg)/day |
Human Equivalent
Dose (mg/kg)/day |
Tumor
Incidence |
---|---|---|
0
|
0
|
3/20
|
421
|
27.8
|
15/50
|
841
|
55.5
|
31/49
|
__II.B.3. Additional Comments (Carcinogenicity, Oral Exposure)
The administered doses are TWA-adjusted for frequency of exposure (5/7 days). Human equivalent doses were adjusted for length of exposure (546 days of a potential lifespan of 637) and weight of the animals (assumed to be 0.032 kg). The vehicle control group incidence data was used in modeling.
Toxic tubular nephropathy was noted in treated animals of both species. Rats, but not mice, exhibited dose-related increases in mortality.
The unit risk should not be used if the water concentration exceeds 3E+4 ug/L, since above this concentration the unit risk may not be appropriate.
__II.B.4. Discussion of Confidence (Carcinogenicity, Oral Exposure)
Adequate numbers of animals were treated and the tumor response was dose-related. Background incidence of these tumors is high.
_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
__II.C.1. Summary of Risk Estimates
Inhalation Unit Risk — 4.0E-6 per (ug/cu.m)
Extrapolation Method — Linearized multistage procedure, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level
|
Concentration
|
---|---|
E-4 (1 in 10,000) | 3E+1 ug/cu.m |
E-5 (1 in 100,000) | 3E+0 ug/cu.m |
E-6 (1 in 1,000,000) | 3E-1 ug/cu.m |
__II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure
The inhalation risk estimates were calculated from the oral data presented in II.B.2.
__II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)
The unit risk should not be used if the air concentration exceeds 3000 ug/cu.m, since above this concentration the unit risk may not be appropriate.
__II.C.4. Discussion of Confidence (Carcinogenicity, Inhalation Exposure)
See II.B.4.
_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)
__II.D.1. EPA Documentation
Source Document — U.S. EPA, 1980
The values in the Ambient Water Quality Criteria Document for Chlorinated Ethanes received extensive peer and public review.
__II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review — 07/23/1986
Verification Date — 07/23/1986
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 Hexachloroethane conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to 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 — Hexachloroethane
CASRN — 67-72-1
Last Revised — 04/01/1991
_VI.A. Oral RfD References
Gorzinski, S.J., R.J. Nolan, S.B. McCollester, R.J. Kociba and J.L. Mattsson. 1985. Subchronic oral toxicity, tissue distribution and clearance of hexachloroethane in the rat. Drug Chem. Toxicol. 8(3): 155-169.
NTP (National Toxicology Program). 1983. Subchronic study with hexachloroethane in rats. Unpublished report submitted by contract laboratory. Internal working document.
NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of hexachloroethane (CAS No. 67-72-1) in F344/N rats (gavage studies). NTP Tech. Report Ser. No. 361. PB 90-170895/AS.
Weeks, M.H., R.A. Angerhofer, R. Bishop, J. Thomasino and C.R. Pope. 1979. The toxicity of hexachloroethane in laboratory animals. Am. Ind. Hyg. Assoc. J. 40: 187-198.
_VI.B. Inhalation RfC References
None
_VI.C. Carcinogenicity Assessment References
NCI (National Cancer Institute). 1978. Bioassay of Hexachloroethane for Possible Carcinogenicity. CAS No. 67-72-1. NCI-CG-TR-68. Tech. Report Ser. No. 68. U.S. DHEW. Publ. No. (NIH) 78-1318.
U.S. EPA. 1980. Ambient Water Quality Criteria for Chlorinated Ethanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA 440/5-80-029. NTIS PB 81-117400.
_VII. Revision History
Substance Name — Hexachloroethane
CASRN — 67-72-1
Date |
Section |
Description |
---|---|---|
09/30/1987 | I.A. | Oral RfD assessment on-line |
03/01/1988 | I.A.5. | Confidence levels revised |
03/01/1988 | II.B.3. | Text clarified |
03/01/1988 | II.B.4. | Confidence statement revised |
03/01/1988 | II.C.4. | Confidence statement revised |
01/01/1991 | II. | Text edited |
01/01/1991 | II.C.1. | Inhalation slope factor removed (global change) |
04/01/1991 | I.A. | Text edited |
04/01/1991 | I.A.7. | Secondary contact changed |
04/01/1991 | II. | Text edited |
04/01/1991 | VI. | Bibliography on-line |
12/01/1991 | I.B. | Inhalation RfC now under review |
12/01/1991 | IV.F.1. | EPA contact changed |
01/01/1992 | IV. | Regulatory actions updated |
12/01/1992 | I.B. | Work group review date added |
02/01/1994 | II.D.3. | Secondary contact's phone number changed |
08/01/1995 | I.B. | EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. |
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. |
10/28/2003 | I.A.6., II.D.2. | Screening-Level Literature Review Findings message has been added. |
_VIII. Synonyms
Substance Name — Hexachloroethane
CASRN — 67-72-1
Last Revised — 03/31/1987
- 67-72-1
- AVLOTHANE
- CARBON HEXACHLORIDE
- DISTOKAL
- DISTOPAN
- DISTOPIN
- EGITOL
- ETHANE HEXACHLORIDE
- ETHYLENE HEXACHLORIDE
- FALKITOL
- FASCIOLIN
- HEXACHLOR-AETHAN
- Hexachloroethane
- 1,1,1,2,2,2-HEXACHLOROETHANE
- HEXACHLOROETHYLENE
- MOTTENHEXE
- NA 9037
- NCI-C04604
- PERCHLOROETHANE
- PHENOHEP
- RCRA WASTE NUMBER U131