SCANNED
A-e"C11 I s 8ANNso
PHASE II REPORT COMPREHENSIVE SITE ASSESSMENT MEDFORD SITE 320 MIDDLESEX AVENUE MEDFORD, MASSACHUSETTS VOLUME 4 (Appendices H through K)
MCP Waiver No. 92-3-3290-2 Prior MCP Waiver No. 90-3-3290-1
Prepared for:
GENERAL ELECTRIC AIRCRAFT ENGINES 1000 Western Avenue Lynn, Massachusetts
Prepared by:
ECKENFELDER INC. ECKENFELDER INC. 227 French Landing Drive 1200 MacArthur Boulevard Nashville, Tennessee 37228 Mahwah, New Jersey 07430 (615) 255-2288 (201) 529-0800
November 1992
6255.08
Q:\6255\HICVRDOC APPENDIX H
TOXICITY PROFILES FOR THE FOLLOWING
CONSTITUENTS OF INTEREST:
* Acetone * * Antimony
* Arsenic, inorganic
* Barium
* Beryllium * 2-Butanone (Methyl Ethyl Ketone, MEK)
* Cadmium
* Chloroethane (Ethyl Chloride) * Chloroform
* Chromium (III)
* Chromium (VI)
* Copper
* 1,1-Dichloroethane * 1,1-Dichloroethene (1,1-Dichloroethylene) * Lead and compounds (inorganic)
* Manganese
* Methylene Chloride (Dichloromethane)*
* Nickel, soluble salts
* Toluene
* 1,1,1-Trichloroethane * Zinc and compounds
* Toxicity profiles not available for aluminum, calcium, iron, and vanadium
* Laboratory/field contaminant Acetone; CASRN 67-64-i (12/01/90)
Health risk assessment information on a chemical i.s inciuded in IRIS only after a comprehensive review of chronic toicity data by work grc'ups composed of U.S. EPA scientists from several Procram Offices. The summaraieS presented in Sections I and !I represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particular ' EPA program and has been subjeact to review procedures prescribed by that Program Office. The regulatory actiohs in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and ma'y take into account factors other than health effects (e.g. , treatment technology) . When considering the use of regu lator/ action data for a particu.lar Situation, note the date of the regulastory action, the date of the most recent risk assessment relating to that action, and wh'ether technol ogical factors were corsidered. Background information and explan- ati ons of the methods used to derive the values rgiven in IRIS are provided in the fiV Background Doctimerirs in Service Code 5, which correspond to Secti ons I through V of the cheMrical fi 1eS
CSTATUSOF DATA FOR Acetone
File n-Line 03/31/B7
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) on-line 12/01/90
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 12/01/90
Drinking Water Health Advisories (III.A.) no data
U .S. EPA Regulatory Actions (IV. ) on-line 07 /01/90
Supplementary Data (V. ) no data
I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
E.. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- A icetone £ CAERN -- 67-64-- Last Revised - 12/01/90
The Reference Dose (RfD) is based on the asitumption that thresholds exist for
1 certain toxic effects such as cellular necrosis but may not exist for other toxic effects such as carcAriogericity. 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 sLbqroLps) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Please refer to Background Document 1 in Service Code 5 for an elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of compounds which are also carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EFA has evaluated this substance for potential human carcinogen- icity, a summary of that evaluation will be contained in Section II of this file when a review of that evaluAtion is completed.
Ac( ene
. . 1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MrF RfD
Increased liver and NOEL: 100 mg/kg/day 1000 1 1E-1 i.idney weights and mg / kg/day nephrotoxicity LOAEL: 500 mg/kg/day
Rat Oral Subchronic Study
U.S. EPA, 1986
*Conversion Factors: Actual dose tested
< Acetone >
I .A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
U.S. EPA. 1995. Ninety-day gavage study in albino rats LSing acetone. Office of Solid Waste, Washington, DC.
Acetone was administered by gavege for 90 days to groups of albino rats (3t/sex/group) at , 100, 500. or 2500 mg/kg/ay. Body weights, food consumption, clinical chemistry, hematology, and histopathologic parameters. as well as organ weights and organ-to-body weight ratios, were measured and analyzed. Animals were sacrificed after 30 or F0 days of exposure. No effects were seen at the 100 mg/kg/day dose level throughout the study. RBC parameters were significantly increased in the 2500-mg/kg/day group at 30 days (males only) and at 90 days in males and females. Statistical analysis of the absolute and relative organ weight data revealed significantly increased 1 idney weights for females in the 500- and 25f0-mg/kg/day groups and increased kidney-to-body and brain weight ratios for males and females in the 2500- mg/hg/day groups. Liver weight and liver/body weight ratios were also. - increased in the 2500-mg/kg/day males and females. Histopathologic studies revealed a marked increase in severity in tubular degeneration of the kidneys and hyaline dropilet accumulation with increasing doses. This accumulation was significant in the 500- and 2500-mng/kg/day males and the 2500 mg/kg/day Jema le.
Based on the above findings, the NOEL for this study is 100 mg/kg/day and the LOAEL is 500 mg/kg/day based on increased liver and kidney weights and nephrotoxicity.
< cetone >
2 I .A.J. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 1000. An uncertainty factor of 1000 is used; 100 for inter- and intraspecies extrapolation and 10 to extrapolate from subchronic to chronic exposure.
MF = 1.
<<< Acetone >
I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Limited human studies have shown that workers exposed to acetone vapors (600 to 2150 ppm) experienced transient eye and nose irritation. Anima)s exposed to acetone vapors at 45,134 mg/cu.m experienced slight, but not significant, decreases in organ and body weights.
< Acetone >>>
1.A.5. CONFIDENCE IN THE ORAL RfD
Studv: Medium Data Base: Low RfD: Low
Confidence in the principal study is rated medium, since a moderate number of animals/dose/sex and an extensive number of parameters were mea- aured. The data base is rated low because a very limited number of studies are available and no pertinent supporting studies were located. The overall confidence rating for the RfD is low.
<< Acetone >>>
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 RfD Work Group Review: 12/13/85, 05/30/36
Verification Date: 05/30/86
_I.A.7. EPA CONTACTS (ORAL RfD)
Harnal Choudhury / ORD -- (513)569-7535 / FTS 684-7536
W. Bruce Peirano / ORD -- (513)567-7540 / FTS 684-7540
_1.2. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Acetone
3 CASRN -- 67-64-1
Not available at this time.
-II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Acetone CASRN -- 67-64-1 Last Revised -- 12/01/90
Section II provides information on three aspects of the carcinogenic risk assessment for the agent in question; the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen. 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. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity.
<< Acetone >
_II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINDGENICITY
II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity
Basis -- Based on lack of data concerning carcinogenicity in humans or animals.
<< Acetone >>>
-II.A.2. HUMAN CARCINOGENICITY DATA
None.
<< Acetone >V>
1I.A.3. ANIMAL CARCINOGENICITY DATA
None.
< Acetone >
II.A.4. SUPPORTING DATA FDR CARCINDGENI CITY
Acetone did not show mutagenic activity when tested in Salmonella
4 typhimurium strains TA98 and TA100 or in Schizosaccharomyces pombe strain F1 either in the presence or absence of liver homogenates (McCann ot al., 1975; Abbondandolo et al., 1980; Maron et al., 1991; Hallstrom Et al., 1981) or in cell transformation systems (Freeman et al., 1973; Rhim et al., 1974; Duarles et al., 1979ab). Furthermore, acetone gave negative results in assays for chromosomal aberrations and sister chromatid eychange (Norppa et al., 1981; Norppa, 1961; Tates and Kriek, 1951), DNA binding (Kubinski et al., 1981). point mutation in mouse lymphoma cells (Amacher et al., 1980), and transfection of E. coli CR63 cells (Vasavada and Padayatty, 1981). In one study, however, acetone was reported to produce chromosomal aberrations but not sister chromatid exchanges (Kawachi et al., 1980).
------cetone > ------
II.B. OUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
None.
------<< Acetone ------
_II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
None.
------<< A.ce > >>*------
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
II.D.1. EPA DOCUMENTATION
U.S. EPA. 198S. Updated Health Effects Assessment for Acetone. 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.
<< Acetone ]->>>--
II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The 19S9 updated Health Effects Document for Acetone has received Agency review and is approved for publication.
Agency Work Group Review: 12/06/89
Verification Date: 12/06/89
II.D.3. U.S. EPA CONTACTS (CARCINOSENICITY ASSESSMENT)
Charles Ris / ORD -- (202)382-5875 / FTS 3S2-5S9S
5 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
III.A. DRINKING WATER HEALTH ADVISORIES
Subetance Name -- Acetone CASRN -- 67-64-1
Not available at this time.,
11I.B. OTHER ASSESSMENTS
Substance Name -- Acetone CASRN -- 67-64-1
Content to be determined.
-IV. U.S. EPA REGULATORY ACTIONS
Substance Name -- Acetone CASRN -- 67-64-1 Last Revised -- 07/01/90
EPA risk assessments may be updated E. new data are published and as assessment methodologies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the regulatory actions in this section with the verification dates for the risk assessments in sections I and II, as this may explain inconsistencies. Also note that some regulatory actions consider factors not related to health risk, such as technical or economic feasibilit,'. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning these regLlatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatory action in Background Document 4 in Service Code 5.
Acetone>>
_1V.A. CLEAN AIR ACT (CA;)
No data available
-- < cetone ------
6 __IV.F- SAFE DRINKING WATER ACT (SDWA
No data available
------Acetone ------
I _IV.C. CLEAN WATER ACT (CWA) I rNo data available
-- -- Acetone
IV.D. FEDERAL INSECTICIDE. FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
a -- K _IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available ------<<<' Acetone >>------ I IV.F. RESOURCE CONSERVATION AND RECOVERY ACT RCRA) IV.F.1. RCRA APPENDIX IX, for Ground W'ater Monitoring StatuE -- Listed Reference -- 52 FR 25942 (07/09/97) EPA Contact -- RCRA/SLperfund Hotline (00)424-E'34S / (202)382-Z000 / FTS 382-3000 ------cetone>Y------ __IV.G. SUPERFUND (CERCLA) 5V.G..1 REPORTABLE QUANTITY (RD) for Release into the Environment Value (status) -- 5000 pounds (Final, 1985) Considers technological or economic feasibility? -- NO iScLISSion -- The final adjusted RQ for acetone is 5000 pounds, based on the application of the secondary criterion of biodegradation to the primary 7 criteria RU of 1000 pounds, determined by ignitability. Available data indicate a flash point of -4F and a boil ing point of 133F, which correspornds to an RD of 1000 pounds. The final RD takes biodegradation into account, since acetone biodearacles when released into the envircrnment. The bi ol ocicAl oxygen deman for 5 days (BODS) is 46-55%. Reference - 50 FR 13456 (04/04/85) EFA Contact -- RCRA/Superfund Hotline (800)424-9346 / (202)382-3000 / FTS 382-7000 _V. SUPPLEMENTARY DATA Substance Name -- Acetone CASRN -- 6T-64-1 Not available at this time. VI. BIBLIOGRAPHY Substance Name -- Acetone CASRN -- 67-64-1 Last Revised -- 07/01/90 VI .A. ORAL Rf D REFERENCES U.S. EPA. 1986. Ninety-day gavage study in albino rats using acetone. Office of Solid Waste., Washington. DC. ------Acetone >------ VI .B. INHALATION RfD REFERENCES None VI .C. CARCINOGENICITY ASSESSMENT REFERENCES Abbondandolo, A., S. Bonatti., C. Corsi, et al. 1980. The use of organic solvents in tmutagenicity testing. Mutat. Res. 79: 141-15C). Amacher, D.E., S.C. Paillet, G.N. Turner, V.A. Ray and D.S. Salsburo. 1980. 8 Point mutations at the thvmidine kinase locus in L5173Y mouse lymphoma cells. 2. Test validation and interpretation. Mutat. Rea. 72: 447--474. Freeman. A.E.. E.. WeisburQer. J.H. Weisburger, R.G. Wolford.. J.M. Maryak and R.J. Huebner. 1977. Transformation of cell cultures as an indication of the carcinogenic potential of chemicals. J. NatI. Cancer Inst. 51(3): 799-808. Hallstrom, I., A. Sundvall, U. Rannug,5 R. Grafstrom and C. Ramel. 1981. The metabol ism of drugs and carcinogens in isolated subcel lular fractions of Drosophila melancaster. I. Activation of vinyl chloride, 2-amnicanthrecene and benzo(a)pyrene as measured by mutagenic effects in Salmonella typhimurium. Chem. Biol. Inter. 34: 129-143. Kawachi T. , T. Yahacii, T. Kada et al. 1990. Cooperative progra-mme on short-term assays for carcinogenicity in Japan. In: Molecular and Cellular Aspects of Carcinocien Screening Tecsts. R. Montesano, ed. WHO, IARC, Lyon, France. p. 323-.33.t kubinski, H., G.E. Gutzke and 2.0. K.ubinski. 1981. DNA-cell-binding (DCB) assay for suspected carcinogens and mLtagens. Mutat. Res. 89: 95-136. Maron, D., j. Kat:enellenbogen and B.N. Afmes. 1.981. Compatability of organic solvents with the Salmonella/microsome test. Mutat. Rea . 83: 343-350. McCann, u.,- E. Choi, E. Yamasaki and F.N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. 72(12): 5135-5139. Norppa, H. 1951. The in vitro induction of sister chromatid exchanges and chromosome aberrations in human lymphocytes by styrene derivatives. Carcinogenesis. 2(3): 237-242. Norppa, H., K. Hemminki, M. Sorsa and H. Vainio. 1981. Effect of monosubstituted epoxides on chromosome aberrations and SCE in cultured human lymphocytes. Mutat. Res. 31: 243-250. uuarles, j.M., N.W. Sega, C.K. Schenley and W. Lijinsky. 1979a. Transformation of hamster fetal cells by nitrosated pesticids in a transplacental assay. Cancer Res. 39: 4525-4533. Quarles, J.M., M.W. Sega, C.K Schenley and R.W. Tennant. 1979b. Rapid screening for chemical carcinogens: Transforming activity of selected nitroso compounds detected in a transplacental host-mediated culture system. Nat!. Cancer Inst. Monoar. 51: 257-2S3. Rhim, J.S. , D.K. Park, E.K. Weisburger and J.H. Weisburger. 1974. Evaluation of an in vitro assay system for carcinogens based on prior infection of rodent cells with nontransforminq RNA tumor virus. J. Natl. Cancer inst. 52( 4) 1167-1177:. Tates, A.D. and E. Kriek. 1951. Induction of chromosomal aberrations and sister-chromatid exchanges in Chinese hamster cells in vitro by some proximate and ultimate carcinogenic arylamide derivatives. Mutat. FRes. e5: 397-410. Vasavada, H.A. and J.D. Padayatty. 191. Rapid transfection assav -for screening mutaqens and carcinogens. Mutat. Res. 91: 9-14. U.S . EPA. 1920. Updated Health Effects Assessment for Acetone. Prepared by the Cifice of Health and Environmental Assessment, Environmental Criteria and 9 Asessmnent Office, Cincinnati, OH for the Office of Solid Wste and Emr-ergency rE-. p r.E , Wa.E:.hrh n tori, DC. ------A cetone- -- - VI.D. DRINKING WATER HA REFERENCES None SYNONYMS Sub5tance Name -- Acetone CASRN -- 67-64-1 Last Revised -- 03/31/97 67-64-1 ACETON Acetone DIMETHYLFORMALDEHYDE DI METHYLKETAL DIMETHYL KETONE KETONE, DIMETHYL KETONE PROPANE beta-KETOPROPANE METHYL KETONE PROPANONE 2-PROPANONE PYROACETIC ACID PYROACETIC ETHER RCRA WASTE NUMBER U002 UN 1C0C 10 Antimony; CASRN 7440-36-0 (03/01/91) Health risk assessment information on a chemical is included in IRIS only after a comprehensive review of chronic toxicity data by work groups composed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections I and I1 represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g., treatment technology). iWhen considering the use of regulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background information and explan- ations of the methods used to derive the values given in IRIS are provided in the five Background Documents in Service Code 5, which corresp.jond to Sections I through V of the chemical files. STATUS OF DATA FOR Antimony File On-Line 01/31/87 Category (section) Status Last Revisd Oral RfD Assessment (I.A.) on-line 02/01/91 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment II.) no data Drinking Water Health Advisories (III.A.) no data U.S. EPA Regulatory Actions (IV.) on-line 03/01/a8 Supplementary Data (V.) no data _I. CHRONIC HEALTH HAZARD ASSESSMENTS .FOR NONCARCINOGENIC EFFECTS ±.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- An timony CASRN -- 74-- Last Revised -- 02/01/91 I The Reference Dose (Rf.'D) is based on the assumption that thresholds exist for certain toxic effects cuch as cCellular necrosis, but may not ex: is t for othcer toxic effec tb such as carcinoqenicity. In qener , the Rf is cn estimzt (with uncertainty spanning perhaps an order OT magnittde) of a daily exposure to the humnri popul ation (including sensitive subciroups ) that is 1.ikely to be without an appreciable risk of del eterious effects during a lifetime. F'lease refer to Backciround Doc unment 1 in Service Code 5 for an el&aboration of these concepts. RfDs can al so be derived for the noncarcinogenic health effects of compounds which are al so carcinoQers. Therefore , it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has ev'luated this substance for potertiEa l human carcinogcri- icity, a summary of that evaluation will be contained in Section II of this file when a review of that evaluation is completed. << Antimony I . A1 . ORAL RfD SUMMARY Cri tical Effect Experimental Doses* UF MF RfD Lngevity, blood NOEL: none 1000 1 4E-1 glucose, and cho- mg/ Y/day lesteroi LOAEL: 0.35 mg/kg bw/day Rat Chronic Oral Pioassay - Schroeder et al., 1970 *Conversion FEctors: 5 mog/L (S ppm) given as 0.350 mg/kg/dey in the discussion section of the critical study Antimonv _ .. 2. PRINCIPAL AND SUPPORTING STUDIES (0RAL RfD) Schroeder, H.A., M. Mitchner and A.. Nasor. 1970. Zirconium, nioobium, antimony, vanadium and lead in rats: Life term studies. j. Nutrition. 100: 53--66. An experimental group of 50 male and 50 female rats was administered 5 ppm potassium antimony tartrate in water. Over the period of study, growth rates of treated animals were not affected, but male rats survived 106 and Temales 107 Tewer days than did controls at median lifespans. NonTfasting clood glucosE levels were decreased in treated males, and cholesterol levels were altered in both sexes. Since there was only one level of an timony admin- istered, a NOEL was not es-tablish-ed in this study. P decrease in moan heart weiaht for the males was no ted. No increase in tumors waS seen as a result of treatient. 1.-though not precisely stated, the concentration of 5 ppm antimony was expressed as an exposure oCf 0.35 mg/kg/day by the authors. A-ntimony .> >>r, I .A.3. LNCERTA I NTY AND MODI FYI NG FACTORS (ORL RfD) UF = 1000. An uncertainty factor of 1000 (10 for interspec conversion. 10 to protect sensitive individuals, and 10 because the ffect level was a LOAEL and no NOEL was established) was applied to the LOAEL of 0.35 mg/kg bw/day. 2 MF = 1 -Antiimony A.4. ADDITIONAL COMMENTS (ORAL RfD) in a similar study (Kanisawa and Schroeder, 1969), groups of CD-I mice 54/sex) were given puassiLm anti mony tartrate in drinking water at 0 or 5 mg/L (5 ppm) for 540 days (18 months) . Lifespans were significantly reduced in both males arid females, but the degree of antirnony toxicity was less severe in mice than rats. Bradley and Fredrick (1941) and Browriing (1959) reported disturbances in glucose and cholesterol mretabolism in rats ingesting ' mg/L antimony, but no signs of injury to the heart were observed in rats receiving doses up to 100 mg/kg/day. Substantially higher doses of antimony trioxide were tolerated by rats in studies by Sunagawa (1981) and Gross et al. (1955a, b) suggesting a NOAEL of 500 mg/kg, but these studies are of inadequate duration to assess adverse effects on tox icity. Seventy people became acutely ill after drinking lemonade containing 0.013% antimony (Dunn, 1925 and Monier-Wi iams, 1934). The lemonade had been prepared and left overniciht in bucl::ets coated with an enamel containing 2.88% antimonv trioxide. Fifty-six people were taken to the hospital with burning stomach pains, colic, nausea and vomitir. Most recovered within 3 hours, but in some cases recovery was not comiplete for several days. It is estimated that a person consuming 300 mL of lemonace would have recived a dose of approximately -36 mg antimony, or approximately 0.5 mg/kg for a 70-kg adult. According to U.S. EPA (1980), multimedia antimony exposures are essentially negligible by comparison to occupational exposures at which discrete clinical health effects have been observed. Myocardial effects are among the best-characterized human health effects associated with antimonv exposure. Studies by Brieger et al. (1954) suggest an inhalation NOEL for myocardial damage to be approximately 0.5 mg/cu.m. This exposure is approximately equivalent to an oral reference dose of 0.003. mg/kg b w/day (i.e., 0.5 mg/cu.m x 10 cu.m/day x 0.5 / 1.0 x 5 days/7 days / 70 kg / 101. Parallel studies in rats and rabbits resulted in observation of EKG alterations following exposure to .- 5 mg/cu.m. There are, however, no adequate data on oral exposure to antimony which permit reasonable estimate of no effect levels regarding heart damage. One study (Belyaeva, 1967) indicated that women workers exposed in an antimony plant experienced a greater incidence of spontaneous abortions than did a control group of nonexposed working women. A high rate of premature deliveries among women workers in antimony smelting and processing was also observed (Aiello, 1955). Antimony -I. .5. CONFIDENCE IN THE ORAL RfD . otLdy: Low D'ta Base; Low RfD: Low Confidence in the chosen study is rated as low because only one species was used, only one dose level was used , no NOEL was determined and g ros- pathology and histopathology were not well described. Confidence in the data base is low due to lack of adequate oral exposure investigations. Low confidence in the RfD follows. 3 Antimony I.A.6. EPA DDCUMENTATION AND REVIEW OF THE ORPAL RfD U.S. EFA. 1980. Ambient Water Quality Criteria Document for Antimony. Prepared by the Office of Health and Environimental Assessrent, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA-440/W5-8-070. NTIS PP 81- 1 17319. The ADI in the 1980 ASibient Water Quality Criteria Document was exteniveiy reviewed by the Agency and was reviewed by the public. U.S. EPA. 1955. Health and Environmental Effects Profile for A)ntimwony Oxides. Prepared by the Office of Health and Environmental Assessment. Ervironmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washinaton., DC. Limited peer review and estensive Agency--wide review, 1985. Agency RfD Work Group Review: 11/06/85 Verification Date: 11/06/95 I.A.7. EFPA CONTACTS (ORAL RfD) Christopher T. DeRosa / ORD -- (513)569-7534 / FTS 694-7534 Michael L. Dourson / ORD -- (513)569-7544 / FTS 634-7544 I .B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Antirmony CASRN -- 7440-36-0 Not available at this time. II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Antimony CASR:N -- 7440-36-0 This substance/agent has not been evaluated by the U.S. EPA for evidence of human carcinogenic potential 4 III . HEALTH HAZARD ASSESSMENTS FOR VARI ED EXPOSURE DIRATIONGS __III.A. DRINKINS WATER HEALTH ADVISORIES Substance Name -- Antnimony CASRN 744-36--O Not available at this time. -I I I .B. OTHER AGSESSMENTS Subs tance Name -- Antimony CASRN --- 7440--38-C Content to be determined. IV. U.S. EA REGULATORY ACTIONS Substance Name -- Antimony CASRN -- 7440-3.6-: Last Revised -- 03/01/88 EPA risk assessments mav be updated as new data are publ ished and as assessment methodologies evolve. Regulatorv actions are frequently not upOdated at the same time. Compare the dates for the regulatory actions in this section with the verification dates for the risk assessments in SEctions I and II, as this may explain inconsistencies. Also note that some regulatorv actions consider factors not related to health risk, such as technical or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning thneSe regulatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatorv action in Backgr-ound Document 4 in ServicE Code 5. < I.A. CLEAN AIR ACT (CAA) No data available -- < < iAnt imon >------ _IV.B. SAFE DRINKING WATER ACT (SDWA) 5 No data available ------An timony - ' IV.C CLEAN WATER ACT (CWA) U __IV. C.1. AMDIENT WATER QUALITY CRITERIA, HLLmZar Health Water and Fish Consumption: 1 . 46E+2 u/L Fish Consumption Only: 4. 5E+4 uc/L I Considers technological or economic feasibility? -- NO Discussion Reference -- 45 FR 77315 (11/2D/80) EPA Contact -- Criteria and Standards Division. OWRS (202)475-7215 / FTS 475-7715 Antt imonv IV. C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms Freshwater: AcLte LEL -- 9E+3 ug/L Chronic LEL -- 1.6E+3 ug/L Marine: None Considers technological or economic feasibility? -- NO Discussion -- The values that are indicated as "LEC" are not criteria, but are the lowest effect levels found in the literature. LECs are given when the minimum data required to derive water quality criteria are not available. Reference -- 51 FR 8361 (073/11/86) EPA Contact -- Criteria and Standards Division, OWRS 3 (202)475-7315 / FTS 475-7315 ------Antimony >>------ _IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND R5DENTICIDE ACT (FIFRA) No data available ------An-timonyi I _VE. TOXIC SUBSTAiNCES CONTROL ACT (TSCA) 1g No data available ---- Antimonyn ------ _IV.F. REEURCE CONSERirATION AND RECDVERY ACT (RCRA) IV. F. 1. RCRA k'PENDIX IX., for Ground Water Monitoring Statu-s -- Listed I Reference -- 52 FR 25912 (07/09/87) EFA Contkct -- RCRA/Super-fund Hotline 800)424-9345 / (22)32-3000 / FTS 382-3000 I ----- << Antimony _ IV.G. SUPERFUND (CERCLA IV. G.1. REPORTABLE -QUANTITY (R) tor Release into the Environment Value (status) -- 5000 lbs (Final ?86) Considers technological or economic feasibility? -- ND Discussion -- No data have been found to permit the ranking of this hazardous substance. The available data for acute hazards may lie above the upper limit I or the 5000-pound RD, but since it is a designated hazardous substance, the largest assignable RD is 5000 poLnds. Reference -- 51 FR 3.4534 (09/2?/86) EPA Contact -- RCRA/Superfund Hotl ine 800)424-9346 / (202)3.82-3000 / FTS 382-3000 3 V. SUPPLEMENTARY DATA Substance Name -- Antimony QASRN -- 7440-36-0 Not available at this time. VI. BIBLIOGRAPHY Substance Name -- Antimony 7 CRN-- 7440--36-O 3Lat Revi sed -- 02/01/91 VI.A. ORAL RfD REFERENCES UI Aiel lo, G. 195. Pathology of antimony. Folia Med. Naples). 38: 100. (ItalI.) Belyaeva, A.F. 1967. The effect of ant imoriy on reproduction. Gic . Truda Prof. Zabol. 11: 32. I Bradley, W.R. and W.G. Frederick. 1941. The toxicity of artimiony--anrarimal studies. Ind. Med. 1( Ind. Hyg. Sec. 2: 15-22. IBrieger, H. .J. bemiech, . Stasney and D. A. Pl a.ittne. 1.954. Industrial antimony poisoning. Ind. Med. Surg. 25: 521. I Browning, E. 1969. Antimony. In: Toxicity of Industrial Metals, 2nd ed. Appleton-Century-Craft. New York. p. 23-33. Dunn, J. T. 192. A curious case of antimony poisoning. Analyst. 53: Bros, F., J.H. V.- Brown, M.L. Westrick , R.P.Srsic , N.L. But ler and T .. Hatch. 1 955a. A toxcoiogical study of calcium halophosphats phospher and antimony trioxide. I. Acute and chronic toxicity and some pharmacological aspects. Arch. Ind. Health. 11: 473/-479. Gross, P'., M.L. Westrick, J.H.V. Br-own, R.P. Srsic. H.H. Schrenk and i.r. Hatch. 1955b Toxicologic Study of calcium halophosphate phosphors and antimony trioxide. II. Pulmonary studies. Arch. Ind. Health. 11: 479-486. Kanisawa, M. and H.A. Schroeder. 1569. Life term studies on the effect of trace elements on spontaneous tLmor in mice and rats. Cancer Res. 29: 892-895. Monier-Williams, G.W. 1934. Antimony in enamelled hollow-ware. Report on Public Health and Medical Subjects, No. 73., Ministry of Health, London. U p- 18. (Cited in U.S. EPA, 1985) Schroeder, H.A., N. Mitchner and A.F. Nasor. 1970. Zirconium, niobium, 359-68.antimony, vanadium and lead in rats: Life term studies. J. Nutr. 100(1): Sunagawa. 8. 1991. Experimental studies on antimony poisoning. akU S.enkyu. 51(3): 129-142. (3ap.) (CA 096/0C80742D) U.S. EPA. 1930. Ambient Water Quality Criteria Document for Antimony. Prepared by the Office of Health and Environmental Assessment, nvroniTental I Cr-teria and Assessrment Office, Cincinnati, OH for the Oifice of Air Quality Planning and Standards, Washing ton , DC. EPA 440/ 5-8--020. UL.S'. EPA. 19 5. Health and Envi ron mental Ef fec t= Prof il e for Antimony xides . Prepared by the Office of H eal th and Envi rnn tal Assessmen t, Environmental Criteria and Assessment, Cincinnati, OH for the Office of Solid - waste and ETergencry Response., Washington, DC. 8 - ---- AntImn rnomPD .------ UVI.B. INHALAfT ION RfDU REFERENCES None I- -- Anmon - 5 ,I.C. -A.CINOENICTTY ASSESSiMiENT REFERENCES -- - +-Antimcrony --- -- I I.. DRIN;:ING WATER HA REFERENCES None SYNDNYMS Substance Name -- Antimony A- 'RN -- 744C-36-0 Last Revised -- 01/3-1/@7 7440-36-0 Antimony ANTINONY BLACK ANTIMONY POWDER ANTIMONY, REGULUS ANTYMON C.I. 77050 STIBIUM- UN1142871 9 Arsenic, inorganic; CASRN 7440-.--2 (0:2/01/91) Health risk assessment information on a chemical is included in IRIS only after a comprehensive review of chronic toxicity data by work groups composed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections I and II represent a consensus reached in the review process. The other sections contain U..S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g., treatment technology). When considering the use of regulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and wheth-r technological factors were considered. Background information and explan- ations of the methods used to derive the values given in IRIS are provided in the five Background Documents in Service Code 5, which correspond to Sections I through V of the chemical files; STATUS OF DATA FOR Arsenic, inorgianic File On-Line 02/10/RE Category (section) Status Last Revised ' Oral RfD Assessment (!.A.) pending Inhalation RfC Assessment (1.B.) no data Carcinogenicity Assessment (II.) on-line 02/01/91 Drinking Water Health Advisories (11IA.) no data U.S. EPA Regulatory Actions (IV.) on-line 06/01/90 Supplementary Data (V.) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS __I .A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Arsenic, inorganic CAERN -- 7440-38-2 A risk assessment for this substance/agent will be reviewed by an EPA work group. I I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Arsenic, inorganic CASRN -- 7440-38-2 Not available at this time. II. CARCINOGENICITY ASSESSMENT FOR LIFETINE EXPOSURE Substance Name -- Arsenic , inorganic CASRN -- 7440-3S-2 Last Revised -- 02/01/91 Section II provides information on three aspects of the carcinogenic risk assessment for the agent in question; the U.S. EPA cls-sification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgiment of the likelihood that the agent is a human carcinogen. 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 i in 1,000,000. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity- < << Arsenic, inorganic >> _II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOSENICITY _II.A.i. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification --- A; human carcinogen Basis -- based on observation.of increased lung cancer mortality in populations exposed primarily through inhalation and on increased skin cancer incidence in several populations consuming drinking water with high arsenic concentrations. < Arsenic, inorganic > II .A.2. HUMAN CARCINOGENICITY DATA Studies of smelter worker populations (Tacoma, WA; Magma, UT; Anaconda, MT; Ronnskar, Sweden; Saganoseki-Machii, Japan) have all found an association between occupational arsenic exposure and lung cancer mortality 2 (Enterline and Marsh, 1922; Lee-Feldstein, 9S:; AXeisorn et al.., 1978;:. Tokudome and Kuratsune. 1976; Rencher et al., 1977). Both proportionate mortality and cohort studies of pesticide manufac turing workers hive shIown an excess of lung cancer deaths among ex:posed persons (Ott et al, 1.974 .; Mabuchi et al., 1979). One study of a population residing near a pcisticide manufacturing plant revealed that these residents were also at an excess risk of lung cancer (Matanoski et al., 19@1). Case reports of arsenical pesticide applicators have also demonstrated an association between arsenic exposure and lung cancer (Roth, 1958). A cross-sectional study of 40,000 Taiwanese exposed to arsenic in drinking water found significant excess skin cancer prevalence by compar-ison to 7500 residents of Taiwan and Matsu who consumed rel CAtively arsenic-free water (Tseng et al., 1968). This study design limited its usefulness in risk estimation. Arsenic-induced skin cancer has also been attributed to water supplies in Chile. Argentina and Mexico i(orgono and Greiber, 1972; Bergoglio, 1964; Cebrian et al., 1983). No excess skin cancer incidence has been observed in U.S. residents consuming relatively high levels of arscenic in drinking water (Morton et al., 1976; Southwick et al. 1981). The results I of these U.S. studies, however , are not necessarily inconsistent with the existing findings from the foreign populations. The statistical powers of the U.S. studies are considered to be inadequate because Of the small sample size. A follow-up study (Tseng, 1977) of the population iivinq in the same area of Taiwan, where arsenic contamination of the water supply was endemic, found significantly elevated standard mortality ratios for cancer of the bladder, lung, liver, kidney, sk.in and colon. This study of bladder, liver and lung cancer cases in the endemic area found a significant association with arsenic exposure that was dose-related. The association of arsenic ingestion and cancer of various internal organs has also been cited in a number of case reports (Chen et al., 1925, 1985). Persons treated with arsenic-containing medicinals have also been shown to be at a risk of skin cancer (Sommers and McManus, 1953). I < Arsenic. inorganic >> 1.A... ANIMAL CARCINOGENiCITY DATA None. There has not been consistent demonstration of arsenic carcinogenicity in test animals for various chemical forms administered by different routes to several species (!ARC, 1980). There are some data to indicate that arsenic may produce animal tumors if retention time in the lung can be increased (Pershagen et al., 1982, 1984). Arsenic, inorganic > II .A.4. SUPPORTING DATA FOR CARCINOGENICITY Sodiumr arsenate has been shown to transform Syrian hamster. embryo cel is (Dipaolo and Casto, 1979) and to produce sister-chromatid-exchange in DON cells, CHO cells and human peripheral lymphocytes exposed in vitro (Wan et al., 19e2; Ohno et al., 1922; Larramendy et al., 1981; Andersen, 1933; Crossen, 1983). While arsenic compounds have not been shown to mutate bacterial strains, it produces preferential killing of repair deficient strains (Rossman, 1981). ------<<< Arsenic, inorganic >>.------ 3 11.B. LANTITATI'E ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE The Risk Assessment Forum has completed a reassessment of the carcinogenicity risk associated with ingestion of inorganic arsenic. This report, which has been extensively peer-reviewed by outside reviewers (including SAB review) concluded that the most appropriate basis for an oral quantitative estimate was the study by Tseng et al. (1977), which reported increased prevalence of skin cancers in humans as a consequence of arsenic exposure in drinking water. Based on this study a unit risk of 5E-/ug/L was proposed. A recent memorandum by the Administrator of the EPA recommended that the above unit risk be adopted. The memorandum further counsel, that "in reaching risk management decisions in a specific situation, risk managers must recognize and consider the qualities and uncertainties of risk estimates. The uncertainties associated with ingested inorganic arsenic are such that estimates could be modified downwards as much as an order of magnitude, relative to risk estimates associated with most other carcinogens. in such instances, the management document must clearly articulate this fact and state the factors that influenced such a decision.' ------:<< rsenc, inorganic ------ II .C. QUANTITATIVE ESTIMATE OR CARCINOGENIC RISK FROM INHA-LATION EXPSURE II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 4.73E-3/ug/cu.m Extrapolation Method -- absolute-risk linear model Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) 2E-2 ug/cu.m E-5 (1 in 100.000) 2E-3 ug/cu.m E-6 (I in 1,000,000) 2E-4 ug/cu.m ... Arsenic, inorganic >>> II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- lung cancer Test Animals -- human, male Route -- inhalation, occupational exposure Reference -- Brown and Chu. 1983abc; Lee-Feldstein. 1983; Higgins 1982; Enterline and Marsh, 1982 Ambient Unit Risk Estimates Exposure Unit Geometric Mean Final Estima tes Source Study Risk Unit Risk Unit Risi Anaconda Brown and Chu, 1.25 E-3 smelter 1983a,.b,c Lee-Feldstein, 1923 2.86: E-3 2.56 E-3 4 Hiagins, 1932; 4.90 2-3 i- 29 E-3 Hircgins t al . , 19B2; Welch et al., 1982 A S;lR CO Enterline and 6.01 E-3 7.19 E-:3 .nmel ter Marsh, 1902 7.6C E--3 < Arsenic. inorqanic >> II .C. 3. ADDITIONAL COMMENTS (CARCINOIGENICITY, INHAiLATION EXFOSURE) A geometric mean was obtained for data sets obtained within distinct exposed populations (U.S. EPA, 1984). The final e-stimate is the cgonetric mean of those two values. It was asFsurmed that the increase in i e--scific mortality rate of lurng cancer was a function onjy of cumulative expOSLreS. The unit risk should not be used if the air concentration exceeds 2 LA/cu.m, sice bove this concentration thU Linit risk may riot be appropriate. Ai inorganic> I____ I .C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITV, INHALAT ION EXPOSURE) Overall a large study popul atR:n was observed. Exposure assessments included air mEaLrements for the Anaconda smelter and both air mseisuremients and urinary arsenic for the ASARCO smelter. Observed ILnQ cancer incidence was signiFicantly increased Over expected values. The rano.e of the estimates derived from data from two different exposure areas was within a factor of 6. Arenic, inorganic p:.:------ II .. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) I I . D. 1. EPA DOCUMENTATION US. EPA. 1934. Health Assessment Document for Inorganic Arsenic. Envi ronmental Criteria and Assessment Office, Research Trian lie Park , NC. EPA 600/S-83-021F. «K Arsenic, inorganic 1.. REVIEW (CARCINOGENICITY ASSESSMENT) The 1984 Health Assessment Document for inornanic Arsenic received Agency and external review -including a review -by SA:-. Agency Work Group Review: 01/13/33 Verification Date: 01/13/98 II . D . 3. U. S. EPA CONT ACT S CAR CINOGEN I CT TY ASSESSMENT Herman J. GibL / ORD -- (202)392-5893 / FTS 3.2-5893 5 Chao W. Chen / ORD -- (2E2)32-598 / FTS 332-5898 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPDSURE DURATIONS _III.A. DRINKING WATER HEALTH ADVISORIES Substance Name -- Arsenic, inorganic CASR14 -- 7440-38-2 Not available at this time. III . 2B. OTHER ASSESSMENTS Substance Name -- Arsenic, inorganic CASRN -- 7440-3-rS2 Content to be determined. IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Arsenic, inorganic CASRN -- 7440-38-2 Last Revised -- 06/01/90 EPA risk assessments may be updated as new data are published and as assessment methodologies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the regulatory actions in this section with the verification dates for the risk assessments in sections T and II . as this may explain inconsistencies. Also note that some regjuiatory actions consider factors not related to health risk, such as technical Or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regiulatory actions listed in this section involve enforceable federal standards. Please_ direct any questions you may have. concerning these regulatory actions to the U.S. EPA 'contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatory &ction in BackqrounCi Document 4 in Service Code 5. Arsenic, inorganic I.A. CLEAN AIR ACT (CAA) No data available 6 ------< ---- Arsenic, inoroanic __IV.B. SAFE DRINKING WATER ACT (SDWA) IV. B-. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinkinq Water Value (status) -- 0.05 mg/L (Proposed., 1985) Considers technological or economic feasibility? -- NO DiSCLLSsion -- An MCLG of 0.05 mq/L for arsenic is proposed based on the current MCL of 0.05 mg/L. Even though arsenic is potentially carcinogenic in humans by inhalation and ingestion, its potential essential nutrient value was considered in determination of an MCLG. The basis for this evaluation is nutritional requirements by NAS (NAB, 193, Vol . 5, Drink ing Water and Health, National Academy of Sciences Press, Washington, DC.) Reference -- 50 FR 46936 Part IV (11/13/35) EPA Contact -- Criteria and Standards Division, ODW / (202)322-7571 / FTS :32-7571; or Drinking Water Hotline / (300)426-4791 Arsenic. inorganic __._iV.B.2. MAXIMUN CONTAMINANT LEVEL (MCL) for Drinking Water Value (status) -- 0.05 mq/L (Interim, 1930) Considers technological or economic feasibility? -- YES Discussion -- As an interim measure the U.S. EPA is usinq the value previously derived by the Public Health Service. Reference -- 45 FR 573.32 (03/27/80) EPA Contact -- Criteria and Standards Division. ODW / (202)382-7571 / FTS 332-7571; or Drinkinq Water Hotline / (800)426-4791 Arsenic, inorganic >>>------ _IV.C. CLEAN WATER ACT (CWA) IV. C. 1. AMBIENT WATER QUALITY CRITERIA, Human Health Water and Fish Consumption -- 2.2E-3 uq/L Fish Consumption Only -- 1.75E-2 uq/L Considers technological or economic feasibility? -- N0 Discussion -- For the maximum protection from the potentia l carc inogen rC proparties of this chemical, the ambient water concentration should be zero. However. zero may not be attainable at this time, so the recommended criteria represents a E-6 estimated incremental increase of cancer risk over a I ifetime. 7 Reference -- 45 FR 7971e ('!1/29/0) EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 Arsenic, inorganic IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms Freshwater: Acute -- 3. E+--2 ug/L (Arsenic III) Chronic 1.9E+2 u/L (Arsenic III) Marine: Acute 6.9E+1 uq/L (Arsenic III) Chronir -- 3.6E+1 lug/L (Arsenic III) Considers technological or economic feasibilitv7 -- NO ~ Discussion -- The criteria given are for Arsenic III. Much lens data are available on the effects of Arsenic V to aquatic organisms, but the toxicity seems -to be less. A complete discussion may be found in the referenced notice. Reference -- 50 FR 30784 (07/29/E5) EPA Contact -- Criteria and Standards Division. OWRS (202)475-7315 / FTS 475-7315 ------<<< Arsenic, inorganic >>>------ _IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FFR) No data available ------< Arsenic , inorganic >>>- - __IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available -<<< Arsenic, inorganic ------ _IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA) IV.F.I. RCRA APPENDIX IX, for Eround Water Moritoring Status -- Listed Reference -- 52 FR 25942 (07/09/87) 8 EPA Contact -- RCRA/Superfund Hotline ('0)424-9346 / (202)82-.000 / FTS 32--3000 ----- Arsenic, inorgan ic -___IV . SUPERFUND (CERCLA) IV. G.1. REFORTABLE QUANTITY (RD) for Release into the Ervirorunent Value (status) -- 1 pound (Proposed., 137) Considers technological or economic feasibility? -- NO DiSCuSSiOn -- The proposed 1-pound RG for arsenic is based on its potential carcinogenicity. Available data indicate a hazard ranlking of high based on a potency factor of 14:.1/mg/kg/day and a weight-of-evidence group A. which co-responds to an RO of 1 pound. Evidence found in "Water-Related Environmental Fate of i79 Priority Pollutants" (EPA 440/4-79'-29a) also indicates that this material, or a constituent of this material, is biraccumulated to toxic levels in 'the tissue of aquatic and marine organisms., and has the potential to concentrate in the food chain. Reference -- 52 FR' B14 (03/16/87) EPA Contact -- RCRA/Superfund Hotline (300)424-9346 / (202)382-3000 / FTS 132-3000 V. SUPPLEMENTARY DATA Substance Name -- Arsenic, inorganic CASRN -- 7440-38-2 Not available at this time. VI. BIBLIORAPHY Subs-tance Name -- Arsenic, inorganic CASR'jN -- ast Revised -- 06/01/90 VI.A. ORAL RfD REFERENCES None 9 ------rsenic ., inorganj c VI .. INHALATION RfD REFERENCES None ------<<< Arsenic. inorganic I VI .C. CARCINOEENICITY ASSESSMENT REFERENCES Anderson, 0. 193.S Effects of coal combustion products and metal coiipounds on sister chromatid exchange (SCE) in a macrophage cell line. Environ. Hea th Perspect. 17: 239.-Y- 253 . IAxelson, 0., E. Dahlgren, C.D. Jansson and S.D. Rehnlund. 1970. Arsenic expoSure and mortality: A case referent study from a Swedish copper smalter. B3r. J. Ind. Med. 3.5: E.-15 . Bergoglio, R.M. 1964. Mortality -from cancer in regions of arsenical waters of the province of Cordoba Argentine Republic. FrEnsa Med. Argent. 51: Borgono, J.M. and R. Greiber. 1972. Epidemiological study of arsenicism in the city of Antofagasta. In: Trace Substances in Enviroonmental Hea.lth-V. Proceed. 5th Annual Conference, University of Missouri. Cal umbia, MO, June 29- July 1, 1971. D.C. Hemphill, Ed., University Of Missouri, Columbia, MO. p. 13-24. Brown, C.C. and K.C. Chu. 19S. a. Approaches to epidemiiologic analysis of prospective and retrospective studies: Example of lung cancer and exposure to arsenic. In: Risk Assessment Froc. SIMS Conf. On Environ. Epidemiol. June 28- July 2, 1982, Alta, VT. SIAM Publication. Brown, C.C. and K.C. Chu. 193b. Implications of the multistagte theory of carcinogenesis applied to occupational arsenic exposure. J. Nati. Cancer in rST 70: 455 - .46 Brwn, C.C. and K.C. Chu. 1983c. A new method for the analysis of cohort Studies, implications of the multistage theory of carcinogenesis applied to ;ccupational arsenic exposure. Environ. Health Perspect. 50: 293-3S. Cebrian, M.E., A. Aibores, M. Aguilar and E. Blakely. 1973. Chronic arsenic poisoning inr- The north of M~exico. Human Toxicol.2:1-3. Crossen P. E. 1983. Arsenic and SCE in human lymphocytes. Nutat. Res. 119: 415-419. Diaclo, J. and B. Casto. 1979. Quantitative studies of in vitro morphological transformation of Syrian hamster Ucella by inorganic metal salts. Cancer Rec. 39: 1002-1013. Higgins, I. 1932. Arsenic and respiratory cancer amony a sample of Anaconda smelter workers. Report submitted to the Occupational Safety and Health Administration in the comments of the kennecott Minerals Company on the inorganic arsenic rulemaking. (Exhibit 203-5) 10 Higgins, I. , K. Welch arid C. Burchfield. 1932. Mortal itv of AncOrida smelter workers in relation to arsenic and other exposures Uni vr.it of Michigan, Dept. Epidemialogy, Ann Arbor, MI. IARC (International Agency for Research on Cancer). 17980. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vol . 23. Some metals and Metallic Compounds. World Health Organization, Lyon, France. Larramendy, M.L., N.C. Popescu and J. DiPaolo. 1981. induction by inorganic metal salts of sister chromatid exchanges and chromosome aberrations in human and Syrian hamster strains. Environ. Mutagen. 3: 597-606. Lee-Feldstein, A. 1983. Arsenic and respiratory cancer in man: Follow-up of an occupational study. In: Arsenic: industrial, Biormedical, and Environmental Perspectives, W. Lederer and R. Fensterheim, Ed. Van Nostrand Reinhold, New York. Mabuchi, K., A. Lilienfeld and L. Snell. 1979. Lung cancer among pesticide workers exposed to inorganic arsenicais. Arch. Environ. Health. 34: 312-319. Matanoski, G., E. Landau, J. Tonascia, C. Lazar, E. Elliot, W. McEnroe and K. King. 1991. Cancer mortality in an industrial area of Baltimore. Environ. Res. 25: 8-28. Morton, W., G. Starr, D. Pohl, J. Stoner, S. Wagner and P. Weswig. 1976. Skin cancer and water arsenic in Lane County, Oregon. Cancer. 37: 2523-2532. Ohno, H., F. Hanaoka and M. Yamada. 1982. Inductibility of sister chromatid exchanges by heavy-metal ions. Mutat. Res. 104: 141-145. Ott, M.G., B.B.Holder and H.I. Gordon. 1974. Respiratory cancer and occupational exposure to arsenicals. Arch. Environ. Health. 29: 250-255. Pershagen, G., B. Lind and N.E. tjorkund. 1992. Lung retention and toxicity of some inorganic arsenic compounds. Environ. Res. 29: 425-434. Pershagen, G., G. Nordberg and N.E. Bjorklund. 1984. Carcinomas of the respiratory tract in hamsters given arsenic trioxids and/or benzo(a)pyrene by the pulmonary route. Environ. Res. 34: 227-241. Rencher, A.C., N.W. Carter and D.W. McKee. 1978. A retrospective epidemiological study of mortality at a large western copper smelter. j. Occup. Med. 19: 754-759. Rossman, T.G. 1981. Enhancement of UV-mutagenesis by low concentrations of arsenite in E. Coli. Mutat. Res. 91: 207-211. Roth, F. 1958. Uber den Bronchialkrebs Arsenge-chodigter Winzer. Virchows Arch. 331: 119-137. Sommers, S.C. and R.G. McManus. 1953. Multible arsenical cancers of the skin and internal organs. Cancer. 5: 347-359. S0outhwick, j. , A. Western, Ml. Beck , T. Whitley. R. Isaacs, 3. Petejan and C. Hansen. 1991. Community health associated with arsenic in drinking water in Millard County, Utah. Health Effects Research Laboratory, Cincinnati, OH, EPA-600/1-31-064. Tokudome, 9. and M. Kuratsune. 1976. A cohort study on mortality from cancer 11 and Cther cau.-es amonq wortEnrs at a metal ref inery. Int. J . Cancer. 17: 310--C17. TsEig, W.P. 1977.c Effects and dose response relationships of skiri c ancer and L.i ack foot disease with arsenic. Environ. Health Perspect. 19: 109-119. U.S. =PA. 1984. Health Assessment Document for inorganic Arsenic. Prepared by Environmental Cri-Leria and Assessment Office, Research Triangle Park, NC. EPA/600/8-83./021F. Wa r- , . R.T. Chris.tian .AF .WCi.5. ocokuLp. 192. Studi's of cytcigenetic effects of sodium ~arsenicals on armalian cells in vitro. Environ . MiutarC. 4: Welch K. , I. Higgins, M. Oh and C. 1urchfield. 19C22. Arsenic exposure, smok ing and respiratory cancer in copper smelter wcorkers. Arch. Environ. Health. 7,: .:25-35. if---- * . K Arsenic, inorglanic t1.------ SVI .D. DRINKING9 WATER HA REFERENCES None SYNONYMS SubStanCe Name -- Arsenic, inorganic CARN -- 7440-3.2-2 Last Revised -- 02/10/82 7440-33-2 A rsenic Aaenic, inorganic gray-arsenic 12 Barium: CASRN 7440-39-3 (0/01/90) Health risk assessment information on a chemical is included ir IRIS only after a comprehensive review of chronic toxicity data by work groupS composed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections I and II represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particul]ar EPA program and has been subject to review procedures prescribed bv that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment., or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g., treatment technology). When considering the use of regulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Eackground information and explan- ations of the methods used to derive the values given in IRIS are provided in the tive Backoround DocumentEs in Service Code 5, which correspond to Sections I through V of the cheiij.cali fils-.. STATUS OF DATA FOR Batrium File On-Line 01/31/97 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on-line 05/01/90 Inhalation RfC Assessment (I.D.) no data Carcinogenicity Assessment (II.) no data Drinking Water Health Advisories (III.A.) no data U.S. EPA Regulatory Actions (IV.) on-line 03/01/83 Supplementary Data (V. ) no data _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOSENIC EFFECTS I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RFtD) Substance Name -- Barium CASRN -- 7440- 39-3 Last Revised -- 08/O1/9 The Reference Dose (RfD) is based on the assumption that thresholds exist for 1 certain toxac effects such as cellular necrosis, but may rot ew::t for other toxic ef fr-r t s L&uCh -ts carcj.ri enri c ty. i gener i, tihe Rf) s An estia ate (with uncertainty spanning perhaps 3fn order of mAgnit.ide) of a da y aposu r e to the human pcpul at i on ( inc I .kd.1nd sensitivesps subgic r t Ih . ;s J i ::e I v ton t withou t an appreciabl e risk of deleterjous effec ts durn I g a i fet.i me. Please refer to Back c round Docunent in Se-vS ce Code " for arn el.a lbrrti on of these concepts. Rf Ds can aIso be derived fcr the noncarci.nogenic hea] th effects of compounds which are also carciogena. Thecifrc-', -it .1s essential to refer to other sources of information concerning the carcinogenicity of thIs ubtance. If the U.S. EPA has evaluated t!Iis subEAiance -for potentiAl human carcin n- icity, a summary of that evaluation will be ccnitaiined in TectionIof thiis fiie whcn a rev ew of that eva luation is Empvied. I <( Critical Effect Expera lietal DoSest UF MF RfD Increased blood NOAEL: 10 mg/L 3 1 /E-2 pressure (0.21 mQ/kg/day) m/kg/dav Subchronic to Chronic LOAEL: None Hum.an Drinking Water Wones et al., 1990; Brenniman and Levy, 194 Conversion Factors: 10 mg/L x 1.5 L/day/70 kg = 0.21 mg/kg/day <<< Barium >>> __I A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Nones, R.G., B.L. Stadier and L.A. Frohman. 1990. Lack of effect of drinkinQ water barium on cardiovascular risk factor. Environ. Health Per pect. 5; 1- 13. Brenniman, O.R. and P.S. Levy. 1984. High barium leveis in piUblic drinkino water and its association with elevated blood pressure. in: Advances in Modern Toxicology IX, E.J. Calabrese, Ed. Princeton Scientific Publications., Princeton NJ. p. 23.1-249. No single study considered alone is appropriate to calculate a lifetime - RfD for barium. The RfD must be based rather on a weiqht of evidence approach which takes into account recent findings of the Wones et &i . (1990) and Brenniman and Levy (1964) epidefmiologic studies as well as the various rodent studies that have been conducted (Perry et al., 1953: McCauley.et a:., 1985; Schroeder and Mitchener, 1975a, b Tardi f e t al , 190) Because of the number of studies involved, the complete reference citations are given in the ecSection VI. W ones et al. (1990) =dmJinistered barium as barium chl oride) in the drinking water of 11 healthy male vol unteers. Subjects ranged in age from 27 o ,1 years and had no previr3us history of diabetes. hypertEi= on, or . cardiOVscuLLar disease. Diets were strictly controlled throughout the i0 -week StUd. S bj ects were givan i. 5 L/day of distil led and cha rcoa 1-fi 1 tered water containing 0 mg/L barium for weeks 0 to 2, 5 mg/i_ for wee::5 .3 to 6, and 10 mg/L for weeks 7 to 10. Bloo and urine samples, as well as morning and 2 evening blood pressures, were taken. Electrocardiograins and 24-hour continuous eJoctrccardiograrhic monitoring weJ.re also performed I here werie no changes in systol i ci or di stol ic blood pr eesureS, or serum chemistry, especj a) ly total cho] esterol, HDL, LDL , trig ] ycerides , potassiumll or cilucoSe levels. There was an increase in serum ca lc ium levels t hat was attributed to a decrease in serim albumin levels This increase, although statistically significant, was considered borderline and riot clinically significant. There were a) sc, no chances in cardiac cycle as noted by electrocardiograms and no sicinificarit arrhythmias. A NOAEL of 10 mg/L was identified in this Study which corresponds to C.21 rq/kg/dav, based on an actual consumpti on rate of 1.5 L/day and a -70-kg body weight. Brenri man and Levy (1984) cCjnducted a retrospective epidemi olcogy study which compared human mortality and morbidity rates in populations ingesting elevated barium levels (2 to 16 mo/ L) in their drinking water to populations ingesting very little or no barium (less than or equal to 0.2 mg/L). Mortality rates for cardiovascular diseases were determined for the years 1971-1975 and were age-adjusted. For the morbidity study, 1175 adult males Wand 12032 adult feiales were selected from coimurri ties in which the averacle drinking water corncentration was 7.3 ng/L. Differences in mortality rates from all cardiovascular diseases were sinnificant] y higher (p<.-:.O5) in the communities with elevated barium-. However these differences were largely in the 65 and over acg e group and did. not account for confcouindirg variables sLIchi as popuilation mobiliy, or use ofT water softeners or- medication. Differences in blood pressure, prevalance of hypertension, stroke, and heart and renal disease were also measured between the individuals in the two communities. Data were analyzed using signed ranked test for aoe-specific rates, the weighted Z test for prevalence rates, and analysis of variance for blood pressures. No significant differences were found in mean systolic and diastolic pressures between the two communities. No significant differences were found when the total populations were broken down by ouration (10 years or more), medication, or use of water softeners. Aso the prevajence rates for hypertension, stroke, and heart and kidney disease were not significantly different between the communities. A concentration of 7.3 mg/L corresponds to a dose of 0.20 mg'/kg/day (assuming a 70-kg adult drinks 2 L/day). <<< Barium I.A.3. UNCERTAINTY AND MODIFYING FACTOR; (ORAL RfD) UF = 3. According to U.S. EPA guidelines, ann uncertainty factor of 10 is applied when a NOAEL from a subchronic human study is employed. However, data are available from chronic human studies which support this NOAEL, as well as several oral chronic animal studies. Therefore, this UF is not considered necessary. In addition, another factor of 10 is used with a human study to protect sensitive individuals. However. the data base supports the finding that the critical effect is hypertension which results from long exposure durations, and that the popul ation mOst a't risk is the adu3 t male. Furthermore, the chosen study is a careful observation of this critical ef fect in adult males. Because of both the critical study's unaioue focus and the upporting stud .i,* a 3-fold6 UF instead of a 10-fold UF, was chosen as most appropriate to protect for sensitive indvicuals wi thin that population. UF=1 <<< Barium 3 _ . .4. AD IT*NL COMMENTS CORAfl F: I ) Occupa ti onalItudies tf wcorkers expo- I. =eSd to aL.'ruri d u si t haive shown t hat work:e rs develop "ha r . tosi . " Af-i ec ted wo rk e rs shO-Jed o yim.ptms, n ab[ncrma phvsica l signs, no loss of vital capacity or interference with function, SalthOLgh they had a LIsignificaIntly higher incidenre of hypertension. McCaule y et al . ( 1.985 ) studied the histologic and cardiovascular effct of drinking water containing C', 1.0, .. : or 251 m/L f*rnrm 36 L- io ; , 1, 10, 100, or 1000 g/L barium for 1.6 weeks, or 1, 10., cr 2507. m ( 1 .4, 14, 35, or 14 ng/kg Ba) barium for 68 wei on male Spragnue-Dawev rats (6/group) . Females were exposed to Ci or 250 moin/L far 46 weeks. No sioni ficant histologic, carcinogeni c , or cardi:vaicular including hype rtension) effects were observed. No changes were reported j- body weight, or food and water consmLIptior i.n any of the treated animc als. Anima Is treated at the highest dose (1000 mg/L) did exhibi t U trastructural chane' in tha? k idney g omerli and the presence of myel in figur.s. No other r fect were reported at any do-se l evel for males or feml es. Ferry et rA . (1'73 ex posed wenr 1 r g rats to bariun at 1, 1 r 10 ppm in drinking vater fur up to 16 months (average daily barium doses f 0. 051 0.51, and 5.1 mg/kg, respectively) . There were no signs of tox ci tv at any barium doce level. Systolic blood pressure Creasuremient:s reveal d no increase in animals expsced to 1 ppm for 16 months, an increase of 4 mm Hg p<.01) in animals ex'PosEd to 10 ppm barium for 16 months, ansd an increase of 16 (imm Hg (p 0C)) in animals exposed to 100 ppm bar ium fmr 1 mon ths. The animals in this study were maintained in a special contaminant-free environment and ted a diet designed to reduce exposure to trace metals. It is possible thiac tnne restricted inta:e of certain beneficial metals (e.g., calcium and potEssium) may have predisposed the test ani-mals to the hypertensive Effc te of bar'ium (U.S. EPA, 11985). Schroeder and Mitchener (1975a,b) exposed rats and mice to 5 mg/L barium in drinking water for a lifetime (approximately 0.25 mg/kg/day for rats and 0.925 mg/kg/day for mice). No adverse effects were observed; however, blood pressure was not measLred. Tardiff et al. (190) exposed rats to barium at 0, 1', 50.. or 250 ppm in drinkinq water for 4, B, and 1-3 weeks, The barium concentrations were approximately 0, 2.75, 13.7, and 66.25 mg/kg/day at the beginning of the study and 0, 1.7, 6.6, and 71.5 mg/kg/day at the end of the study. Although the barium body burden increased with increasing barium dosage, no conclusive signs of barium toxicity were observed in these animals. Blood pressure was not measured . I.-.5. CONFIDENCE IN THE 5RAL RfD Study: Medim Data Base: Medium s previously.V stated. E7 does not believe thit any single study, con s id ered aIo n ,- is- ade-OUate to calculaeR- anI- fD for bar iumi1. However., EP;A believes that medium confidence can be placEd in the total data base ued to determine the RfD. a < Barium 4 I II.B. OTHER ASSESSMENTD Substance Name -- Darium CASRN -- 7440-.39-3 Content to be determined. IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Barium CASRN -- 7440-39-3 Last Revised -- 03/01/88 EPA risk assessments may be updated as new data a2re pLiblished and as assessment methodoloqies evolve. Reoulatory actions are frequently not updated at the same timne. Compare the dates for the r-egqulairtory actions in this section with the verification dates for the risk assessments in sections I and II, as this may explain inconsistencies. Al so note that some regiulatory actions consider factors riot related to health risk., such as technicai or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning these regulatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatory action in Background Document 4 in Service Cods 5. <<< Barim __V.A. CLEAN AIR ACT (CAA) No data available ------<< Barium ------ _IV.B. SAFE DRINKING WATER ACT (SDWA) IV..l.jI MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinkinq Water Value (status) -- 1.5 mg/L (Proposed, 1985) Considers technological or economic easibility? -- NO Discussion -- An MCLG of 1.5 mq/L for barium is proposed based on a provi- sional DWEL of 1.2 mq/L. A DLJEL was calculated from a LOAEL of 5.1 mg/kq/day barium for hypertensinogenic and cardiotoxic effects in rats (16-month drinkinq water study) . An uncertainty factor of 100 based on mini mized exposure to calcium) was applied and consumption of 2 L of water/day was 6 EPA Ccn tat -- FkCR:A /SuperFf und Hot Iline ((0) 4 2 4-9346 / (202)382-.000 / FT1 82-300C) ------< arium >>------ _IV.G. SUPERFUND (CERCLA1 ) No data available V. SUPPLEMENTARY DATAp Substance Name -- BagrimLLm CAlSRN -- 7440-37-3 Not available at this time. VI. BIBLIOGRAPHY Substance Name -- arium CASRN -- 7440-39-3 Last Revised -- 08/01/90 _VI.A. ORAL RfD REFERENCES Brenniman, G.R. and P.S. Levy. 1984. Epidemiological study of barium in Illinois drinking water supplies. in: Advances in Modern Environmental Toxicology IX, E.3. Calabrese, R.W. Tuthill and L. Condie. Ed. Princeton Scientific Publications, Princeton N. p. 231-240. McCauley, P.T., B.H. Douglas, R.D. Laurie and R.J. Bull. 1985. Investigations into the effect of drinking water barium on rats. Environ. Health Perspect. Vol. IX, E.j. Calabrese, Ed. Princeton Scientific Publications, Princeton, NJ. p. 197-210. Perry, H.M., S.J. Kopp, M.W. Erlanger and E.F. Perry. i993. Cardiovascular effects of chronic barium ingestion. In: Trace Substances in Environmental Health, XVII, D.D. Hemphill, Ed. Proc. Univ. Missouri's 17th Ann. Conf. on Trace Substances in Environmental Health. University of Missouri Press, Columbia. MO. Schroeder. H.A. and M. Mitchener. 1975s. Life-term effects of mercury, methyl mercury and nine other trace metals on mice. j. Nutr. 105: 452-458. Schroeder, H.A. and M. Mitchener. 1975b. Life-term studies in rats: Effcts of aluminum, barium, beryllium and tungsten. j. Nutr. 105: 421-427. 8 Tardaft R.G., M. Robinturi ard N.S. Ulrmr. 135?. Subchronic oral tuxicaty of BaC12 in rats. J. Environ. Pathci. Toxicol. 4: 267-275. U.S. EPA. 1995. Draft Drinkinc Water Health EffectF Criteria Docurnent on B.ariur. Office of Drinking Water, Washington, DC. NTIS PB 86-l1B31i/AS. Wones, R.G., B.L. Stadler and L.A. Frohman. 1990. Lack of effect of drinkinc water barium on cardiovascular risk factor. Environ. Health Ferspect. 85: 1- 13. ------< B . r iumrr ------ VI . B. INHALATION RfD REFERENCES None ------<< arium >> ------ _VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None -. ------Barium ------ VI .D. DRINKING WATER HA REFERENCES None SYNONYMS Substance Name -- Barium CASRN -- 7440-39-3 Last Revisec -- 7440-39-3 Barium . UN 1399 UN 140D UN 1G54 9 Berylliu-tm; CASRN 744Q-1-7 (011/01/91.) Health risk assessment information on a chemical is incl ded in IRIS only after a comprehersive review of chronic to icity data by work gnroupS c uo m ppoed c of U.S. EPA scientists from several Frogram Offices . The SLmIIrLxiC-s presented in Sec tions I and II represen t a cnsensLs reacticd in the r &v1eviw proce=ss The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subjcct to review procedures preicribed by that1c ProQram Office. The regulatory actions in Section IV rvy not be based on the Miost cUrrent risk assessDent * or may be based on a cuirrent , but unreviewed, risk assessmen '- , and may take into account factoure other- than heal th effects (e.g. treitment technology) . When corsidering the use of r-g'c-ulatory action data for a particuilr situation, note the date of the reujlkr1atory action, the date of the most recent risk assessment relatini to that action, and whether techno loq ic al factors were con si dered. Bac kg round information and ex plan- ations of the methods used to derive the valLues agiven in IRIS are provided in the five Ba ckOroLnd Documents in Service Code 5, which correspond to Sections I throuiqh V of the chemical files.- STATUS OF DATA PU beryllium File On-Line 01/31/67 Category (section) Status Last Revised Oral RfD Assessment (I. A.) on-line 09 /!'1/ Inhalation RfC Assessment (I.B.) no data Carcinogenici ty Assessment i.II.) on-line 01 DrinKinc Water Health Advisories (III.A.) no data U.S. EPA Regulatory Actions (IV.) on-line 09/01/90 tuppiementary Data (..) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOENIC EFFECTS __l. A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDf substance Name -- Bervilum CASRN -74--1- Last Revised -- 09/01/90 The Reference Dose (ifD) is based on the assLImption that thresholds exist for I certain toxic effects such as cellular necrosis, but may not exist for other toxic efiects ouch Ls carcinOgerticity. . in genera] t!fDthc- R.rci ai r can timate with uncertainty spanning perhaps an order of magnitude! of a daily expooure to the human popu)ation Cincluding ensitive subgroups) that is likely to Le without an appreciable risk of deleterious effects during a lifetime. Flease refer to Background Document 1 in Service Code 5 for an elaboration of these conceptE. RfDs can also be derived for the noncarcinogenic health effects of compounds which are alEo carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this subStance. if the. U... EPA has evaluated this substance for potential hura n carcinogen- icity, a stummary of that evaluation will be containd in Section 11 of this iile when a review of that evauatio i1 completed. -< Beryl lium >>> I.A.i. D'RAcL RfD UMARY CriticEal Effect Experimental Dc.est UF MF RID No adverse effects NCAEL: 5 ppim1 in 100 1 5E--. drinking water (0.54 mg/kg/day Rat, Chronic Oral mg/kg bw/day) Bioassay Schroeder and LOAEL: none Mitchner, 1975 *Conversion Factors: 5 ppm (5 mg/L) x 0.035 L/day / 0.325 kg bw = 0.54 mg/kg bw/day Beryllium >>> i.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Schroeder, H.A. and M. Mitchner. 1975. Life-term studies in rats: Effects of aluminum, barium, beryllium and tungsten. 3. Nutr. 105: 421-427. Fifty-two weanling Long-Evans rats of eazh sex received 0 or 5 ppm beryllium (as BeSO4, beryllium sulfate) in drinking water. Exposure was for the lifetime of the animals. At natural death the rats were dissected and gross and microscopic changes were noted in heart, kidney, liver, and spleen. There were no effects of treatment on these organs or on lifespan, urinalysis, serum glucose, cholesterol, and uric acid, or on numbers of tumors. Male rats experienced decreased growth rates from 2 to 6 months of age. Similar studies were carried out on Swiss (CD strain) mice in groups of 54/sex at doses of approximately 0.95 mg/kg/day (Schroeder and Mitchner, 1975) . Female animals showed decreased body weight compared with untreated mice at 6 of S intervals. Male mice exhibited slight increases in body weight. These effects were not considered adverse, therefore, 0.95 mg/kg/day is considered a NOAEL. An unpublished investigation by Cox et al. (1975) indicates a mch higher dose level (approximately 25 mg/kg/day) in the diet may be a NOEL. L eny 1 1 iUMi I.A.3. UNCERTAINTY AND MDIFYING FACTORS (DRAL RID) UF = 100. The uncertainty factor of 100 reflects a Tactor of 10 each for 2 interspecies converjaion and for the protection of sec-nsitive humtn ubpopulations. MF = 1. 3 < Beryl ium SI.A.4. ADDITIONAL COMMENTS (ORAL RfD) This RfD is 2limited to So)luble beryl Iliu sal tE. Data on the terato- genicity or reproductive effects of beryllium are limited. it has been reported to produce embryolethali ty and terata in chick embryos (Puzanova et al., 1978). < eryliuI >> I.A.5. CONFIDENCE IN THE ORAL RfD I tudy: Low Data Base: Low R1D: Low. * Confidence in the study is rated as low because only one dose level was administered. Although numerous inhalation investigations and a supporting chronic oral bioassay in mice exist, along with the work by Cox et al. (1975) which indicates that a higher dose level might be a NOEL these studies are U considered as low to mediutm qual ity; thus, the data base is given a low confidence rating. The overall confidence in the RfD is low, reflecting the need for more toxicity data by the oral route. f I .A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 19c5. Drinking Water Criteria Document for Beryllium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. The 1985 Drinking Water Criteria Document for BerVlium is currently under- going Agency review. Agency RfD Work Group Review: 12/02/85 Verification Date: 12/02/85 I .A.7. EPA CONTACTS (ORAL RfD) Cvnthia Sonich-Mullin / CR0 -- (513.)567-7523 / FTS 64-7523 I Krishan [nanna / ODW -- (202) 32-7582 / FTS 382-7588 E------I.B.-REFEREN-E-CONCENTRATION-FOR--HRONIC--NH-LA -I .8P. REERsrI'NCE CO.ICEk-- RAT I ON FOR CHRON IC I NHA-"LAT-,ION E )'POSURE ( RfC) 3 SLbstance Name -- Bery.Illiurm C 7.40-41-7 Not available a.t this time. II. CARCINDGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Beryllium CASRN -- 7440-41--7 Last Revised -- 01/01/91 Section II provides information on three aspects of the carcinogeniic rik assessment for the agent in question: the U.S. EPA classification, and quant- itative estimates of risk from or-al erxposire ind from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the aqent is a human carcinogen. The quantitati.ve rik 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/leg)/day. The unit risk is the qucantitative estimate in terms of either risk per Lug/L drinking water or risk per ug/cu.m aEiir breathed. The third form in which r is:: is presented is a drinking water or air concentration providing cancer risks of 1 in 3.0,00 ) i in 100,000 or 1 in 1,000,000. BackgrOund Documer:nt 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicitv. << Beryllium > II.A EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINDGENICTTY II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen. Basis -- Peryllium has been shown to induce lung cancer via inhalation in rats and monkeys and to induce osteosarcomas in rabbits via intravenoLs or intramedullary injection. Human epidemiology studies are considered to be inadequLI.at e. << ryllium > I .A.2. HUMAN CARCINOSENICITY DATA . InaCequate. Reported increases, while apparently associated with exposure, did not take a variety of possible confounding factors into account. Wagoner et al. (1980) observed 47 deaths from cancer among 3.055 white males employed in beryllium-processing with a median duration of employment of 7.2 months. Among the 2062 fo llowed for 25 years or mere, 20 lung cancer deaths were observed. Those increased incidences were statistical. lv significant. When lung cancer mortality data became available for 1968-1975, e number of expected death- was recalculated ard the increaed incidence was statistically significant only among workers followed 25 years or more (Baliss, 1920: Machahon 1977. 1978) When the number of expected deaths was adjusted for 4 mCk ing the increas.ed i ncidence Va.E no I onaer siign if i catn t (I. S . *EA I 9.) rn earl i sr %.tuciycf wor-. er s f ro.m ti s saE bery1 1 iur pir ocec ing pl ant , arId several studies of workers from this plant combi ned with workers from otIser beryl l ium plants, have reported a statistically sicinificant increascd incidence of lung cancer (Bayliss and Wagoner, 1977. MaIcuso., 1970., 1979., 1980 ) . No adj ust.meri t was made for soriolk ir in these studies, ard al I were limited in their ability to detect a possible increased incidence of lung cancer becausecf mthc:do logic al constraints and deficiencies. <<< BEryllIiumn> II .A.3. ANIMAL CARCTNOGENICITY DATA Suf ficient. Based on the evidence for induction of tumors by a variety of beryll ium compounds in male and female monk-eys and in several strains of rats of both sexes, via inhalation and intratracheal instillation, and the induction of osteosarcomas in rabbits by intravenous or intramedullarv injection in multiple studies. light increases in cancer incidence (not statistical ly significant in comparison with controls) were reported in Lonq-Evans rats (52/sex/group) admrixnist.ered 5 ppm berl1lium sulfate in the drinking water for a lifetime. The authors reported a slight excess of grossiv observed tumors in the 5 ppm group (9/33) over 'controls (4/26) in the male rats. The power of this test to- detect a carcinogenic effect was reduced by high mortality (approximatey 60.'. survived a pneumonia epidemic at 20 months) (Schroeder and Mitchener. 1975E). Schroeder and Mitchener (1975b) administered 5 ppm beryllium sulfate in drinking water to Swiss mice (54/sex/group) over a lifetime. non- statistically significant increase in incidence of lymphoma leukemias were reported in the females (9/52) relative to controls (3/47). An increase in reticulum cell sarcomas of the lungs was seen in male, but not female Wistar-derived rats administered bervllium sul fate in the diet at 5 and 50 ppm, but not at 500 ppm (Morgareidge et al., 1977). The incidence in males equaled 10/49, 17/35, 16/40 and 12/39 for the control, low, intermediate and high dose groups, respectively. Since the results were published only as an abstract, and since no response was seen at the highest dose, these resuts are considered to be only suggestive for the induction of cancer via this rouIte. Osteogenic sarcomas were induced in rabbits by intravenous injection of beryllium compounds in at least 12 different studies and by intramedullary injection in at least four studies (U.S. EPA, 1987). Bone tumors were induced by beryllium oxide, zinc beryilium silicate, beryllium phosphate, beryllium Sil icate and bervl l ium metal . No bone tumors were reported to be induced by intravenous in jc tion of beryl l ium ox ide or zinc bery 1 ium silicate in rats or quinCe pigs (Sardner and Hesl inoton , 1946). Positive results, however. were r eported in mice injected with zinc beryllium silicate, although the numbers were not listed (Cloudman et al . , 1949). The sarcomas were generally reported to be quite malignant and metastasized to other organs. Lung tumors. primarily acenomas and sdenocarcinomas, have been induced via the inhalation route in bth riale and inale praue-wley rat_= during Pxposureperiods of up to 72 ws'elks by beryl ium sul fate (Reeves e t al., 1967), in both male and female Sherman and Wistar rats by oery 1 ium phosphate, beryl I ium fluoride and zinc LIeryll um silicate (Schepers. 1951) inr male Charles River CR-CD rats by beryI ore (Wagner et al. 1969) and in both male and female rhesus monkeys by beryllium sulfate (Vorwald. 1968). Positive results were seen in rats exposed to beryl Ilium sul 1 ate at concentrations a 5 lCwW E. 72 C /CLI m (V rwa,W 1 ). umo rs wereF f a i ndr k b v i r it rat r ach i n s*ti 1 1 ati on of met a 1 i c eryllium, hery 11 ium-->a 1uinrum a 1 loys and bery l J in o: i 1 fnd -. :th Wistar rats r6 rhesu'% mon k:ys . Adunnroai&s, EEde'noca rc i.nom as and ma a3qri at 1 ymphomat were seen in the Lunqs, with 1 ymphI-icsarcomas and fi brosarcomas present at ex: t r 6apu moar y sites ( Gr-oth ct al. 198; Ishinishi et a]., .190) II. A.4. SUPPORT ING DATA FOR CARCINOGENICITY Beryllium s0fate and berylli um chloride have baer shown to be nonmutenic in bacterial and yeast gerne mutat.on assays ( Simmon et al 197) In contrast, gene mutation studies in Chinese hamster V79 and CHO cells were positive (MiyaI:;i et al., 1979; Hsie t al. 1979). Chromosomal aberrations and sister chromatid exchange were also induced by beryl lium in cul1tured human l ymphocytes and Syrain hamster embryo cells (Larrameindy et al. 1981). Ber i ium ------ Ii.B. QLANT1TTATI'E ESTIMATE OF 'CARCINOGENIC RISK FROM ORAL EXPOSURE II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 4.3 permg/k)/day Drinkinq Water Unit Risk -- 1.2E-4 per(uQ/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drink ing Water Concentrations at Specified Risk Levels: Risk Level Concentration E--4 (1 in 10,000) 8. 3--1 Lg/L E-5 (1 in 100,000 ) .3E-2 ug/L E-5 (1 in 1,000,o 00 8. 3E:-3 ugI/ L II.B.2. DDSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) TImor Type -- Qrcss tumors, all sites com-bined Test Animals -- rat/Long-Evans. male Route -- oral, drinking water Reference -- Schroeder and Mitchener, 1975a ------Dose--- TL1Mo r Admin- Human Incidence intered EqUivalent (mg/kg/day) ppm mg/kg/day 6 5 0.54 0.09 9/33 < II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The solubility and speciation of beryllium in air and water media vary, with ambient air characterized by relatively insoluble beryllium compounds such as beryllium oxide and metallic beryllium, and water characterized by more soluble forms. Carcinogenic potency varies according to the form of beryllium present. Human equivalent doses were calculated using a human bcdv weight of 70 :g, an animal weight of 0.325 kg and length of exposure, experiment and lifespan of 1126 days for treated and control animals. The unit risk should not be used if the water concentratioi exceeds S.3E+1 ug/L, since above this concentration the unit risk may not be appropriate. < Beryl l i > II.B.A. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) The estimate is derived from a study which did not Ehow a significant increase in tumorigenic response. While this study is limited by use of only one non-zero dose group, the occurrence of high mortality and unspecified type and site of the tumors, it was used as the basis of the quantitative estimate because exposure occurred via the most relevant route. Oral risk estimates derived by extrapolation from studies in other species/strains for the intravenous and inhalation routes (also highly uncertain) are within an order of magnitude. ------Bqeryllium >>>.:------ _II .C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 2.4E-3 per (ug/cu.m) Extrapolation Method -- Relative risk Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) 4E-2 ug/cu.m E-5 (I in 100,000) 4E-3 ug /cu.r m E-6 (I in 1,000,000) 4E-4 ug/cu.m < Bert-yl liuLm > 11.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Beryllium 95 percent 7 conce n tr ati on Frac tion E f fic tive Upper--bcund Uni i. 3 n Vor-kpl ace of dose Estimate of Rirk ( U/cu k m ) Lifetime (ug/cu .m)M tive F: i s /Lci/cL. m 100 i.0 21.92 1.98 i.iE-3 2.09 1.79E-3 4.258.4 1.98 6.44E-3. 2.09 7.16E-3 1000 1.00 219.12 1.92 i.61E-4 S2.091.-4 25 54 .79 1.90 - 44E--4 2 'i9 7.IE-4 (< Beryl lium >. II.C. . PDDITIONAlL COMMENTS (CARCI NOGENICI1 TY,- T iNHALATION EXP.rULiRE Human data were used for the inhalation exposure quantitation despite limitations in the study. Humzans a-re mos~t lievto be epedby inhalation to beryllium oxide, rather than other beryllium sal t A.nimal studies Oy inhal ation of beryl 1 ium oxide have utilized intratracheal instillation, rather than general inhalation exposure. Ef fec tive dose was determined by adj ustIng for uIr atIon of dal lV (8/24 hours) and annual (240/365 days) exposure, and th- fraction of the if etime at risk (i.e., time from onset of employment to termination of follow-up). The risk estimates were based on the data of Wagoner et al. (1980) in which the smokinq adjusted, expected LnO cancer deaths were found to range from 13. to 14.67., in comparison to 20 0'oserved. Reative risk estimates of I.6 and 1.44 were derived ard the 957 confidence 1i mits of these est imates., I.9 and 2.09, respectively, were usCd to estimate the lifetiJe cancer risk. Note that all of the above estimates are based on one data set using a range of estimateo exposure and exposure times. Because of uncertainties regarding workplace beryllium concentration and exoosure duration, unit risks were derived using two estimates each of concentration, iraction of liffetime exposed and relative risk. The recommenoed value is the arithmetic mean of the B derived unit risks. The unit risk should not be used if the air concentration exceeds 4 uq/cu.m, since above this concentration the unit ris. may nort be Fppropriate. <<< Beryllium >- _II . C.4. DISCUSSION OF CONFIDENCE (CARCINOGEN ICITY. INHALATION EXPOSURE) The estimate of risk for inhalation exposure was based upon an epidemiologic study having several confounding variables. The estimates of exposure levels and duration were also somewhat uncertain. While quantitative assessment based on several animal studies resuIted in a similar estimate of risk (which increases the confidence somewhat), the quality of the E avail able studies was pC-or- (that is, they were conducted at sincile dose levels or lacked control groups) --I------lLLey :> :>------ a _I.D. EPA DOCUMENTATION, REVIEW, AND CONTA-CTS (CARCINOENICITY ASSESSMENT) 8 _. II .D. .EPA-) DLOCUMENTATi QN U. S. EPA. 1986. Health AsEessment Document for Beryllium. oflice Ef Health and Environmental Assessment. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EFA 600/8-81i-02SF. U.S. EPA. 1987. Drinking Water Criteria Document for Beryllium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. (External Review Draft) Fjer-yllium >>> II.D.2. REVIEW (CARCINOGENICITY A SSESSMENT) The values in 19S4 Health Assessment Document for Beryllium received Agency and external review. The 1984 Drinking Water Criteria Document received Agency review. Agency Work Group Review: 05/04/28, 02/01/29, 12/07/89 Verification Date: 05/04/82 (inhalation); 02/01/29 (oral) II.D3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) William Pepelko / ORD -- (202)382-5904 / FTS 382-5904 David Bayliss / ORD -- (202)382-5726 / FTS 382-5726 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III .A. DRINKING WATER HEALTH ADVISORIES Substance Name -- Beryllium CASRN -- 7440-41-7 Not available at this time. -11I.B. OTHER ASSESSMENTS Substance Name -- PEer-vium CASRN -- 7440-41-7 Content to be determined. 9 IV. U.S. EPA REGULATORY ACTIONS if bstLSance Name -- BeryLli CASRN -- 7440-41-7 Last Revised -- 09/01/90 EPA risk assessments may be uprdated as new data are pIublished and a Iiassessment methodoilogies evolve. Regulatory actions are frequintly not Updated at the same time. Compare the dat.s for the regLlatory actions in this section with the verification dates for the risk assessmente in sections I and II, as this may explain incosistencies. Al so note that sorme rEculatory actions consider factors not related to health risk, such as technical or economic feasibi lity . Such considerations are indicated for each action. In additicn, not all of the regulatory actions listed in this sec tion involve enforceable federal standards. F)ease direct ny questicns yoL may have concerning these regulatory actions to the U.S. EF-A contact l isted for that particular action. Users are sEtrongLy Lrged to read the backg:round inform- ation on each regulatory action in Biackg:Tround Document 4 in Service Code 5. U IV.A.i. NATIONAL EMISSIONS STANDARDS FOR HAZARDOUS AIR POLLUTANTS (NESHAP) Considers technological or economic feasibility? -- YES Discussion -- Beryllium was listed as a hazardous air pollutant under section 112 of the CAA in 1971 on the basis that it can cause the chronic luno disease berylliosis. Emission standards promulgated for extraction ceramic, and propellant plants. foundries, incinerators and machine shops are 10 g/24 hr or attainment of an ambient concentration near the source of 0.01 ug/ca.m, 0C day average. This ambient concentration was judgd adequate to protect he public health with an ample margin of safety. More complex standards were also promulgated for beryllium rocket motor firing. The NESHAPs are now under review, and will consider new health evidence that berylli y be a 3Carcinogen. LCmyb Reference -- 40 CFR Part 6i, Subparts C & D EPA Contact --- Emissions Standards Division, ARPS 17i)54i-557i / FTS 529-5571 -- r .iufu-> ~A------Brll- I _I.B.SAFE RINKjYI NGJWATR ACT ( SDWA) No d a available ------ery lim > ------ 10 IV .C . CLEANF l>ATER A C T CW A) IV.C.D. AMBITENT WTER GULITY CRITERIA, Human Heal th Water and FiEh Consumption: 6..8E-3 ug/L Fish Consumption Only: 1..17E-1 LC/L Considers technological or economic feasibilit.'? NO DisLssion -- For the max imfIum protection from the potertial carciioenic properties of this chemical., the ambient water concentration should be zero. However, zero may not be attainable at this time, so the recommeded criterion repreSent a E-6 estimated inc remental increase of cancer risk over a lifetime. Reference -- 45 FR 79318 (11/28/80) EPA Contact -- Criteria and Standards Division, CWRS (202)475-7315 / FTS 475-715 < EerylliLm IV. C. 2. AMBIEkiT WATER DUALITY CRITER.IA, Aquatic Organisms Freshwater: ACute LEL -- 1.E+2 ug/L Chronic LEL -- 5.3E+0 uo/L Marine: None Considers technological or economic feasibility? -- NO Discussion -- The values that are indicated as "LEC" are not criteria, but are the lowest eftect levels found in the literaturec. LECs are given when the minimum data required to derive water quality criteria are riot available. Reference -- 45 FR 7318 (11/28/80) SPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 ------B ryl LIum ------ IV.D. FEDERAL INSECTICa- DE, FUNGICIDE, AND RODENTICIDE ACT FiFFR) No data available ------ryl ------ _IE. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available 11 ------ry im TV.F. RESOURCE C0NSERWvTI~ ON AND RECOVERY A.CT (RCRA>) IV. F.1. RCRAr APRPrENDIX IX., for Ground Water Mronitoring Status -- Listed Reference --- R 255.42 (07/ 09/7) EFA Contact -- RCRA/uI per furid Hotline 800 )424-9346 / (202)382-3000 / FTS 3s2-3000 ---- Ber'y 1 i U -fl- V .G. SUPERFUND (CERCLA) IV. G1. REPORTAE'LE GUANT1TY (RE) for Release into the Ervironment Value (status) -- 10 pOunds (Proposed,- 1937) Considers technological or economic feasibility? -- ND Discussion -- The proposed RD for beryil±um is baSed on potential carcinogenicity. Available data indicate a hazard ranking of medium based on a potency factor of 79.70/mg/kg/day and a weight-of-evidence group 92, which correspond to an RD of 10 pounds. Reference -- 52 FR 8140 (03/16/87) E Contact -- RCRA-/Superf Lnd Hotline (800)424-9346 / (202)382-3000 / FTS 3t2-3000 V. SUPPLEMENTARY DATA Substance Name -- Beryllium Not available at this time. VI. BILIOGRAPHY zubstance Name -- Beryl lfiuM CASRN -- 7440-41-7 Last Revised -- 09/01/90 12 VI .A. DRAL RfD- REFERENCES Cox, G.E., D.E. Bailey and K. orgareidge. 1975. Ch'ronic fucding stLtdies w iith beryllium sulfate in rats. Unpublished report SLbmi tted by the Food and DLruc; Research Laboratorie.o * Inc., to the Alulin Cmpaniy of Amer ica, Pittsburgh, PA. PuZ anova, L., M-. Doskocil and A. Duubikova.- 1978. Disturbanics c:'f t development of chick embryos after th- adcmfinistrationi of beI Iium chIorid at early stages of embryogenesis. Folia. Miorphologica. 26(3) : 229-231. Schroeder. H.A. and M. Mitchener. 1975. Life-term studies in rats: Effects of aluminum, barium, beryll ium and tungcisten . J . Nutr . 105: 421- 427. U.S. EPA. 1985. DrinI:ing Water Criteria DOcOmen t for Beryllium. Prepared by the Of-fice of Health ard Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. -. Beryi i uUm :.------ Vi .B?. INHALATION RfD REFERENCES None ----. : Beryllum ------ VI .C. CARCINOGENICITY ASSESSMENT REFERENCES Bayliss, D.L. 1980. U.S. EPA, Washington, DC. Letter to William H. FOge, M.D., Center for Disease Control., Atlanta, GA. November 12. Bayliss. D.L. and j.K. Waooner. 1977. Bronchogenic cancer and cardio- respiratory disease mortality amonq white males employed in a berylli ium production facility. OSHA Beryllium Hearirig1 1977, Exhibit 13.F. Cloudman, A.M., D. Vining, . Barkulis and J.3. Nickson. 1949. Bone changes following intravenous injections of beryllium. Am. J. Pathol. 25: 810-811. Gardner, L.U. and H.F. Hcslinqton. .1946. Osteo-sarcomia from intravenous beryLlii compounds in rabbits. Fed. Proc. 5: 221. (Cited in U.S. EPA, 1987) Lroth, D. ,i C. Kommineni and S. R. Mackav. 1980. Carcin-cgnicity OT beryllium hydroxide and alloys. Environ.res. 21(1): 63-84. H sie A.W., J.P. O'NIll, j.R. San Sebastian, nt aI. 1979. Quantitative mamma: ian cell genetic tcxicology: tudy of the cytotoxicity and mutagenicity4 of seventy individual environmfental eents related to energy technoloies and three subfractions of crude synthetic oil in the CH/HGPRT system. Env.iron. Sci. Res. 15: 219-315. 13 1Ihiia h: Ni. , M.mrUnoe, Mi - T. InarnJIcl 3Lt Sfand A. Hi sar 1 . 1980. Experi nen:Tt al uLdy' in C arci n og en ic ity of rliur 1 o-ide,1im and arsenic trioxide to t Ie 1 ung of rats by an ir t r atrac heal inst .i 11 atibonr. FLLkIOk a I gA Z asZhi . 71. (1. 19-2b. (Jap. with Eng, abstract) arr amendy, M.L. . N.SC. Fopescu and j.A. DiPaol a. 1 981 . Induction by inorganic metal a1 ts oF sister chromatid exc hanges arid chromosome aberrations in hLAman and Syrian hamster cell Etrair . Envi ron . Mutaraen. : 97-606. MacNahon , B. 1977. Evaluation of epidemiological mterials. januar v 1a0, 1978. Brush Wl IFmin, Cl e) and OH. JSHA Bery liu Harings 5. Macrahon, B. 1978. OEHA Bery ilium Hearings, comment on rcent post-hearing SSubmliis.sio~nFS. Docket Nc(. H FO,February 9, 1979. Mancuso, T.F . 1970. Relation of duration of Employment aid prior respi ratory ii InEES to reepi ratory cancer among beryi . j ur wcrkers. nvi ron. Res. 3. r51-27 2 Mancuso, T.F. 1979. occupati ona 1l ung cD ncer mn'g berylium wori::cr in dLsts and disease. In: Proc. Conference on Occupational Ex'posure to Fibrous and Particul ate Dust and Their Extension into the Enviro:nment, . Lemren arid 3. Dcien t Ed. Pathrotox Pub 1 ishers nc Mancuso, T.Fr 198 . Mortli ty study of berylliu industry workers' occupational lung cancer. Environ. Res. 21: 4-55. livak i, M., N. Akaa tu T. Gno Hi. Koyaia . 1979. MiutaCen ic i tV of mEtal cations in cultured cl s trom chinese hamster. Mutat. Res. 68: 259-263. Morgareidge, K., G.E. Cox, D.E. Bailey and M.A. Gallo. 1977. Chronic oral toxicity of beryllium in the rat. Toxicol. Appl. Pharmocol. 41(1): 204-205. Reeves, A.L., D. Deitch, and A.J. 7vorwald. 1967. Beryllium carcinogenesis: I. Inhalation exposure of rats to berylium sul fate aeroso±. Cancer Res. 27(1): 439-445. Echepers, G.W.H. 1961. Neoplasia experimentally induced by beryllium compounds. Prog. Exp. Tumor Res. 2: 203-244. Schroeder, H.A. and M. Mitchener. 1975a. Life-term studies in rats; Effects of aluminum, barium, beryilium and tungsten. . Nutr. 105: 421-427. Echroeder, N.PA. and M. Mitchener. 1975b. Life-term effects of mercury, methyl mercury and nine other trace metals on mice. j. Nutr. 105: 452- 45.. Cimmon, Y.F. , N.. Rosenkranz E. Zeiger and L.A. Poirier. 1979. MutaQenic activity of chemical carcinogens and related compounds in the intraperitoneal host-mediated assay. j. Na t.. Cancer inst. 62(4): 911-918. .S . EPA 1.1 Healt A=s s s t Document for Bery 11 Lm. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. Research Trianle Park , NC. EPA 500/E-34-02*F. LI.S. EPA. 1987. Drinkin Water CI-iteria Document for Bbr1liu. Prepared oy the Office of Halth and Environen tal AssessmEnt, E nvironmenta C ritr5i and Assessment Office. Cincinnati, OH for the Office of Drinr'ing Water, Washington, DC. (External Review Draft) 14 VorwLaa]d. A. . 1968. Bio Io0c i niri feEtaticns cf to:ic inhaIarts in Onir:eys. In : Ue of Nonhuman Primates in Dr-ug Ealuation,*H. Y.agtborg, Ed. University of Tei:t Fress, Austin, TX. p. 222-228.. Wagner, W.D... D.H. Groth, J.L. Holt.:, G.E. Madden arid H.E. EStoi-inger. 1?69. Conpar ative chroni c inhal ati on to.-ic ity of bery1li ore bertrandi te and bery 'l , with produttion of pulmonary tumfor o by ber-y . To i c:ol . A ppi . Pharmacol. 15: 10--29. Wagoner, J.K.., F'. - 1nfante'IE aind D.L. Bayliss. 1''80 . Fiery).llium. An otiol o ic agent in the induction of ilunQ cancer-, nonneop-latic respiiraory diease, and heart d isease among industrial ly1 x posed wolrker S. Ervi ron. Res. 21: 1.5-34. ------. Beryl iu > ------ YI.D. DRINKING WATER HA REFERENCES N o)net 1YNO N Y MS S ubstance Namne -- Beryi 1 iurn CASRN -- 7440-41-7 Last Revised -- 01/31/87 7440-41-7 Beryl l im Beryl ium-F G I LC 1iJnum RCRA waste number POI15 UN 1567 15 Methyl ethyl ketone (MEK) CASRN 78-93-3 (06/01/90) Health risk assessment information on a chemical is inclLude-d in IRIS only after a comprehensive review of chronic toxicity data by work gi rouips conmposed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections I and II represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects e.g. treatment technology). When corsidering the use of regul atorV action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that acti. on, arId whether technological factors were considered. Background in-formation and explan- eti ons of the methods used to derive the values given in 1RIS are provided in the five Background Documents in Service Code 7, which correspond to Sections I through V of the chemical files.' STATUS OF DATA FOR Methyl ethyl ketone (MEK) File On-Line 011/1/S7 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on-line 06/I?/9E Inhalation RfD Assessment (I.B.) pending Carcinogenicity Assessment (II.) on-line 12/I/89 Drinking Water Health Advisories (III.A.) no data U.S. EPA Regulatory Actions (IV.) on-line 06/0i/19u I. CHRONIC HEALTH HAZARD ASSESSMEENT FOR NONCARCINOGENIC EFFECTS Substance Name -- Methyl ethyl ketone (MEK) CASRN -- 78-93-3 Last Revised -- 06/01/90 The Reference Dose (RfD) is based on the assumption that thresholds exist for certam toxic effects such as cellular necrosis, but may not exist for other toxic effects such as carcinogenicity. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a dayily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Please I refer to Backrournd Docuriient I in Service Code 5 for arn elaboration o-f these concepts. RfDs can also be derived for the noncarcinogeni c heal th effects of compounds'e which are also carcinoens. Therefore, it is essential to refer to other sources of information concernrinu the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human carcinogen- icity, a summary of that evaluation will be contained in Section II of this file when a review of that evaluation is completed. <<< MEK >> I .A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDo) NOTE: The Oral RfD for methyl ethyl ketone may change in the near future pending the outcome of a further review now being conducted by the Oral RfD Work Group. I A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* LIF MF Rf0 No adverse effects NOAEL: 235 ppm 1000 1 5E-2 observed (693 mq/cu.m) converted mg/kg/day to 46 mg/kg/day Rat Inhalation Subchronic Study LaBelle and Brieer, 1955 Fetotoxicity in rats LDAEL: 130.5 mg/kg/day (estimated) Rat Developmental Toxicity Study Schwetz et al., 1974 "Conversion Factors: 7 hour/24 hour, 5 days/7 days., 0.223 cu.m/day/.35 k:g (rat breathing rate/rat body weight) 0.5 absorption rate; thus, 693. mg/cu.m > 7 hour/24 hour x 5 days/7 days x 0.223 cui.m/day / 0.35 kg x 1.5 46 mg/kg/day < MEK > 1 .A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfLD) LaBelle, W. and H. Brieger. 1955. The vapor toxicity of a composite solvent and its principal components. Am. Med. Assoc. Arch. Ind. Health. 12: 623-627. Schwetz, T.A., B... Leong and P.J. Gehring. 1974. Embryo- and fetocoxicitv of innajed carbon tetrachloride, 1,1-dichicirciethane and methyl ethyl ketone in rats. Toxicol. Appl. PhArmanc. 28(3): 452-464. Adequate chronic toxicity testing has not been performed with methyl ethyl ketone. Although severeal more recent subcnronic studies have been con- ducted (Freddi et al., 152; Cavender- et al., i983; Takeuchi et al., 1983). only the NOAEL of the LaBeile and Brieger (1955) study provides the lowest and most protective dose for deriving an RfD. in this study, 25 rats were exposed 2 to 235 ppm of methyl ethyl ketone for 7 hours/day , 5 days/week for 12 weeks. No effec.ts were c'berved, but on) y a few parameters wcre meaisured. Methvy ethyl ketone has also been tested for teratogenicity (Schwetz et al.. 1974; Deacon et al., .1981), and the observed LOAELs for fetotoxicity were higher than the NOAELs of LaSelle and Brieger (1955). The I-oute extrapol ation introduced uncerta.rinty because of dif ferences in pharmacokinetic parameters. notably absorption and elimiriation. 5<<< MEK>> _I .A. . UNCERTAINTY AND MODIFYING FACTOlRS (ORAL RfD) UF = 1000. The uncertainty factor of 1000 reflects .10 for both intraspecies and interspecies variability to the toxicity of this chemical in lieu of specific data, and 10 for extrapolation of a subchronic effect level to its chronic equivalent. MF = 1. _ _I.A.4. ADDITIONAL COMMENTS (ORAL RfD) No oral chronic studies are available at this time. I.A.5. CONFIDENCE IN THE ORAL RfD Study: Medium Data Base: Medium RfD: - Medium The study is given medium to low confidence because only 25 rats were exposed to only one dose, and the sex, strain, and amount of control animals were unspecified. Confidence in the data base can be considered medium to low because four different studies lend some support to the chosen NOAEL. Confidence in the RfD can also be considered medium to low. << MEK>> S.A.6. EFA DOCUMENTAT ION AND REVIEW OF THE ORAL RfD0 The only U.S. EPA documentation at present is on IRIS. Agency RfD Work Group Review: 06/24/95, 07/09/95 'eri fication Date: 07/08/35 . .A.7. EPA CONTACTS (ORAL RfD) Christopher T. DeRosa / ORD -- (513)569-7534 / FTS 684-7534 Michael L. Dourson / CRD -- (513)569-7544 / FTS 684-7544 ------CC MEK> I 3 I .. REFERENCE DOSE FOR CHRONIC INHALATION EXPOSURE (Rfrui) A risk assessment for this chemical is under review by an EPA work group. II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Methyl ethyl ketone (MEK) CASRN -- 78-93-3 Last Revised -- 12/01/89 Section II provides information on three aspects of the carcinorenic risk assessment for the agent in question- the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen. The quantitative risk estimates are presented in three ways. The sloep' 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 I in 001in 10 100,000 or I in 1,000,000. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity. < ME > 1I.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY II.4.I. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Rasis -- Based on no human carcinogenicity data and inadequate animal data. II.A.2. HUMAN CARCINOGENICITY DATA Non e. II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. No data were available to assess the carcinogenic potential of methyl ethyl ketone bv the oral or inhalation routes. In a skin carcinogenesis study, two gropLIS of 10 male C3H/He mice received dermal applications of 50 mg of a solution containing 25 or 29% methyl ethyl ketone in 70% dodecylbenzene twice a week for 1 year. No skin tumors developed in the group of mice treated with 257% methyl ethyl ketone. After 27 weeks, a 4 sincile skin tumor developed in I of 10 mice receiving 29% methyl ethyl Ietone (Horton et al., 1965). <<<. MEKL> II.A.A. SUPPORTING DATA FOR CARCINOGENICITY Methyl ethyl ketone was not mutagenic for Salmonella typhimurium strains TA92, TA100, TA1535, or TA1537 with or without rat hepatic homogenates (Florin et al., 1980; Douglas et al., 19890). Methyl ethyl ketone induced aneuploidy in the diploid D61, M strain of Saccharomyces cerevisiae (Z immermann et aI 1905). Low levels of methyl ethyl ketone combined with low levels of nocodazole (another inducer of aneuploidy) , also produced significantly elevated levels of aneuploidy in the system (Mayer and Goin, 1937). - < ME: >>- 1iI.. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISk FROM ORAL EXPOSURE None. II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None.7 II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) II.D.1. EPA DOCUMENTATION U.S. EPA. 1985. Health and Environmental Effects Profile for Methyl Ethyl Ketone. 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. U.S. EPA. 1922. Updated Health Effects Assessment for.Methyl Ethyl Ketone. 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. < II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) The 1928 Updated Health Effects Assessment for Methyl Ethyl Ketone has received Agency review. Agency Work Group Review: 05/30/89 5 Veri fication Date: 05/30/89 II..3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Dharm V. Sinah / ORD -- (202)382-5958 / FTS 382-59sB III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS Substance Name -- Methyl ethyl ketone (MEK) CASRN -- 78-93-3 Not available at this time IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Methyl ethyl ketone (MEK) CASRN -- 73-93-Z Last Revised -- 06/01/90 EPA risk assessments may be updated as new data are published and as assessment methodologies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the regulatory actions in this section with the verification dates for the risk assessments in sections I and II, as this may explain inconsistencies. Also note that some regulatory actions consider factors not related to health risk, such as technical or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning these regulatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatory action in Background Document 4 in Service Code 5. I.A. CLEAN AIR ACT (CAA) No data available IV.B. SAFE DRINKING WATER ACT iSDWIA No data available -- -c CMEK ----- 6 IV.C. CLEAN WATER ACT (CJA) No data available .------.EK-<<< IV.D. FEDERAL INSECTICIDE. FUNGICIDE, AND RODENTICIDE ACT (FIFRA) No data available ------<<< MEK ------ IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available MEK:>:---- IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA) IV.F.1. RCRA APPENDIX IX. for Ground Water MonitorinQ Status -- Listed Reference -- 52 FR 25942 (07/09/87) EPA Contact -- RCRA/Superfund Hotline 800) 424-9346 / (202)382-3000 / FTS 382-3000 ---M << >>>------ _IV.G. SUPERFUND (CERCLA) IV.G.l. REPORTABLE QUANTITY (RO) for Release into the Environment Value (status) -- 5000 pounds (Final, 1995) Considers technological or economic feasibility? -- NO Discussion -- The final 5000-pound RO takes into consideration the natural biodeqradation of this hazardcus substance. The lowest primary criteria RG tor methyl ethyl ketone (100C) pounds based on chronic toxicity and ignitability/reactivity) has been adjusted upward one PQ level. Reference -- 50 FR 13456 (04/04/85) EPA Contact -- RCRA/Superfund Hotline (200)424-9346 / (202)392-3000 / FTS 332-3000 7 V. SUPPLEMENTARY DATA =ubstance Name -- Methyl ethyl ketone (MEK;) CASRN -- 7G-93-3 Not available at this time VI. BIBLIOGRAPHY Substance Name -- Methyl ethyl ketone (MEK) CASRN -- 78-93-. Last Revised -- 12/01/89 VI .A. ORAL RfD REFERENCES Cavender, F.L., H.W. Casey, H. Salem, J.A. Swenberg and E.J. Gralia. A 90-day vapor inhalation toxicity study of methyl ethyl ketone. Fund. AppI. Toxicol. 3: 264-270. Deacon, M., M. Pilny, D. John, et al. 1921. Embryo- and fetotoxicity of inhaled methyl ethyl ketone in rats. Toxicol. Appi. Pharmacol. 59: 620-622. Freddi, A., A. Paci, 0. Vittori, R. De Ciantis and P.F. Ottaviano. 1982. Clinical and electromyographic study of workers exposed to methyl ethyl ketone vapor. Ann. Fac. Med. Chir. Univ. Studi Perugio Atti Accad. Anat.-Chir. 73(1): 111-1Z6. CA 100: 108491b. (Abstract) LaBelle, C.W. and H. £rieger. 1955. The vapor toxicity of a composite solvent and its principal components. Am. Med. Assoc. Arch. Ind. Health. 12: 623-627. Schwetz, B.A., B.K.J. Leong and P.J. Gehring. 1974. Embryo- and fetotoxicity of inhaled carbon tetrachloride, 1,1-dichloroethane and methyl ethyl ketone in rats. Toxicol. Appi. Pharmacol. 29(3): 452-464. akeuchi, Y., V. Ono, N. Hisanaga, et al. 19I3. An experimental study of the combined effects of n-hexane and methyl ethyl ketone. Fr. J. Ind. Med. 40: .199-203". << MEK>>--- S ------VI.B. INHLATION RfD REFERENCES None I-8 _VI .C. CARCINOGENICITY ASSESSMENT REFERENCES Douqlas G.R., E.R. Nestmanr, J.L. D(etts, et al. 1980. Mutaqenic activity in pulp mill efffuents. Water chlorination: Environ. Impact Health Effects. U 3: 65-880. Florin, I., L. Rutberg, M. Curvall and C.R. Erzell. 19'80. Screening of tobacco smoke constitLents for TUtagenicity LISing the Ames test. To~xicology. 18: 219-232. Horton, A.W., E.L. Bingham, M.J.G. Burton and R. Tye. 1965. Carcinogenesis I of the skin. III. The contribution of elemental sulfur and of organic sulfur compounds. Cancer Res. 25; 1759-1763. Mayer, V.W. and C.J. Goin. 1967. Effects of chemical combinations on the induction of aneuploidy in Saccharomyces cerevisiae. Mutat. Res. 167(1): 21-- . U.S. EPA. 1985. Health and Environmental Effects Profile for Methyl Ethyl Ketone. Prepared by the Office of Health cand Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington. DC. U.S. EPA. 1988. Updated Health Effects Assessment for Methyl Ethyl Ketone. Frepared 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. Zimmermann, F.K., V.M. Mayer, I. Scheel and M.A. Resnick. 1985. Acetone, methyl ethyl ketone., ethyl acetate. acetonitrile and other polar aprotic solvents are strong inducers of aneuploidy in Saccharomyces cerevisiae. ILtat. Res. 143(35) : 339-351. IMEK >------ _V 1.D. DRINKING WATER HA REFERENCES None SYNONYMS 378--93-3. ethylmethvl keton 2-butan on a bLtanone-2 ethyl methyl cetone ethylmethyl keton ethyl methyl ketone ketone, ethyl methyl 9 meet co M EK methyl acetone Methyl Ethyl Ketone metiletilchetone metyloetyloketon RCRA waste number U159 UN 113 UN 12-1:1 10 Cadmium, CASFN 7440--4--9 (04/01/91) Health risk assess-ient information on a chemical is mC:iluded in III'RI onl y after a comprehensive rcv.ew of c-hronic toxicity dat. by work grou.rpE- corm5posea of U.S. EPA scientists TI-om -several Program Of-ficcs. The eLmmaries presented in Sec tions I and I I represent a corsenus reachod i r the review process. The other sections contain U.S. EPA information which is specific to a particular EFA program and has been subject to review procedures prescri bed by that Program Office. The regu latory actions in Section IV may not be based on the most current risk assessment , or may be based on a current., but unreviecwed. risk assessment, and may tak e into account fac tos other than health ef fe- tF (e.g. , treatment technology) . When considei;ring the use of reqloatory ;cCtior data for a particular sitLtation., note the date of the regnulatorv actin , thE- date of the most recent risk assessment relating to that action, iand whether technoloQical fac tons were considered. Background information and explan- ations of the methods used to derive the yvalues gjiven in IRIS are provided in he five Dackoround Docurents in Service Code 5, which correspond t:o Sections I throuch V of the chemical fils.; STATUS OF DATA FOR Cadmium File On-Line '3/31/i7 Category (section) Status Last Revised Oral RfD Assessment (I . A. ) on--I n 1/01u/S9 Inhalation RiC Assessment (I.B.) pending Carcinogenicity Assessment (II.) on-line Drink ing Water Health Advisories ( II I.A.) no data U.S. EPA Regulatory Actions (IV.) on-line 06/01/0 Supp1ementary Data (V. ) no data 1. CHRONIC HEALTH HAZARD ASSEESSiENTS FOR NONCARtCINOENIiC EFFECTS I. A. REFERENCE DOSE FOR CHRONIC DRAL EXPOSURE (RtD) Substance Name --- Cadmium ARN--- /744--4--9fl Last Revised --- 1=/d/39 The Reference Dose (RfD) is based on the assumption that thresnolds exist for 1 cert ai.n toxic ef fect.s S Uc h as cCl lul ar necrosis, but may not eist for ocher tosi C ef fect s urLc h iiS c ar c.i-jCnogeniq c±ci y . rn Qenetrai.i -,t. he Rf is an ctstimate (with unceortainty spanning perhaps an order of magn i tudet of a daixyI e poure to the hum!LAn po pL I a tion (i r c J Lid iI gi FiE*:i t.i Ve s ubg roup[:s ) ti)at iS I iil. y to be vi thout an apprec iab le risk of deleterious Eff Ec t dLri ng a ii fetime. F-I Ease rE er to BackgrCund DocLment 1 in Ser vice Code 5 for an El aborattion of these concepts. R fDs can a) so be derived for th- noncarci nogen ic hea 1 th effects of compounds which are also carcinogens. Therefore, it is Fssentia I to refer to other source f inofformation concernirg tie carcinoqenicity of this SuLbstance. If the U. S EPA has ev\l uriated ti S substance for poten tial Ihuman c arc inogen-- icity, a summary UT t.11t evaLuati will be contained in 5ectio sir I of this f i.ie wh en a r u. ew.v of th.Iat e:'va] La tion .S cromp.. e.E? .C admnium SI . .1. oRAL Rf D SUMir A.Y Critical Effect Exp'rimental Dome: UF MF R fD Signnificant N4C:EL (water) 0.005 10 1 5E4 p rotein Uria Tmg/kq/day mg/kg/day (wa ter) Human Fstuldies involving chronic NOAEL (fodd) 0.01 1 1 1E- Ex posures ng / kg /d ayv mg / k q /d av (f ood) U. S. EPA, 1985 *Conversion Factors: Sce text forOSdJiscusifn Cadmi L >> AI.A.2. PRINCIPAL AND SUPPCRTING STUDIES (ORAL RfD) U.S. EPA. 1985. Drinking Water Criteria Document on Cadmium. Office OT Drinking Water, Washington, DC. (Firal draft) A concentration of 200 ug cadmium (Cd) /gm wet human renal cortex is the highest renal level not associated with ignificart proteinLria (U.S. EP 1985). A toxicokinetic model is available to determine the level of chronic hIman oral exposure (NOAEL) which resLults in 200 ug Cd/gm wet human renal cortex; the model assImes that 0.01X day of the Cd body burden is eliminated per day (U.S. EPA! 1965) Assuming 2.5% absorption of Cd from -food or 5% from water. the toxicokinetic model predicts that the NOAEL for chronic Cd exposure is 0.005 and 0.01 mg Cd/kg/day from water and food, respectively (i.e.., lIVIS which would result in 200 ug Cd/cm wet weight human renal cortex) . Thus, blased on an estimated NOAEL of 0.005 mg cd/k//dav for Cd in drinking watVer anEF'd "n UF of 10. an F-D cf .000C5 m g Cd/kg/day (water) was calculated; an equivalent RfD for Cd in foad is 0.001 mg Cd-/i:/day- (e-Section VI.A. for references). -KCadmium _ . A . 3. UNCERTAINTY AND MCDI EYING FACTORS ORAL RfD F =10. This uncertain-ty factor is used to aiccoLn7t for intrahuman variability to the toxic ity of this chemical in the absence of spcific data on sensitive individuals. M",F = 1. 2 I.A.4. ADDI T ONAL CDMMENTS .DRAL R-f) Cd is unusual in rel ation to most , if not all , of the sLtbstances for which afn oral RfD has been determi.ned in tha.t a vai t qLJanrti ty of both hUma1&nf an1d animal toxicity data are available. The Rf is based on the highest level of Cd in the hrnmah renal cortex< (i.. . the cr i tical l evel not aScCc i ated with sionificant proteinuria (i.e. , the critical effect) A toxicokinetic model has been Lised to determine the highest level of ex posLre ciciO5Cated with thE lack of a critical effect. Since the fraction of injested Cd that is absonrbced appears to vary with the source (e.g., food vs. drinking watcr) it is necessary to allow for this difference in absorption when using the toxicokinetic model to determine an RfD. I. A5. CONFIDENCE IN THE ORAL RfD Study: Not applicable Data E:ase: High RfD: Hiqh The choice of NOAEL does riot reflect the information from any alingle study. Rather, it reflects the data obtained from many studie -s on the oxicity of cadmium in both huans and animals. These data a Iso permit Calculiation of pharmacokinetic parameters of cadmium absorption, distribution metabolism and elimination. All of this information considered together gives high confidence in the data base. Hiqh confidence in either RfD foll owa as well < Cadmium >>> I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1985. Orink-ing Water Criteria Document on Cadmium. Office of Drinking Water, Washington, DC. (Final draft) Agency RfD Work Group Review: 05/15/S6, OS/i:/B6, 09/17/S7, 12/15/67, 0i/20/88, (F5/25/88 Verification Date: 05/25/98 __ A.7 EPA CDNTACTS (ORAL RfD) Ken .ailey / 0DW -- (202 -5 / FT 372-1575 Warren Banks / OWRE -- 202)382-7EE3 / FTS 322- o-773 _.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC Substance Name -- Cadmium CAR --- 7440--43- 9 3 A ri5kI for-sssment thi S ubtanCe/tpent i.E under re-vi ew by an EFA work ~rocup. II. Cg.RCINGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Namief- Caimium CASRN -- 7140-43-9 Last Revised -- 03/01/91 ection II provides inforriation on trree aspects of the carcinC'geni.c risk assessment for the agent in question. the U.S. EPA classification, and quart- itative estimates of ris1 f rom ora 1xposure and from in halatioi e osure. The classification reflects a weight-of-evidence i udQment Cf the lik elihood that the agent is a humkfian cact-cinogen. The qLLntitative risk stimates are presented in three ways. The slope factor is the reSUlt of applicatiin of a low-dose extrapol ation procedure and is presented as the risk per (/)/dav he unit rik is th uantitativek estimate in terms 0f ither rik per uQ/L clrinkinCJ water r- risk per Lgcuf ir. brea ted. The third form in which risk is presented is a drinking water or air concentration proviingd cancer risk:s f 1. in 1C 0 , 1 in 100000 E00r : in 000. Eack g r, n d D CUMen t 2 (Service Code 5) provides details on the rationale end methods used to oerive the carcmnogenicity valee found in IRIS. Users are referred to Section I for in formation on long-term toxic effects other than carcinogenicity. << Cadrfitm II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENIIY II . A.. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B1; probable human carcinogen Basis -- Limited evidence from occupational epidemiologic studies of cadmium is consistent across investigators and study populations. There is sufficient evidence of carcinogenicity in rats and mice by inhalation and intramuscular and subcutaneous injEction. Seven studies in rats and mice wherein cadmium salts (acetate., sul fate, chloride) were administered oral ly have shown no evidence of carcinogeic response. Cadmium ) II.A.2. HUMAN CARC INOGENICITY DATA Limited. A 2-fold excess risk of luna cancer was observed in cadmium me± -er workers . The cohort consisted of 602 white miales who had beer employed in production work a mainmum of 6 months during the years 1940-1959 The population was followed to the end of 19/73. Urine cadmium data available or 251 workers employed after 1760 Suggested a highly exposed population. The authors were able to ascertain that the increased 1 unq cancer risk was p robabl y not due to the presence of arsenic or to smoking (Thun Et al., 1 98). *An evaluation by the Carcinogen Assessment Group of these possible confounding factors has indicated that the assumptions and methods used in accounting for 4 then may rnt bE. va] id. As the MR, observed were lcow arid there is a lack rof U clear cut evidence of a causal r-lationship of the cadmium e xu re onlyv this Study is considered to supp ly orly, 1:mited evicience of humarn carcingnic:: t. other stud ies which cancer risk was also observed in three I were.A howeverexce2SS , lungcomproii sed by the pres4ence of other carc rinoc.ers (ar eer ic, Qmoki rg ) in the exposure or by a Smli popul ation ( karner , 1983; Sorahan and Waterhouse, 1983; Prmst rong-i and Kaiantri, 1983). Four studies of wo r k er exposed to cadmiu m dust t- f LumefS p rov ided Civ .idceC of a statistical ly sini. - icant positive associ at ion- with pros tate canc er Ki pinq and Waterhous-e , 1 7 ; Lernen et a l. 1976; Hol3 iern 1 9 0 Sor ahan and aterhouse, 197.3) , LLLt the total r-number of cases was sera 1 in each study. Th ThLLn et al . (195) study is an update of a: earlier study (Le'en et al ., 176) and does not show excess prostate cancer risk ir these won: ers Studi es of human inQestion of cadnium are inadequate toassess Cadmium I II.A.3. ANIMAL CARCINOSENICITY DT A Exposure of Wistar rats to cadmium as cadmium chloride at concentrations Of 12.5, 25 and 50 ug/cu.m for 18 months, with an additional 1-3-month obser- vation periodc resul ted in significant increases in lung tumors (Tai.ena[: et al.,1983). In ttrtrac heal instill atic:n of cadmium ox i de did not pr oduce l unQ tumors in Fischer 344 rats but rather mammary tumors in females and tumrsi at I mulit ple sites in males (Sanders and Maha-ffey, 1984). injection site tumors and distant site tumors (for example, testicular) have been reported by a number of authors as a consequence of intrEimuscul&-r or sucutaneous administration of cadmium metal and chloride, sulfate, oxide and sulfide compOunds of cadmium to rats and mice (U.S. EPA, 1985). Seven studies in rats And mice where cadmium salts (acetate, Sulfate, chloride) were administered orally have shown no evidence of a carcinogenic response. 3 «( Cadmium II .. 4. SUFPORTING DATA FOR CARCINOGENICITY ResuitS of mutag'±nicity tests in bacteria and yeast have been inconclu- Eive. Positive responses have been obtained in mutation assays in rhinese hnamster cells (Dom and V79 lines) and in mouse lymphoma cells (Casto, 19Tc Ochi and Ohsawa, 1983; Oberly et al., 1982). Conflicting results have been obtained in assays of chromosomal aberra- tions in human lymphocytes treated in vitro or obtained from exposed workers. Cadmiumn, treatment in vivo or in vitro appears to interfere with spindle fo rmationand to result in aneupl oi dy in germ cel s of mice and hamsters (*imada et al., 1976; Watanabe et al. . 197; Gilliavod and Leonard, 1975) ------<<< .admiium------ I _II. A TIT ATIE C ST IMAT OF I CARC I NOGENIC IK FROM *DRkAL EXPOCURE tot a/& I able. There are no positive stud ies of oral iv anqes ted cadmiiium suitable for quantitation. ------< Cdmiu --- 5 -- 11. C. GUANTITATIVE ESTIMATE OF CARCINOGENIC RISK F-ROM INHLATION EXPOSURE II.C.1. SUMMARY OF RISK ESTIMATES inhalation Unit Risk -- 1.8E- per (ug/cum) Extrapolation Method -- Two stage; only first affected by esposure; extra risk- Air Concentrations at Specified Ris: Levels: Risk Level Concentration E-4 (1 in 10,000) 6E-2 ug/cu.rm E-5 (I in 10 . 000) E- ugi/cu., E-6 (I in 1,0:0,000) E-4 ug/cu.m < II.0.2. DDSE-RESPONSE DATA FDR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- lung, trachea, bronchus cancer deaths Test Animals -- human/white male Route -- i nlalation, exposure in the-workplace Reference -- Thun et al , 1985 No. of Expected Observed NO. Lung, Trachea and of Deaths Cumulative 24 hour/ Bronchus Cancers (lung, trachea, Exposure Median ug/cu . m Assuming No bronc hus (mg/day/cu.m) Observation Equivalent Cadmium Effect cancers) less than or equal to 5S4 280 158 3.772 585-2920 1210 727 4.61 7 greater than or equal to 2921 4200 2522 2. 50 7 The 24-hour equivalent = median observation x 10E-3 x 3/24 x 1/365 x 240/365. < CadmiUmti II.C.3. ADDITIONAL COMMENTS (CARCINOENICITY, INHALATION EXPOSURE) The unit risk should not be used if the air concentration exceeds t ug/cu.m, since above this concentration the unit risk may not be appropriate. <<< Cadmium II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) The data were derived from a relatively large cohort. Effects of arsenic and smoking were accounted for in the quantitative analysis for cadmium 6 ef fects. Ar i nhal a iorn ni t ri i:: for cadmi Lrr based on tIi. T alkena k El ct al. (1 Q3) &1 lysis is 7.2 E-2 per (ug/cu. m) . Wh ie this estimat, is hi gher than that derived from human data [1. CE-3 per (ug/cu. m) ] and thus more c ors.ervati ve, it was felt that the use of avail able human data was mrore reliable because of cspecies variations in response and thes' type Of eXpSLtre (CcdiuLrmr sal £t v' . cadmium fiume and cadmium or ide) --- < Cadmium --- TI .D. E'A DOCUMENTATION, REVIEW, AND CONTACTS (CAARCINGENICITY rSSESMENT) I I.D. 1. EA DOCUMENTATION U.S. EF. 1985. Updated Mutagenicity and Carcinocienicitv Assessment of Cadmium: Addendum to the Health Assessment Document for Cadmium (May 1"; S, EPA 600/B-B -023) . EPA 6 00/BF-m3-025F. CCadmium >>>' . ._Di.2. REVIEW (CARCINOGENICITY ASSESSMENT) The Addendum to the Cadmium Health Assessment has received both Agency and external review. Agency Work Group Review: 11/ 12/ 6 Verification Date: 11/12/86 II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) William E. Fepelko / ORD -- (202)322-5904 / FTS 3,2-5904 David Bayliss / ORD -- (202)3.32-5726 / FTS 332-5726 II.. HEALTH HAZARD ASSESSMENTS FOR' VARED EXPOSURE DURATIONS __I.A.--DRINKING sjATER HEALTH ADVISORIES Substance Name -- Cadmium CASRN -- 7440-- Not available at this time. 7 III . DB. GTHER VEEESSMNr ELutbstarrce Name -- CadmfiumI CASRN -- 74 40--9 - Con tent to be determined. IV. U.S. EFP REGULATORY ACTIONS Substance Name -- Cadmium CASRN -- 7440-43-9 Last Revised -- f06/01/0 EPA risik assessments may be updateu as new data are published and as assessment methodolocies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the regaulaitory actions in this section with the verification dates for the risk assessments in sec tions 1 and 11, as this may explain inccinsisterncies. Alo note that Some requlat'rV actions consider factors not related to health risk, such as technical or economic feasibility. Such considerations are indicated for each action. In addition, not all of the requlatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning theSe regulatorv actions to he U.S. EPA contact listed for that particular action. Users are strongly urged to read te background infurmj- ation on each regulatory -;ction in BackQround Document 4 in Service Code 5. < Cadmium> IV .A. CLEAN AIR ACT (CAA) _V.A.1. CAA REGULATORY DECISION Action -- Intent to list under Section 112 Considers technological or economic feasibility? -- NO Discussion -- Cadmium is a probable human caracinoQen (IARC category 2Ai) and according to EPA's preliminary risk assessment from ambient air exposures, public health risks are significant (3-7 cancer cases/year and maximum lifetLime incividual risks of 0.003. Thus, EPA ind icated that it intends to .dd cadmium to Lhe list of hazardous air pollutants for which it intends to establish emission standards under section 112(b)(1)(A) of.the Clian Air. Act. The EFA will decide whether to add cadmium to the list only after studying Possible techniques that miciht be used to control emissions and further assessing the public health riskc. The EPA will add cadmium to the list if emission standards are warranted. Reference -- 5C0 FR 42000 i10/16/25 EPA Contact -- Emissions Standards Division, GAGPS (919)541-557i / FTS 627-5571 8 .,ak 0r~l a fl. IV . S.SAFE DRI I NGO WWAT EER ACT ( SDWA _IV.1.. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water value (status) -- ).005 mq/L (F'roposed, 1785) Considers techrological or economic feasibility? -- NO Discussion -- An MCLE3 of 0.005 mq/L for cadmium is proposed based on a provisional DWEL of 0.01 mg/L and drinking water contribution (plus aquatic organiscn) of 25X. A DWEL of 0.013 mg/L was calculated from a LOAEL of 0.3c52 mg/day for renal toxici ty in humans (calculated) wNi.th an uncertainty factor of 10 applied and consumption of 2 L of water/day assufled. Reference -- 50 FR 46936 Part IV (11/13/35) EPA Contact -- Criteria and Standards Division, OW / (202)382-7571 / FTE. 382-7571; or Drinking Water Hotline / (300)425-4791 (CCadmium _IV. .2. MAXIMUM CONTAMI NANT LEVEL (MCL) for Drinking Water Value (status) -- 0.01 mg/L (Interim, 1920) Considers technoloical or economic feasibility? -- Discussion -- Reference -- 45 FR 57332 E2A Contact -- 1.enneth ailey / Criteria and Standards Division, ODW / (202)32i-7571 / FTS 32-7571; or Drinking Water Hotline / (200)42-479i ------< Cadmium )n ------ IV.C. CLEAN WATER ACT (CWA) IV. C.1. AMBIENT WATER DUALITY CR1 TERI A Human Health Water and Fih Consumption: 1E+1 ug/L F7ish Consumption Only: None Co_*nsider t echnologial or economic feasibility? -- NO DicueiL -- Thr crt icaE it the same as the exiTtinu standard -i-or dnk iirin water. Reference -- 45 FR 77312 (11/2/80) EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 9 Cad.iumE IV!'. C.2. AMBIENT WATER DUALITY CRITERIA, Aquatic Orgnisms- Freshwater: 4CLtte -- 3.9E+0 ug/L (1-hour average) Chronic J--1. E+0 ug /L (4--day average) Marine: Acute -- 4.3E+1- ug/L (1-hour aVerage) Chronic -- 9.3E-0 ug/L (4-day average) Considers technological or economic feasibility? -- NO Discussion -- The freshwater criteria are hardness dependent. Values given here are calculated at a hardness of 100 mg/L CaCO3. A complete discussion can be found in the referenced notice. Reference -- 50 FR 30784 (07/29/e5) EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 ------<%< Cadmium ------ -IV.D. FEDERAL INSECTICIDE, FUNGICIDE. AND RDDENTICIDE ACT (FIFRA) IV.D.1. PESTICIDE ACTIVE INGREDIENT. Registration Standard None << Cadmium >>> IV.D.2. PESTICIDE ACTIVE INGREDIENT, Special Review Action -- Final regulatory action - P)D4 (1987) Considers technological or economic feasibility? -- YES Summary of regulatory action -- The basis for selection of the final regulatory option is presented in Position Document 4. Reference -- 52 FR-31076 (03/19/87) EPA Contact -- Special Review Branch, OFP / (703)557-7400 / FTS 557--7400 --- ~adiu------< _IV.E. TOXIC SLrESTANCES CONTROL ACT (TSCA) No data available 10 IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA) IV. F. 1. RCRA APPENDIX IX, for Ground Water Moni. torniring Status -- Listed Reference -- 52 FR 25942 (07/09/87) EPA Contact -- RCRA/Superfund Hotline (800 )424-9346 / (202)3.2-3000 / FTS 32---3000 ------< Cadmium -- IY.G. SUPERFIND (CERCLA) SV.G.1. REPDRTP:LE QUANTITY (R0) for Release into the Environmcnt Value (status) -- 10 pounds (Proposed, 1987) Considers technological or economic feasibility? -- NO Discussion -- The proposed RG for cadmium is 10 pounds, based on potentia1 carcinoqenicity. Available data indicate a hazard rankinQ of me'dium, based on a potency factor of 57.27/mg/kg/day and weight-Of-evidence group S1, which corresponds to an RP of 10 pounds. Cadmium has also been found to bioaccumulate in the tissues of aquatic and marine organisma, and -as the potential to concentrate in the food chain. Reference -- 52 FR 2140 (03/15/27) EPA Contact -- RCRA/Superfund Hotline ( 00 )424-9346 / (202)382-3000 / FTS 392-3000 V. SUPPLEMENTARY DATA Substance Name -- Cadmium CASRN -- 7440-4--3 Not available at this time. VI. BIBLIOGRAPHY Substance Name -- Cadmium 11 CAR-jON -- 7440-A41--9 Last Rx.'i LEAd --- 10/01 / 219 VI . A. ORAL RfD REFERENCES Foulkes. E.C. 1986. Absorption of cadmium. in: Handbook of Experiment&al1 Pharmacology, E.C. Foulkes, Ed. Springer Verlag, Berlin. Vol. 30, p. 75-100. Friberg, L., M. Piscator, S.F. Nordberg and T. Kjellstrom. 1974. Cadmium in the environment, 2nd ed. CRC Press, Inc., Boca Raton, FL. Shaikh, Z. A. and i.-.C. Smi th. 1980. Metabolism of oral ly ingested cadmium in humans. In: Mechanisms of Toxicity and Hazard Evaluation, B. Holmstedt et al., Ed. Elsevier Publishing Co., Aimsterdami. p. 569-574. U.S. EPA. 1985. Drinking Water Criteria Document on Cadmium. Office of Drinking Water, Washington, DC. (Final draft) WHO (World Health Organization). 1972. Evaluation of certain food additives and the contaminants mercurv, lead.. and cadmium. Sixteenth Report of the Joint FAG/WHO Expert Committee on Food Additives. WHO Technical Report Series No. 505, FAD Nutrition Meetings Report Series No. 51: Geneva, Switzerland. WHO (World Health Organization). 19S4. Guidelines for drinking water quality -- recommendations. Vol. 1. Geneva, Switzerland. ------<< Cedmium ------ VI.B. INHALATION RfD REFERENCES None ------< Cadmium ------ VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Armstrong, B.G. and G. Kazantzis. 1983. The mortality of cadmium workers. Lancet. June 25, 1983: 1425-1427. Casto, B. 1976. Letter to Richard Troast. U.S. EPA. Enclosing mutagenicity data on cadmium chloride and cadmium acetate. Gillievod., N. and A. Leonard. 1975. Mutagenicity tests with cadmium in the mouse. Toxicology. 5: 43-47. Holden, H. 190C. Fut:her mortality studies on wor:crS exposed to cadmium fumes. Presented at Seminar on Occupational Exposure to Cadmium. March 20, 1980, London, England. Kipling. M.D. and j.A.H. Waterhouse. 1967. Cadmium and prostatic carcinoma. Lancet. 1: 730. 12 Lemn, R.A.,.2. JLe 3 .K . WagCo nc-r aId HI. P. B1 eir . 1976. Cancer ro tal i ty aronQ ca(r6i'um prcduc t ion woi:.or r. Ann. N. Acad. Sci. 271: 2 7. Ober y . T., C. E. Piper and D.S. 11cDor,lad. 1982. M.DUtagCenic tv of meta 1 sal ts in the L5172 Y mouse I ymphoma assay . J. Toxico I. Environ. Health. 9: 367--3.7. Ochi, T . and M. Ohsawa . 1 93. IIduction Lf -- thitouanine-resistan mtans and single-strand scissaion DNA by cad-ium chloride in cIltUrLed Chies hamster cell s. Mutat. Fe;. 11: 69-78. Sanders , C.L. and 3 . A. Ma h-.aIfF. 19a4. Carc i ncEqen7 ci tv of ingle and muLI tipl e in tratrac heal instil 1 ations of cadiLUfm ul ide in the rat. Environ. Res. -3. 2-7 2. Shimada, T. T. Watanabe and A. Endo. 1975. Potential riIutagenici ty of cadmium ir mammal ian oocvts. Mutat. Res. 40: 389-396. Sorahan, T. and . A.H. Waterhouse. 193. tMortal1it' study of nickel-Cadmium battery workers by the method of regr ession modelis in life tables. Br. j. In- di . Me-d . 40 :) 293--300 .-- Takenaka. G., H-. Ol d i o H ke.onic, D. Hochrainer and G. ber derster . 19-3. Carcinogenicity of cadniur aerosoers in Witar rats. J. Nati . Cancer Inst. 70 367-373. ThLn, M.J. T . M. Sc hr.orr A.B. Smith and W.E. Hal perin. I1985. Mortali±ty among a cohort of U.S. cadmium production workers: An update. J. Nati. Cancer Inst. 74(2): 325-333. U.S. EPA. 1995. Updated Mutapenicity and Carcinocenicitv Assessment of Cadmium. Addendum to the Health Assessment Document for Cadmium (EP A 600/B-P1-023) . EPA 600/B---3--025F. Varner, M.O. 1?983. Updated epidemiologic study of cadmium smelter workers. Presented at the Fourth International Cadmium Conference. UnpubliShed. Watanabe, T., T. Shimada and A. Endo. 1979. Mutaaenic effects of cadraiLum on mammal ian oocyte chromosomes. Mutat. Rea. 67: 349-356. ------<< Cadmium > ------ VI.D. DRINKING WATER HA REFERENCES None ubstance Name -- Cadmium CASN -7440-43-9 Lat R4Sd--- 03/31/-7 13 7 440-42--9 C. il. 77180v C ad mT i ural 1 I14 I Ethyl chloride; CASRN 75-00-3 (0-/01/91) Health risk assessment information on a chemical is included in IRIS only after a comprehensive review of chronic toxicity data by work groups comiposed of U.S. EPA scientists from several Program Offices. TheLummarie; presented in Sections I and IT represent a cnisenss reached in the review process. The other sections contain U.S. EPA information which is snpeci fic to a particular EPA program and has been subiect to review proc edures prescribed by hat. Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current., but unreviewed, risk assessment, and may take into account factors other thar health effects ?e.g., treatment technology). When considering the use of regulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background information and ex;plan- Ations of the methods used to derive the values given in IRIS are provided in the five Background Documents in Srvice Code 5, which correspond to Sections I through V of the chemical file.' STATUS OF DATA FOR Ethyl chloride File On-Line 04/01/91 Category (section) Status Last Revised Oral RfD Assessment (I.A.) no date inhalation RiC Assessment (I.B.) on-line 04/0i/91 Carcinogenicity Assessment (II.) no data Drinking Water Health Advisories (III.A. ) no data U.S. EPA Regulatory Actions (IV.) no data Supplementary Data (V.) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGSENIC EFFECTS I.A. REFERENCE DOSE FDR CHRONIC ORAL EXPOSURE (RfDi Substance Name -- Ethyl chiloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane Not available at this time. 1 I1.B. REFERENCE. CONCENTRATION FOR' CHRONIC INHALATION EXPOSURE (FfC) Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym ~-- Chlororthane Last Revised The inhalation Reference Concentration (RfC) is anal OQOuS to the oral fD antd is likewise based on the assumption that threeholds exist for certain toxic effects such as cellular necrosis, but may not exist for other toxic effects such as carcinogenicity. The inhalation RfC considers toxic effects for both the r-espiratory system (portl-of-et ry) and for- aff-cts per-iphiera} to thre respiratory system (extLrarespiratory effects) - It is appropriately expressad in i ts of vog/cu... In genera l, the RfC is- an estimate (with uncertainty spanning perhaps an order of imTaQnitude) of a daily inhalZation exposure of the huniri popul6tior (including sensitive st.bgroups) that is likely to be Vithout an appreciable risk of deleteriouS effects during a lifetime. Inhalation RfCs are derived according to the Interim Methods for Devlopr-ent of Inhal£ti on Reference Doses (EPA/600/8-88/O66F uLgust 1989) deve.c.ped by U.S. EPA scientists and peer-reviewed. For more information on the interim nature of these methods and future plans see the INFOMORE Section of IRIS. RfCs can also be derived for the norcarcirogenic heal th effects of compounds which are carcinocens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. E'A has evaluated this substance for potential human carcinogenicity, a summary Of that evaIlation will be contained in Section II of this file when a review OT that evaluation is completed. << Ethyl chloride IB. 1. INHALATION Ff0 SUMMARY Critical Effect Exposurest UF MF RfC Delayed fetal NOAlEL: 4000 mjg/cu.m (1504 ppm) 3 1 1E+1 ossilication NOAEL(ADJ) : 4000 mc/cu.m m g/cu .M NOAEL(HEC): 4000 mg/cu.m Mouse Developmental Inhalation study LOAEL: 13,000 mg/cu.m (4946 ppm) LOAEL(A-DJ): 13000 mg/cu.m Scortichini et a!., LOAEL(HEC): 13,000 mg/cu. m *Conversion Factors: MW = 64 .5. Asuming 25C a.d -760 mm Hq, NOAEL (mg/cu.m) = 1504 ppm x MW/24.45 = 40 mg/cu .- m. For developmental ef fec ts this concentration is not adjusted; therefore NOAEL(ADJ)= NOAEL. The NOtAEL(HEC)L was calculated for a gas:extrarecpiratory effect assuming periodicity was attained. ba lambda(a) is unknown, b:a lamnbddIa) = 2.69 (Gar- as et 1989). Since b-a lambda(a) is unknown, a default value of 1.0 is used for .3..- .A n r1:1 thi ratio. NOAEL(HEC) = NOAEL(ADJ) x 1 = 4000 ml/cu.m. I .. 2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) 2 ocortichini, B .H., KF.A. Johnson, J.J. Miomany-Pfruender , and T -R . Hanly. e r. 1985. Ethyl chlorade: inhalat ion teratology study in CF-1 mice. D:w Chemica2 Co. EPA Document #GS-870002248. In a developmental study conducted in groups of 30 CF-1 mice, Scortichini et al. (19B6) exposed animals to mean time-weighted averaqes of (air) ., 491 +/-37 ppm (1.3 g/cu . ml) , 1504 +/- 84 ppm (4000 mg/cu. fl) and 4946 +1- 159 ppmi (13,000 mq /cu . m) 99. '9% ethyl ch 1 oride for 6 hours/day on days 6 through 15 of gestation. The animals were sacrificed on the 18th day of Cest.atior . In accordance with current EPA practice these values are not duration adjLsted. No maternal toxicity was recorded in this study (clinical sigris body weight, liver weight, and food and water consumption were monitored) , al though an e.rlier pilot study wi-th non-pregriant female mice at these same concentrations showed an exposure-related decrease in body weight gain (data not presented). in the present study, no exposure--related changes were noted in resorption rate, litter size, sex ratios, or fetal body weights. No exposure-related fetal visceral malformations were observed. In the fetuSes of the dams exposed to 4946 ppm, there was a statistically significant increased incidence (p < 0.05) of foramrina of the skull bones, a small area of delayed ossification. At this concentration, 5 fetuses were affected in a total of 5 litters vS. 1 fetus in 1 litter in the controls and in each lower exposure group (the skull bones were examined in 22 to -25 litters in the controls and at each exposure level) . The authors cite that the hisLorical incidence of foramina of the skull bones in their facility with this strain of mice is %.2% of the fetuses with a range of 0 to 1.2% The effect in this study at 4946 ppm ethyl chloride represented 4% of the fetuses. Additional information volunteered by one author (TRH) indicated that the foramina in question were small pin-point lesions although apparently the openings were not measured. his skull effect was accompanied by an increasing incidence of cervical ribs ta supernumerary rib considered to be a malformation). The incidence of ietuses having this malformation was 2/257 (1%) of the controls, and, in order of increasing exposure concentrations, 1/299 (0.3%), 6/311 (2%), and 4/242 (.2%). The corresponding figures for the incidence in litters was 2/22 (9ZY in controls and 1/25 (4%), 5/26 (19%), and 4/22 (18%) in the litters of exposed dams. This effect was not indicated as statistically significant and no historical incidence for this mal formation is given in the text. This study shows that exposure to ethyl chloride results in fetotoxicitv. The exposure concentration of 1504 ppm is the NOAEL of this study NOAEL(HEC) = 4000 mg/cu.m based on foramina of the skull bones. The highest concentration used in this study, 4946 ppm, is a LOAEL, (HEC) = 13,000 mg/cu.m. < Ethyl chloride > I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 300. A factor of 10 is used to account for sensitive populations. An uncertainty factor of 3 (rather than 10) is used for interspecies extrapolation due to dOsimetric adjustment of the inhaled concentration. A s no mul tiqeneration reproductive study and no defin itive developmental toxicity studies were available, a full factor of 10 is proposed for data base deficiencies. K thyl c aloride > I.B.4. ADD IT I ONAL STUDIES / COMMENTS (INHALATION RfC) Although usod as a surgical anesthetic , ethyl chloride has a narrow margin 3 of safety for this purpose as anesthesia occurs at 20 to 30 mg.% and respiratory failure at 40 ITIgy (Dobkin and Byles, 1971). Ethyl chloride is explcsi ve at. % (40,00 ppn, 106 g/cu.m in air, overlapping the concentrations required to produce anesthesia (3 to 4.5:). Neurological s'mptoms have been cobserved in human case-studies in instances of ethyl chloride abuse. H es et al. (1979) noted cerebellar-related symptoms including ataxia, tremors, dysarthria (speech difficulties) slowed reflexies, nystagmius involuntarV movement of the eyvebal 1 ) and hallucinations in a 26--year old female who sriiffed 200 to 300 mL of ethyl chloride off her coat sleeve daily for 4 months. Examination revealed that her liver was enlarged (3 cm) and slightly tender and was accompanied by a mi16 and transient disturb ance (rot clinically described) of liver function. A II symptoms were resolved by the end of 4 weeks. Similar neurol ogica1 symptoms were noted in a 52-year old male who had a 30-year history of intermittent ethyl chloride (as well as alcohol and barbiturate) abuse (Nordin et al., 1988) . Questioning upon hospitalization revealed that he had been inhaling at leiast 100 mL of ethyl chloride daily for the previous 4 months. No liver effects were reported arid the patient fully recovered from the neurological symptoms by 6 weeks after admission. Ethyl chloride has been demionstrated to be a cardiac sensitizer (Balazs, et al., 1986) in dogs at or near concentrations producing anesthesia, i.e., 30,000 to 5 ,000 ppm (dU Pont, 1771). In this condition, cardiac tissue is hypersensitized to the effects of stimulatory endogenous catecholamines which can result in arrhythmias and cardiac arrest. Rowe et -al (1939) exposed groups of rabbits (4/group) and rats (12/group; strain unspecified) to 26.4 C/cu.m ethyl- chloride 7.5-8 hours/day,- 5 days/week for 6.5 months. No effects on weight gain, liver weights, histopathology (including lungs), or clinical signs were noted. Landry et a!. (1989) exposed groups of 14 (7/sex) B6C3FI mice to 0 (air), 250 ppm (0.66 g/cu.m), 1247 ppm .(3.3 g/cu.m), or 4843 ppm (12.8 g/cu.m) 99.9% EC, 23 hours/day for 11 consecutive days. The duration-adjusted values for these exposures in increasing concentrations are 0, 0.63, 3.2, and 12.2 g/cu.m. The actual duration of exposure in this study (253 hours) was comparable to that obtained in a 4 hour/day, 5-day exposure week (260 hours). A blind neurobehavioral observation battery was conducted on the 12th day ollowed by collection of samples for clinical chemistry and hematology. Fody and organ weights were taken and histopathology was performed. The only exposure-related effect observed in this study was a slight increase in the mean liver weichts of both male and female mice exposed to 4843 ppm. (The increase in liver weight was approximately 6 g/lOOg vs. 5.3 g/100 g in controls; p=0.05.) Histopathologic examination revealed a minimal increase in the degree of hepatocellular vacuolization in 4 of 7 animals of both sexes at this exposure. These alterations were minimal and not accompanied by any increase in serum enzymes. This study defines a free-standing NOAEL of 4843 ppm, the NOAEL(HEC) for this extrarespiratory effect = 12.2 g/cu.m. Landry et al. (1982) exposed groups of 8-10 week old F344 rats (6/sex /group) to 0 (air), 1500 ppm (4.2 g/cu.m) 4000 ppm (10.6 g/cu.m), or 10000 ppm (26.4 g/cu. m) of 99.7% ethyl chloride 6 hours/day, 5 days/week for 2 weeks. The duration-adjusted values are 0. 0.8, 1.9, or 4.7 g/cu.m, respectivelv. Clinical observations and chemistry, hematology, urinalysis, and complete histopathology (including the entire respiratory tract) were performed. The only exposure-related effect observed was a statistically -ion if iCan t increase in liver to body w.eight ratios in male rats exposed to 4*000 ppm (-.64 g/100g) and 10,000 ppm (3.73 g/i"7-) as compared with controls '47 o/i10 g) ethyl chloride. As this alteration was not accompanied by any histopathology or increases in serum enymes it is considered an adaptive response, not an adverse effect. Therefore this study identifies the highest leVel of exposure in this study (10,000 ppm) as a free--standing NDEL, 4 NOEL(HEC) for extrarespiratory effects = 4.7 g/CLI.m. UEroups of F-44 rats ard P6C3F mice (50/group/sex) were exposed to eith imer . (air) or 15,0')00 ppm of 99.5% ethyl chloride (37.6 g/cu. m) 5 days/vJee,: 6 hcLrs/day for 102 weeks (rats) or 1.00 weeks (mice) in en rNTP (1989) study. The duration-aCjusted concentration becomes 7.1 g/cu.m. The exposure level was set at this limit because of safety considerations for explosions. A single level of exposure was chosen as no exposure-related chances were seen I in the 90--day study (see below) at a slightly hig her cnncertration (19, 0C0 ppm). Monitoring for toxicological effects was by tlwice daily observation., body weights, and a complete necropsy and histoloqic examination including tissues of the entire respiratory tract (3 levels of the nasal epithelium, personal communication with study director) and brain. Survival of female mice after week 82 was significantly lower than controls apparently due to an increase in deaths from carcinomas of the uterus; there were no other statistically significant differences in survival between control and treated animals of either species. The incidences and severity of microscopic pathcloqies noted in tissues (including uterine tissue) were not different between the treated and control animals of either species. Hyperactivity was observed but only in female mice (no incidences given) and only during expos tre. Mean body weights were decreased in both male and female rats. In females, the maximum difference in body weights between exposed and control animals was 13% and occurred at 59 weelk:s of exposure when 49 of 50 test I animals were still alive. Althougjh some fluctuations towards normalcy were observed from this time forward, terminal body weights of 23 surviving treated aniamals were still 10% -less than their corresponding controls. In male rats9 mean body weights were also decreased when compared with controls, al thoucnh he decrease achieved a maximum differential of only 8. The mean body weights of mice were not affected by exposure. Based on the mild decrease in mean body weight gaih, 15, 000 ppm is judged as a free-standing NOAEL. The NDPEL(HEC) = 7.1 g/cu.m. Groups of F344 rats and B6C3F1- mice (10/group) were exposed to either 'u air), 2500 ppm (6.6 g/cu.m), 5000 ppm (13.2 g/cu.m), 10,000 ppm 26.4 g/cu.m or 19,000 ppm (50.1 g/cu.m) of 99.5 ethyl chloride 5 days/week, 6 hours/day for 13 weeks (NTP, 1989). The duration-adjusted concentrations are 0, 1.2, 2.4, 4.7, or 9.0 g/cu.m, respectively. Monitoring for toxicological effects was by daily observation, body weights, and a complete necropsy and histologic examination including tissues of the entire respiratory tract and brain. No exposure-related clinical signs or gross or histopathological effects were observed in either species. Relative liver weights were slightly increased in the male rats (14%) and female mice (18%) exposed to 19,000 ppm. ht decreases in mean body weights were noted in the rats (82 in the males, 4% in the females) exposed to 19,00 ppm; no dose-related tendency could be discerned from the data. As no toxicity was apparent, 19,000opm is considered as a free-standing NOAEL in this Study. The NOAEL(HEC) = 9.0 g./cu-m. The results obtained in the two studies of Troshina (1964 &1566) discussed below do not concur with those found by NTP (1989?) , Landry et zl. 1982, 1789), or Rowe et al. (1939). Al1 of the latter arE carefully conducteLsd studies with appropriate controls and relatively complete esentation and description of the data oCtained. As precented, the studies ofT Tr hinaii may b'e dcscribed as ambiguous lV conduc te'd with deficient uSe 0f Ucontrols and no or little presentation of data. These deficiencies nretlude consideration of thee=e s5ource of information about true toxic effects of this chemicaal 7n the study published in 1964., Troshina exposed 12 rats (sex or strain not specified) for 2 hours/day for O days (assumeC consecutive) 14 /cu.m 5 ethyl cihlorade, the duration-adi Ited vaOlue being 1.2 o/cu.m. There Is mention of but no escriptc r ion of coitro 1 a used in this study. Body wJeig ht, hen.McJtol ogy -omfie histropa2thol ogyv , and the "functional sttate of tie nervoLis svstem and the liver" were assesed for adverse effe-cts.. Body weights were unaffected. Lling a functi onal test of 1.ivur metabolic capacity (conversion of gastrical ly administered sodiurr benzoate to hippuric acid as measured by urinary excretion) , a decrease in hippuric acid excreticin was noted after the exposure, from 90.7% in controls to 7.73.67 in the exposed animals. Lung pathology was described as bronchitis, hyperemia, ard (aprparently) intraalveolar thickeninq. The Author clai ms these effects are exposure- related indications of irritant action, although no mention is made of histology from control lungs. Descripticn of liver p.th'Ology included nodule formation oriqinating from the reticuloeridothelial Cc lis while "very slight" adiposity was also noted. Belying this description of substantial pathology, the author states that these changes were "weakly pronounced. A-fter notinc a inc reased tendency of exposed animals to form cutaneous abscesses (4cf 12) the authors exafmiined other animals (apparently exposed under identical conditions for 2 weeks, n = at least 3) for decrements in phacocytic activity. Their data showed a decrease in phagocyte number-, index (not described), and percent of active cells at the end of the 2--week period, although evaluation past this early time point was apparently not done. No scientific conclusions could be reliably drawn from this study, although effects would sLIugest the exposure Jove] of 1.2 c/cu.m to be a frank-effect level (FEL). For extrarespiratory effects, FEL HEC ) = 1.2 g/cu.m. The FEL(HEC) was &lso calculated for ~a gas:respiratory effect in the thoracic region. Mua = 0.14 cu.m/day, Mt/h = 20 cu.m/day, Sa(TH) = 3461.5 sq.cm., Sh(TH) = 640531 sq.cT. RODR = (Ma/Sa) / (Mh/Sh) = 1.3. FEL(HEC) = FEL(ADJ) x RGDR = 1.6 g/cu.m. In the 1966 study by the Troshina, exposures were lowered substantiall y from the 1954 experiments (presumably due to the frank effects) and are reported as 0, 0.06., or 0.57 g/cu.m in exposures to 12 rats which lasted for 6 months at 4 hours/day, L days/week. The duration-adjusted values would be C), 0.00S5, or 0.0311 g/cu.m. Using the same indicators of toxicity as in the 1964 study, the author reported decreases in phagocytic activity although these indices "iluctuated within considerable limits." Althouqh no data are presented, the author also describes several exposure-related effects including disturbed liver function, lowered blood pressure, fatty liver., and what is interpreted as intraalveolar thickening in the lungs. No scientific conclusions could be reliably drawn from this study, although effects claimed would suggest the exposure level of 0.00 g/cu.m 8.5 mg/cu.m = NOAEL(HEC) based on extrarespiratory effects. The NOAEL(HEC) was also calculated for a gas:respiratory Effect in the pulmonary region. MYta 0.14^ cu . M/day, M/h = 20 cu.m/day, Sa(PU) = 3424 sq.cm., Sh(TH) = 635545 sq.cm. PGOR = (Mva/Sa) / ('MVh/h) 1.3. NOAEL(HEC) = NOAEL(ADJ) x RDR =11.1 mg/cu.m. Experiments conducted by Breslin et al. (198) suggest that exposure to ethyi chloride may disrupt th est-us cycle of mice. Two gr.oupS (10/grop) of fenale 6C3F1 mice were acclimated in exposure chambers over a 2-week period or until the estrus cycles of most mice was a 4-6 day interval (as judged by a Vaginal l technique) . Males were included in each chamber to synchronize and promote regular estrus cyclicity. Following acclimatization one group was exposed to 15,000 ppm (39.6 g/cu .m) ethyl chloride S hourn/day for a minimum of 14 consecutive days (through 3 estrus cycles). No effects on behavior. gross or histopathologv were observed in the group undorgoing exposure althouch the mean body weights in the exposed grou p was sion-ificantily increased rather than decreased. The mean length of the estrus cycle in exposed mice was 5.5 days, significantly longer in duration than the pre- exposure duration for the same group (5.0 days) and for the corresponding controls (4.5 days) . The protraction of the period could not be attributed to an increase in any particular phase of the estrus cvcle and is therefore 6 Suggstive f a gErIeral stre'- response A direct expoSure-re)ated effect of ethyl chloride on neuroencjcrine function cannot be exc lumdd As this effect is reqarded azs a Lvstmic ei-fect, the exposure iS duration adijusted to establish a free-starding LOAEL of 6.6 g/cu.m. The LOAEL(HEC) = 6.6 g/cu.m. X<< Ethyl chloride I .7.5. CONFIDENCE IN THE INHALATION RfC Study : MediUm Data Sase: Medium - RfC: Medium Although the principal studv ,s well1-conducted, it does not establish a firm concentration-response relationship with an adverse effect and was not performed at levels eliciting maternal toxicity. There are no multigenerational reproductive studies for this compound, and without a\ deveiopmentaJ study in a second species, the overall confidence in the data base is medium. Medium confidence in the RfC fol lows. Ethyl chloride >>> I_I.',6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This'assessment is not presented in any existing U.S. EPA document, Other EPA Documentation -- U.S. EPA, 1987. 1988 Agency RfD Work Group Review: 12/ 20C/ 90C Verification Date: 12/20/90 1.2.7. EPA CONTACTS (INHALATION PfC) 3ary L. Foureman / ORD -- (919)541-1183 / FTS 629-1123 Annie N. Jiarabek / ORD -- (919)541-4247 / FTS 629-4247 II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Ethyl chloride CfASRN- -- 75-00-3 Primary Synonym -- Chloroethane This substance/agent has not been evaluated by the U.S. ErA for evidence of human carcinogenic potcntial. III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS 7 II I. . DRI NK ING WrITER HEALTH ADVISO:1ES Substance Name -- Ethyl chloride CASRN -- Frimary Synonym ---- Chlorce thiane Not available at this; time. ------ III.B. OTHER ASSESSMENTS SubFtance Name -- Ethyl chloride CASRN -- 75-00- 3 Primary Synonym -- Chloroethane Content to be determined. -IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Ethyl chloride CASRN -- 75-00-:3 Primary Synonym -- Chloroethane Not available at this time. V. SUPPLEMENTARY DATA Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane Not available at this time. VI B IBLIOGRAPHY Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane Last Revised --- 04/01/91 8 VI .A. ORL Rf REFERENCES None --- -- Ethyl chloride VI.9. INHALATION RfC REFERENCES Balazs, T., J.P. Hanib and E.H. Herman. 1936. Toxic responses of the cardiovascular system. Chapter 14. In: Casarett and Doul's Toxicology, The Basic Science of Poisons 3rd ed. MacMil an Publi _s:hing Co., NY, NY. p. 390. Breslin, W.j., N.M. Gerdasco., J.E. Phillips., and K.A, Johnson. 1988. Ethyl Chloride (E+C1) : Effects on Estrous Cycling in B6C3F1 Mlice. Final report withn cover letter dated 11/21/98. Dow Chemical Company. EPA Document 86-- 890000040 . Dobi::in, A.B. and F.H. Bvles. 1971'. The pharmaccdvnamics of divinvl ether, ethyl chloride, fluorexene, nitrous oxide, and trichloroethylene. In: Textbook Vet. Anesth. p. 94-104. E.I. du Pont deNemours and Company. 1971. Cardiac sensitization testing in dogs with ethyl chloride. EPA Document #-6-870000.A2. Gargas, M.L., R.J. Burgess, D.E. Voisard, G.H. Cason, and M.E. Andersen. 199. Partition coefficients of low-molecular-weioht volatile chemicals in various liuids and tissues. Toxicol. Appl. Pharmacol. 95: 87-99. Hes, 3.Ph., D.F. Cohn and M. Streifler. 1979. Ethyl chloride sniffincg and cerebellar dysfunction (case report). Isr. Ann. Psvchiatr. Relat. Discip. 17(2): 122-125. Landry, T.D., J.A. Ayres, K.A. Johnson and J.M. Wall. 1982. Ethyl chloride: A two-week inhalation toxicity study and effects on liver non-protein sLlfhydryl concentrations. Fund. Appl. Toxicol. 2(4): 230-234. Landry, T.D., K.A. Johnson, J.E. Phillips and S.K. Weiss. 1989. Ethyl chloride: 11-day continuous exposure inhalation toxicity study in B6C3F1 -mice. Fund. Appl. Toxicol. 13: 516-522. NTP (National Toxicology Program) 1989. Toxicology and carcinogenesia studies of chiOcroethane (ethyl chloride) (CAS No. 75-00-3) in F3i44/N rats and 36C3F1 mice. NTP Tech. Report Ser. No. 346. Nordin, C., M. Rosenqvist and C. Holistedt. 1988. Sniffing of ethyl chloride - an uncommon form of abuse with SeriLous mental and neurologicai symptoms. Int. j. Addict. 23(6): 623-627. Rowe V. K., E.M. Adams a.nd -{H.C. Spencer. 1939. Toxicity nf ethyI chloride. Dow Chemi.ca1 Company. EPA DocuMn t #rG-k7000225 . Scortichini., B.H. . K.A . Johnson, 3.J. Moman-Pfruender and T.R. Hanley, Jr. 6. Ethyl chloride: Inhalation teratology study in CF-1 mice. Dow Chemical Co. EPA DocLument #88-570002248. 9 Troshinf , M.M. 19;64. To:icology of ethyl1 chloride. "foksii:ol. Hovykh. Prom. Khim. Vchches Lv . 6 45-55 . ( Rujsi trans ation Troshina, M.M. 1965. Determination of maximLum permissible concentration of ethyl chloride in the atmosphere of work premises. Gig. Tr. Prof. Zabol. 10: U.S. EPA. 19G7. Health Effects Assessment for Ethyl Chloride. Prepared by the Office of Health and Environmen tal Assessment. Environmental Criteria and Assessment Office, Cincinnati , OH for the Office of Solid WLas-te arid Emerncicy Response, Washington, DC. EPA/600/F-S8/036. U.S. EPA. 1903. Summary Review of Health Effects Associated with Monochloroethane: Health Issue Assessmient. Prepared for the Office of Health and Environmental Assessment, Office of Research and Development, U.S. EPA by the Environmental Criteria and Assessment Office, Research Triangil Park, NC. PA/600/B-PS/060. 35 p. ------Ethyl chloride - _V! .5. CARCINOENICITY ASSESSMENT REFERENCES None ------thyl chloride >> ------ _VI .D. DRINiNG WATER HA REFERENCES None SYNONYMS Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane Last Revised -- 04/01/91 Ethane, chloro- Aethylchlorid [German] Aetnhvi is -ETHYLIS CHLORIDUM Anodynon Che len Chloorethaan EDutch] Ch lor en e CForethy C hlo riduLIm 10 ( c m n I Chloroe thane Chlorure d'ethyle E~renchj Ch.oryl I HLORYL ANESTHETIC c C Iloretilo Clorcetano [Italian] Cloruro de etilo [Spanish] CLORURO DI ETILE [Italian] ETH.ANE, CHLORO- ETHER CHLORATUS I ETHER HYDROCHLORIC ETHER MURIATIC Ethyl Chloride ETYLU CHLOREK EPolish] H--SDB 533 Hydrochloric ether Ke lene I Monochl1orethbane Monochloroethane Miuriatic ether Narco0t .Ile NCI-C06224 | UN 1037 11 Chloroform: CASRN 67-66-3. (03/01/91) Health risk assessment information on a chemical is included in IRIS only after a comprehensive review of chronic toxicity data by won: groups; composed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections i and II represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g., treatment technology). When considering the use of reoulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background information and explan- ations of the methods used to derive the values given in IRIS are provided in the five Background Documents in Service Code 5, which correspond to Sections I through V of the chemical files. STATUS OF DATA FOR Chloroform File On-Line 01/71/87 Category (section) Status Last Revised Oral RfD Assessment (1.A.) on-line 06/30/88 inhalation RfC Assessment (I.B.) pending Carcinogenicity Assessment (II.) on-line 03/01/91 Drinking Water Health Advisories (III.A.) no data U.S. EPA Regulatory Actions (IV.) on-line 06/01/90 Supplementary Data (V.) on-line 01/31/87 _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS I.Al. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chloroform CASRN -- 67-66-3 Primary Synonym -- Trichloromethane Last Revised -- 0/30/83 1 The Relerence Dose (RfD) is based on the assumption that thresholds e:at for certain toxic effects such as cellular necrosis, but may not exist for other 3EffectS Suh S carc:igenicity. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of mragnitude) of a daily ex posure to the human po1pulatior (inc Ludincj sensitive sLbCroLps) that is likely to be. without an appreciable risk of deleterious effects during a lifetime. Please refer to BFackgrournd Documeint 1 in Service Code 5 for an elaboration of these concepts. RfDs can also be derived for the nonca-rcinoqenic health effects of compounds which are also carcinooes. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U. S. EF'P has eval uated this substance for potential human carcinogen- ic ity, a summary of that eval uation will be contained in Sec tion II of this file when a review of that evaluation is conipleted. << Chlorofor ri I . AI. 1. ORAL RfD SUMMARY Critical Eifect Experimental Doses* UF MF RfD Fatty cyst forma- NOEL: none 1000 1 1E-2 tion in liver mg/kg/day a LOREL: 15 mg/kg/dav Dog. Chronic Oral (converted to 12.9 Bioassay mg/kg/day) 3 Heywood et al., 1979 *Conversion Factors: 15 mg/kg/day x 6 days/7 days = 12.9 mg/kg/day < Chloroform >. I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Heywood. R.R.J. Sortwell, P.R.S. Noel, et al. 1979. Safety evaluation of toothpaste containing chloroform. III. Long-term study in beagle dogs. J. Environ. Pathol. Toxicol. 2; 35-551. in this study beagle dogs were administered chloroform in a toothpaste base (0.5 mL of toothpaste base/kg/day) in gelatin capsules. A control group composed of 16 males and 16 females received the vehicle, and additional control groups of eight animals/sex were administered an alternative tooth- paste or were left untreated. Experimental groups of eight male and eight female dons received 15 or 30 mg chloroform/kg/day for 6 days/week. Treat- I ment was continued for 7.5 years. Fatty cysts, considered to be treatment- related, were observed in livers Of some dogs in both treatment groups. I Nodules of altered hepatocytes were considered treatment-related but not dose- dependent. r dose-related increase in SGPT levels was rioted and a less marked increase in SGOT was noted in the high-dose animals. The LOAEL was determined to be 12.9 mg/kg/day, and an RfD was set at 0.01 mg/kg/day. Chloroform I .A.. UNCERTPINT Y AND MODIFYING FACTORS (ORAL Ff') 1F.=1-0. uncertainty factors of 10 each were applied to the LOIAEL of 12.9 m oay to account for the interspecies conversion, protection of sensitive Ihuman subpopulations, and concern that the effect seen was a LOAEL and not a NOEL. 2 MF = 1. Chloroform. I .A.4. ADDITIONAL COMMENTS (ORAL RfD) Chloroform is considered to LE? highly fetotoxic , but not teratogenic (Schwetz. 1974; Thompson et al., 1974). A study in rats, using only one treatmernt dose (Palmer et 1l., 1979), identified 60 mg/kg/day by gavage as a LOAEL for decreased weight gain. piasrma cholinesterase and relative liver weight. Other darta in the litcrature (Jorgenson et al.. 1982) also indicate changes in liver fat to be treatment- related. << Chloroform >> I.A.5. CONFIDENCE IN THE ORAL RfD Study: Medium Data Base: Medium RfD: Medium The critical study (Heywood et- al., 1979) was of chronic duration, used a fairly large number of dogs, and measured multiple endpoints; however, only two treatment doses were used and no NOEL was determined. Therefore, confidence in the study is rated medium. Confidence in the data base is considered medium to low; several studies support the choice of a LDAEL, but a NOEL was not found. Confidence in the RfD is also considered medium to lOw. << Chloroform I .A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1995. Drinking Water Criteria Document for Trihalomethanes. Office of Drinking Water, Washington, DC. External Review Draft. The 1985 Drinking Water Criteria Document for Trihalomethanes is currently undergoing Agency review. Agency RfD Work Group Review: 12/02/85, 05/15/86 Verification Date: 12/02/95 _I.A.7. EPA CONTACTS (ORAL RfD) James Murphy / ODW -- (202)382-7591 / FTS 382-7591 M.L. Dourson / ORD -- (513)56-7534 / FTS 684-7534 I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Soubstance Name -- Chloroform CASRN -- 67-66-.3 3 Primary Synonym -- Trichloromethane A risk assessment for this substance/agent is under review by an EPA work I II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE E Substance Name -- Chloroform CASRN -- 67-66-3 Primary Synonym -- Trichloromethane Last Revised -- 03/01/91 Section II provides information on three aspects of the carcinogenic ri:: I assessment for the agent in question; the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the agent is a human carcirogen. The quantitative risk estimates are presented in three ways. The slop-e factor is the result of application of a low-dose extrapolation procedure and is presented as the risk per (ig/k) /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 I in 10,000, 1 in 100, 000 or 1 in 1,000,000. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicitv. I < Chloroform >>> II .A. EYIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY II. .1. WEIGHT-CF-EVIDENCE CLASSIFICATION Classification -- B2- probable human carcinogen Basis -- Based on increased incidence of several tumor types in rats and three strains of mice I<<< Chloroform >>> II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. There are no epidemiologic studies of chloroform itself. Chloroform and other trihalomethanes are formed from the interaction of chlorine with organic material found in water. Several ecological and case- control studies of populations consuming chlorinated drinkino water iri which chloroform was the majior chlorinated organic show small sionificant increases in the risk of rec tal bladder or co)on cancer on an intermittent basis. Many other suspected carcinogens were also present in these water supplies. << Chloroform , I.A.7. ANIMAL CARCINOGENICITY DATi 4 SLffiCient. Chloroform has be-er tested for carciroienicity in eight strains of mice, two strains of rats and in beagle dogs. In a gavage bioassay (NCI, 1.976), Osborne-Mendel rats and B6C3Fi1 mice were treated with chloroform in corn oil 5 times/week for 79 weeks . Pif tv male rats received 90 or 125 mg/kg/day; females initially were treated with 125 or 250 mg/kg/day for 22 weeks and 90 or 130 mg/kg/day there;After. Male mice received 100 or 200, raised to 150 or 300 mic/kg/day at 18 weeks; females were dosed with 200 or 400, raised to 250 or 500 mg/kg/day. A significant increase in k-idney epithelial tumors was observed in male rats and ['hihly siqnificant. increases in hepatocellular carcinomas in mice of both sexes. Li ver nodular hyperplasia was observed in low-dose male mice not developing hepatocellLulaor carcinoma. Hepatomas have also developed in female strain A mice and NLC mice gavaged with chloroform (Eschenbrenrer and Miller, 1945; Rudali, 1967). d Jorgenson et al. (1985) administered chloroform (pesticide quality and distilled) in drinking water to male Osborrie-Mendel rats and female B6C3Fi mice at concentrations of 200, 400, 900, and 13)0 mg/L for 104 weeks. These concentrations were reported by the author to correspond to 19., 38, P1, ard 160 mg/kg/day for rats and 34 65, 13.0 and 263 mg/kg/day for mice. A significant increase in renal tumors in rats was observed in the highest dose group. The increase was dose related. The liver tumor incidence i, female N ice was not significantly increas-ed. This study was specifically designed to measure the effects of low doses of chloroform. Chloroform administered in toothpaste was riot carcinogenic to male C5781, CBA, CF-1 or female ICI mice or to beagle dogs. Male ICI mice administered 0 mg/kg/day were found to have an increased incidence of kidney epithelial tumors (Roe et al., 1979; Heywood et al., 1979). puliionary tumor bioaasav in strain A/St mice was negative as was one in which newborn C57X DP2/F1 mice were treated s.c. on days 1 to S of life (Theiss et al., 1977; Roe et al., 1968). < Chloroform >>> 11..4. SUPPORTING DATA FOR CARCINOGENICITY The majority of tests for genotoxicity of chloroform have been negative. These negative findings include covalent binding to DMA, mutation in Salmrronella, a Drosophila sex-lin-kked recessive,. tests for DNA d.kaae a mnicro- nucleus test, and transformation of BHK cells. By contrast one study demonstrated binding of radiolabeled chloroform to calf thymus DNA following metabolism by rat liver microsomes (DiRenzo, 1982). Chloroform caused mitotic recombination in Saccharomyces (Callen et al., 19830) and sister ci-romatid exchange in cultured human lymphocytes and in mouse bone marrow cells ex.posed in vivo (Morimoto and ioizumi. 1983). The carcinogenicity of c.loroform may be a function of its metabolism to phosqene,* which is known to cross-link DNA. A host-mediated assay using mice indicated that chloroform was metabolized in vivo to a form mutagenic to Saimonella strain TA1537. Likewise urine extracts from chloroform-treated 3Imcm were mLtCgenic (Agustin and Lim-Sylianco, 197:) Chloroform administered to mice in drinking water promo ted Crowth arid mtastasis of Ehrlich ascites cells injected i.p. (Capel et al., 1979). --- Chlor- >------ 5 11 .B. UANT I TATIE ESTIMATE OF CA1RCINUGENIC RI Si:: FROM ORAL EXPE)SLIRCE II.1. SUIIIARY OF RI Sf. ESTIMgATES Oral Slope Factor -- 6..E- p.r (mg/kg)/day Drinking Water Unit Risk -- .1.7E-7 per (ug/L) Extrapolation Method Linearized multastare procedur, extra risi- Drinkinq Water Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) LF42 LI/L E-5 (1 in 100,:00) 6E+1 ugj/L E-6 (1 in ,000,00)i 6E-+ ugi/L Chloroform .. .2. DOSE-RESPONSE DATA (CARCINGENICITY, DRAL EXP'SURE) Tumor Ty pe -- all kidne tumors Test Anirals -- rat/Osborne-Mendel r.ale Route -- oral , drinking water Reference -- Jorgensen et &1. , 1985 Dose Tumor H-ma n Incidence AdinStC - d i stered Equivalent (mg/L) (mg/kg/day) C) 1 /5C 2C) 3. 4 6/313 400 6.9 7/148 14.9 3/ 48 1900 28.9 7/50 < II7..3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Historical control kidney tumor incidence was 5/301. The uniL riSk showuld not be Ltsecd ii the watter concentraction exceeds 6E+4 Lq/L, since above this concentration the unit risk may not be appropriate. Chloroform .B.4. DISCUSSION OF CONFIDENCE (CF'RCINOGENICITY, ORAL EXPOSURE) This assay was desiqned for detection and quantitation of effects at low dsOe; thus, large numb'ers of animals were treated and observed for their lifetime. Exposure route and vehicle is relevant to the medium for which the risk estimate was developed. 6 ------< Chloroform ------ II .C. DUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXF'SL.'RE II.C.1. SUMMARY OF RISK ESTIMATES inhalation Unit Risk -- 2.3E-5 per (ug/cu.m) Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 1000) 4E+0 LQ/CuL.mf E--5 (1 in 100,000) 4E-1 ug/cu.m E-6 (1 in 1,000,000) 4E-2 ug/cu.m < Chloroform II .C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- hepatocellular carcinoma Test Animals -- mouse, S6C3Fl, female ROLLte -- oral. Qavage Reference -- NCI, 1976 ---- Dose ----- Tumor Admin Human Incidence istered Equivalent (mg/kg/day) (mg/kg/day) Feal 0 0 0/ 20 233 9.9 36/45 477,/ i9 .9 39/41 Male O0 0 .1/18 138 6.2 1B/0 277 44/45 Chloroform > _II. C. 3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) This inhalation quantitative risk estimate is based on data from a gavage study. Above doses are TWA; body weights at the end of the assay were 3 , males and 28 g, females. Vehicle control animals were run concurrently and housed with test animals. All treated animals experienced decreased body weight gain. Survival was reduced in high--dose males and in all treated em ales. Experimental data for this compound support co'mpi1 etc absorption of orally administered chloroform under conditions of this assay. There are no apparent species differences in this regard. Extrapolation of metabolism-dependent 7 carcinogenic responses from mice to humans on the basis of body surface area is supported by e, per limen tal data. The incidence data for both male and female mice were usted to derive slope factors of 3.3E-2 and 2.OE-l per mg/kg)/day, respectively. The urit risk was prepared by taking a geometric mean of the slope factor and assuming 100.%for low doses of chloroform in air. The unit risk should not be used if the air concentration exceeds 400 ug/cu .m, since above this concentration the unit risk may not be appropriate. < Chloroform II .C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATIOIJ EXPDSURE) Adequate numbers of animals were treated and observed. Risk estimates derived from nale rat kidney tumor data (2.4E-2) (NCI, 1976) and studies by Roe et al. (1979) (i.0E-1) are generally supportive of the risk estimate. ------<< Clrfm>>------KChloroform _11 .D. EFA DOCLuMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) II . D . 1. EPA DOCUMENTATION U.S. EPA. 1985. Health Assessment Document for Chloroform. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC for the Office of Air Quality Planning and Standards. EPA 600/8-84-004F. U.S. EPA. 1987. Drinking Water Criteria Document for Trihalomethanes. Office of Drinking Water, Washington, DC. Draft. NCI (National Cancer Institute). 1976. Report on Carcinogenesis Bioassay of Chloroform. National Cancer Institute, Washington, DC. NTIS PB 264018. Chloroform >> II .D. 2. REVIEW (CARCINOGENICITY ASSESSMENT) The Health Assessment Document for Chloroform received extensive Agency and external review. The Draft Drinking Water Criteria Document for Trihalomethanes has Rreceived external per review. Agency Work Group Review: 10/29/86, 08/26/87 pVerification Date: 03/26/87 U -II. D.3. US. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) pNancy Chiu / ODW -- (202)382-75S7 / FTS 382-7587 U 8 David L. Bayliss / ORD -- (202)382-5726 / FTS 382-5726 II1. HEALTH HAZARD ASSESSMENTS FOR VARED EXPOSURE DURATIONS _III.A. DRINKING WATER HEALTH ADVISORIES Substance Name -- Chloroform CASRN -- 67-66-3 Primary Synonym -- Trichloromethane Not available at this time. III.B. OTHER ASSESSMENTS Substance Name -- Chloroform CASRN--- 67-66-3 Primary Synonym -- Trichloromethane Content to be determined. - IV. U.S. EPA REGULATORY ACTIONS SLbstance Name -- Chloroform CAGRN -- 67-66-3 Primary Synonym -- Trichloromethane Last Revised -- 06/01/90 EPA risk assessments may be updated as new data are published and as E assessment methodologies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the reQLlatorV actions in this section with the verification dates for the risk assessments in sections -1 a nd as th i5 may explain inconsistencies. Also note that some reQLulatorv actions consider factors not related to health risk, such as technical or - economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve Eenforceable federal standards. Please direct any queStions you may have concerning these regulatorV actions to the U.S. EPA contact listed for that S articular action. Users are stronglv urged to read the background inform- I ktion on each regulatorV action in Background Document 4 in Service Code 5. I K( V--V. CLEAN AIR ACT (CAA) 9 IV.A. 1. CAA REGULATORY DECISION Action -- Intent to list under Section 112 Considers technological or economic feasibility? -- NO Discussion -- Chloroform is a probable human carcinogen (EPA Group P2) and according to EPA's preliminary risk assessment from ambient air exposures, public health risks are significant (13 canrer cases/year and maximum lifetime individual risks of 7.1E-4). Thus, EPA indicated that it intends to add chloroform to the list of hazardous air pollutants for which it intends to establish emission standards under section 112(b)(1)(A) of the Clean Air Act. The EPA will decide whether to add chloroform to the list only after studying possible techniques that might be used to control emissions of chloroform and further assessing the public health risks. The EPA will add chloroform to the list if emission standards are warranted. Reference -- 50 FR 39826 (09/27/85) EPA Contact -- Emissions Standards Division, fAQPS (919)541-5571 / FTS 627-5571 ------<<<' Chloroform ------ _IV.B. SAFE DRINKING WATER ACT (SDWA) IV.B.I. MAXIMUM CONTAMINANT LEVEL (MCL) for Drinkingi Water Value (status) -- 0.10 mg/L (total trihalomethanest] (Interim, 1979) Considers technological or economic feasibility? -- YES Discussion -- An interim MCL of 0.10 ma/L for total trihalomethnes* is proposed based on chronic toxicity data for chloroform and existing technology and treatment methods. Chloroform produced central nervous system depression, hepatic, renal, teratogenic and carcinogenic effects at dose levels from 30 to 350 mg/kg. )Chloroform (87-66-3), dibromochloromethane (124-48-1), bromodichloromethane (75-27-4) and bromoform (75-25-2). Reference -- 44 FR 68624 (11/29/79) EPA Contact -- James Murphy / Criteria and Standards Division, 0DW / (202)362-7571 / FTE 382-7571; or Drinking Water Hotline / (800)426-4791 ------Chloroform >>>------ IY.C. CLEAN WATER ACT (CWA) IV.C.1. AMBIENT WATER QUALITY CRITERIA, Human Health Water and Fish Consumption: 1.9E-1 ug/L 10 Fish Consumption Only: 1.57E+1 ug/L Considers technolouical or economic feasibility? -- NO Discussion -- The WOC of 0.19 ug/L represents a cancer risk level of 1E-6, based on consumption of contaminated organisms and water. A WDC of 15.7 ug/L (cancer risk level of 1E-6) has also been established based on consumption of contaminated oroanisms alone. Reference -- 45 FR 79318 (11/28/80) EPA Contact -- Criteria and Standards Division, OWRS (202)475-73.15 / FTS 475-7315 Chloroform >>> IV.C.2. AMBIENT WATER DUALITY CRITERIA, Aquatic Organismm Freshwater: Acute LEC -- 2.89E+4 uq/L Chronic LEC -- 1.24E+3 ug/L Marine: None Considers technological or economic feasibility? -- NO Discussion -- The values that are indicated as "LEC" are not criteria, but are the lowest effect levels found in the literature. LECs are given when the minimum data required to derive water quality criteria are not available. Reference -- 45 FR 79319 (11/28/80) EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 - - Chloroform >>>------ IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) IV.D.1. PESTICIDE ACTIVE INGREDIENT, Registration Standard None < nChloroform >>- __IV.D.2. PESTICIDE ACTIVE INGREDIENT, Special Review Action -- Risk benefit analysis - PD2/3 (1978) Considers technological or economic feasibility? -- YES Summary of regulatory action -- An outline of regulatory options based on risk-benefit considerations is presented in Position Document 2/3. Reference -- 48 FR 498 (01/05/22) 11 EPA Contact -- Special Review Branch, OPF / (707)557-7400 / FTS 557-7400 ------Chloroform------ChlIorof orm ::,- IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available ------< Chloroform >>------ _IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA) IV.F.1. RCRA APFENDIX IX, for Ground Water Monitoring StatLIs -- Listed Reference -- 52 FR 25942 (07/ 09/87) EPA Contact -- RCRA/SuperfLund Hotline (900)424-9345 / (202) 392-3000 / FTS 382-3000 ------< Chloroform >>------ __IV.G. SUPERFUND (CERCLA) IV..i. REPORTABLE QUANTITY (RO) for Release into the Environment Value (status) -- 10 pounds (Proposed, 1987) Considers technological or economic feasibility? -- NO Discussion -- The RQ for chloroform is based on potential carcinogenicity. Available data indicate a hazard ranking of medium based on a potency factor of 1.97/mg/kg/day and assignment to weight-of-evidence group B2. These correspond to an RD of 10 pounds. Reference -- 52 FR 8140 (03/16/57) EFA Contact -- RCRA/Superfund Hotline (9S00)424-934> / (202 ) 382-3000 / FTS 3230 V. SUPPLEMENTARhY DATA Substance Name -- Chloroform CASRN -- 67-66-3 Primary Synonym -- Trichloromethane Last Revised -- 01/31/87 12 The information corntained in this section (subsec tions A and B) has been extracted from the EPA Chemical Profiles Database, whic h has beer compi led from a number of secondary soLLrces arnd has riot Lndergone formal Agency review. The complete reference listings for the citations in this section are provided in Service Code 5. The user is urged to read Background DOCLIment 5 in Service Code 5 for further information on the sources and limitations of the data presented here. << < ChlorofOrm >>> V. A. ACUTE HEALTH HAZARD INFORMATION Toxicity -- Chloroform is classified as moderately toxic. A probable oral lethal dose for humans is 0.5 to 5 g/kg (between 1 ounce and 1 pint) for a 150-lb. person. The mean lethal dose is probably near 1 fluid ounce (44 g) (Gosselin et al., 1976). Also, it is a central nervous system depressant and a aastrointestinal irritant (Challen et al.. 1952). oChloroform has caued rapid death attributable to cardiac arrest. Medical Conditions Generally Aggravated by Exposure -- Not Found igns and Symptoms of ExpoSLre -- Symptoms of acute exposure include fainting sensation, vomiting, dizziness, salivation, nausea, fatigue, and headache (ACSIH. 1971-1979). Other symptoms are respiratory depression, coma, kidney damage, and liver damage '(IARC, 1972-1985). Liquid in the eye causes tearing and conjunctivitis (Grant, 1974). Symptoms of chronic exposure include loss of appetite, hallucinations, moodiness, and physical and mental sluggishness (NIOSH, 1974). ------<< Chloroform-- _V B. PHYSICAL-CHEMICAL PROPERTIES Chemical Formula -- CHC13 Molecular Weight -- 119.39 Eoilino Point -- 143F, 61.7C pecific Gravity (H2D=1) -- 1.432 at 2iC/4C U Vapor Pressure (mmHg) -- 100 at 10.4C Melting Point -- -82.F, -63.5C Vapor Density (AIR=1) -- 4.12 Evaporation Rate (Eutyl acetate=1) -- (Carbon Tetrachloride = 1) 1.i8 Solubility in Water -- 1 mL/2OO mL at 25C Flash Point [Method Used] -- None Flammable Limits -- None I Appearance and Odor -- Chloroform is a clear, colorless and mobile liquid with a characteristic odor. 13 Conditions or Materials to Avoid -- Chloroform develops acidity from proloroed expLsLtre to air and light (General Electric Co., 1979, MSDS #4315). Chloroform explodes when in contact with alLIminLIfr powder or magresiu m powder or with alkali metals (e.g.. lithium, sodium, and potassium) (NFPA, 1978) and dinitrogen tetroxide. Chloroform reacts vigorously with acetone in the presence of potassiUr hydrox ide or calC i LkM hydrox:ide (Bretheric k, 1979). It is oxidized by strong oxidizerS such as c hromic acid, forming phosgene and chlorine (IARC, 1972-1985). Chloroform reacts vigorously with triisopropy lphosphine ( Bretherick,: 1779). Hazardous Decomposition or Bypr-oducts -- When heated, chloroform emits hydrogen chloride, chlorine , and toxic and corrosive oxides of carbon and chlorine (General Electric Co., 1979. MSDS 44315) and phosgene (ITI, 1982). Use -- Chloroform is Used as a grain fumigant; solvent for pesticides. adhesives (IARC, 1972-1995) fats, oils, rubbers, alkaloids, waxes (Merck., 19h76); chemical intermediate for dyes and pesticides; and a comporent of cough syrups, toothpastes, and liniments (SRI, 1983). Not registered as a pesticide in the U.S. (USEPA/Pesticide Index, 1965). VI. B IBLIOGRAPHY Substance Name -- Chloroform CASRN -- 67-66-3 Primary Synonym -- Trichloromethane Not available at this time. SYNONYMS Substance Name -- Chloroform CASRN -- 67-66-3 Primary Synonym -- Trichloromethane Last Revised -- 01/31/87 Chloroform Formyl Trichloride Freon 20 Miethane Trichloride Methane, Trichloro- Methenyl Chloride Methenyl Trichloride rethyl Trichloride NCI-CO26SR R20 T CM Trichloroform irichloromethane 14 Chromium ( IIl) ; CAERN 16065--3--1 11/01/90) Health risk assessment information on a chemical is included in IRIS only after a comprehensive review of chronic toxicity data by wok; groupEsC composed of U.S. EPA scientists from several F'rogram Offices. The summaries presented in Sections I and II represent a consensus reached in the review proceus. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects e.g. , treatment technology). When consicering the use of regulatory action data for a particular situation, note the date of the regul atorv action, the date of the most recent risk assessment relatinc to that action, and wneth'r technological factors were considered. Background information and explan- ations of the methods used to derive the values given in IRIS are provided in the five vackground Documents in Service Code 5, which correspond to Sections I throuih V of the chemical files: STATUS OF DATA FOR Chromium( III) File On-Line 01/71/@7 Category (section) Status Last Revised 4 hP-. T) )) ) 4hP-M(CMKKKKKKKK:', Oral RfD Assessment (i.A. or- I inE 037/0_1/Ss Inhalation RfC Assessment (I.B.) pending Carcinogenicity Assessment (II.) no data Drinking Water Health Advisories (III.A.) on-1 ine 11/01/90 U.S. EPA Regulatory Actions (IV.) on-line 08/01ni/90 Supplementary Data (V.) no data _-I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINGENIC EFFECTS- 1. A. RE-ERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chromium(!!!) CAISRN --- 10-3- Last Revised -- 03/01/93 The Reference Dose (RID) is based on the assumption that thresholds exist for I certain toxic effects such as cIlular necrosis, but may not exist for other * Ci C E fIi EC t S L c h a ca rc i niogo enai c a v . ri genri l1 , i he RfD i s an e- s, t iml-att c (wI u ncI rtay panniang perhaps kn order offLJ magn i t ' ) of a daily eiCp osu re to- the hu :opuL ation (inc uding lrSe niti.VE' LL rcu.ps ) that is ik ey to be w* i thout an appreciable risk of deleterious effects during a lif etime . PJ ease etr-eier to Paccciriund Doc:Lkihen t I an Ser vice Code 5 5 or an el:1 aborati:'n of these concepts. R f l car a 1so b.e de 'r.ed for the noncarc inogernc health e ffc ts of CoFpourcnsLWhi.Ch are al.o car cirirgenis. Therefore, it is es:seriti al to refer to ot hr souces of iuforatioi coic e rin he c a -cinlogeii .tty oof this substance. If the U.S. EPA hat e'a J L tedIthi Substance foir p oir t: atal hu ijarn c iCrc nogqEn-- iciy, --ufpmfary o~f th-Iat v lu to i lbe c ntarle in r cction.r I I o)f t i St1 w her a revIaw of that. Dva&.at i.,rn i s C Ot( c I I Chromium( II I.A.1 ORAL RfD SUMMARY Cr-i tical Ef fect Dos UFLper-imntl MF Rf-D I Nc effects observed NOEL: 5/. Cr203 in 10 1.0 E+0 diet 5 days/wzeI: for mk/ g / ay Rat Chronic Feedinq 600 feedincs (IC80 Ets a rO SStudv /kg bw average total i nso Ilu b Ie Cos) l t Ivankovic and Preussmann 19 7, LOAEL: none I;iDose Conversion Factors & Assumptions: 1800 g Cr203/kg bw x :100 rg/gx 0.6849 Cr/q Cr203 / 600 feeding days x 5 feeding days/7 deys= 1458 I mg/kg/ day I. I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) ivankovic, S. and R. Freussmann. 1975 . Absence of toxic and carcinocenic effects after administration of high doses of ch1rcmi oxide pigment in sub-- acute and lonc-term feeding experiments in rats. Food CoSmet. Toxicol. 13: 347--351. Groups of 60 male and female rats were- fed chromic oxide (Cr203) baked in bread at dietary levels of (. 1, 2, or 5%, 5 days/week for SOC feedings (t40 Lotal days) . The primary purpose of this study was to assess the carcinc- genic potential of Cr203. Body weiqht and food consumpti on were monitored. The aver-acle total amounts of irnested Cr203 were given as 360D 720. and 180.> /bw o Y-the 1, 2, and 5% treatment groups, respectiv ly. The animals were maintained on control diets fol lowing termination of exposure untrl they became moribund or died. All ma ion organs were examined histologicallv. Other toxicologic Parameters were not mentioned explicitly, but may have i Cncluded some or al of those desc ribed for the accompanying subchronic study see below) . No effects 'De to Cr203 treatment were observed at any dose Ivankovic and Preuss:mann (19 5) a so tated rats (b oth se-'xe., 1 9 rats/group) at dietary le'vel f or 5. C, - in bread, 5 davs/i Eek for 90 days. Food consumption and bo w igh were monit ored. oxic oLic p a ram eters inc luded serum protnin, biirubn, hematologv urinalyi , organ weights. and histopatholigy. The only"fectis observed were reductions (12- 37%) in the abSolute weights of the liverc and spleens of animals in the nigh- dose group. Organ weights relative to boy weight w-ere not reportEd. The 2 hich dose is equivalent to 1400 mg/kq/day (dose converted using r-eported Other sLi[chronic oral studies show no indication of adverse effcc tcs attributable to trivalent chromium compounds. but dose levels were con sider-- a bly lower. < Chromium( III I .A.. UNCERTAINTY AND MODIFYING FACTORS (DRAL RfD) UF = 100. The factor of 100 represents two 10-told decreases in og/kg bw/dav dose that account for both the expected interhuman and interspecice variability to the toxicity of the chemical in lieu of specific data. MF = 10. The additional modifying factor of 10 is adopted to reflect Uncertainty in the NOEL because: 1) the effects observed in the 0--day study were not explicitly addressed in the 2--year tLdy and, thus, the highest NJDAEL in the 2--year study may be a LOAEL; 2) the absorption of chromium ias low (<1%) and is influenced by a number of factcrs; thus, a considerable potential variation in absorption exists; and .) animals were allowed to die naturally after feeding stopped (2 years) and onlyv then was histology performed. << Chrcomium ( I I £ _.A.4. ADDITIONAL COMMENTS (ORAL RfD This RfD is limited to metallic chromium (III) of insoluble salts. Examples of insoluble salts include chromic III oxide (r203) and chromium I1. ;ulfate [Cr2(S04)3]. Very limited data suggpest that Cr III may have respiratory effects on humans. N data on chronic or subchronic effects of inhaled Cr III in ani- mais can be found. AdeouLate teratology data do not exist, but reproductive effects are not seen at dietary levels of .5% Cr203. < Chromium(III) >K I.A.5. CONFIDENCE IN THE ORAL RfD Study: Low Data Base: Low RfD: Low The principal study i.S rated low because of the lack of explicit detail on study protocol and results. Low confidence in the data base reflects the lack of high-dose supporting data. The low confidence in the PfD reflects the foregoin., but also reflects the lack of an observed effect level. Thus, the RfD, as given, should be considered conservative, -sincethe NF addresses only those factors which might lower the RfD. ChromiumII) 7<:.T EPAFA.4.5. DOCUMENTAT ION AND REVIEW OF THE ORAL Rf0 U. S. EPA. 1954 . Health Effects Assessment for Trivalent Chromium. Prenared by the Office of Health and Environmental Asessient, Environmental riteria and AsseSment Office, Cincinnati, OH, OHEA for the Office of Solid Waste ano iEmergency Response. 3 ihe t'I in the 19F4 Health Effects Anyessment dcuannt received an Agency review with ths hel p of two external scientists. Agency RfD Work Group Review: .11/21/D5, 02/05/86 Xerification Date: 11/21/85 . A. 7. EP'A CON-iACTS (ORAL RfD) Michael L. Dourson / ORD --- (513)569-7544 / FTS 624-7544 Christopher T. DeRosa / ORD -- (513)569-7534 / FS 684-7534 I.B. REFERENCE CONCENTRAT ION FOR CHRONIC ItNHALATION EXPOSURE (RfC) Substance Name -- Chromium ( I I I) CASRN --- 16065-03-1 A risk assessment for this substance/agent is under review by an EPA work group. _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chromium(III) CASRN --- 16065---1 This substance/agent has not been evaluated by the U.S. EPA for evidence of human carcinogenic potential. III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III.A. DRINKING WATER HEALTH ADVISORIES Substance Name -- Chrcmium( III) -- 16065-83-1 Last Revis-ed -- I1/01/0? The Office of Drinking Water provides Drinking Wiater Health Advisories (HAs) as technical guidance for the protection of public health. HAS are not enforceable Federal standards. HAs are concentrations of a subtance in drinking water estimated to have negligible deleterious effects in humans, when ingested, for a specified period of time. Exposure to the 4 SL bs3 tac ce - rm o t her med i a is considE-red only in th c driva--tin of the li-.-time HA. tr1i he abenrce of chemic al -- S.pElCi f i C 6 ta the 7-sLumdC:6 f rac: tion of tota 1 in take f rcm drink inc water is 2 0. The 1 i-Fetime HA is cal c u ated from the Drinking Wate EqLuivAQent Level (DWEL wich, in turn is based on the Or-al Chronic Reference Dose. Lifet.ime HAs are nJt deri'ed for cc'rmpourds which are potentiall carcinooen ic for humans becaLuse of the diffe rence in assumptions concerning toxic threshcold for carcinogeLnic and n)t ncarc inoglenic E.*ffccts A more detailed description of the assumptions and methods Lsed in the derivation of HA, is provided in Background )ocLumrit 3:; in Servic Cod' 5. Chrnmium( III)> NOTE: All chromniuLM HAs are based on total chromium (III and VI III .A.1. OWE-DAY HEALTH ADVISORY FOR A CHILD Appropriate cata for calculating a One--day HA are not available. it s recommended that the Ten-day HA of 1.4 mg/L be used as the One-day HA. X III.A.2. TEN-DAY HEALTH ADVISORY FOR A CHILD Ten-day HA -- 1.4E+0 Tg/L NOAEL -- 14.4 mg / k g/day UF --- 100 (allows for interspecies and intrahuman variability with the use of a NOAEL from an animal study) Assumptions -- 1 L/day water consumption for a 10-kg child Principal Study -- Gross and Heller, 1946 Rats were exposed to drinking water containing Cr(VI) (K2CrO4) at levels of 50 or 134 mg Cr(VI)/L for 60 days (2.3 or 14.4 mg Cr(YI)/kg/day, respectively) without adverse effects. Therefore, a NOAEL of 14.4 m C/g/day is identified. <<< Chromium ( Ii) III.A.3. LONGER-TERM HEALTH ADVISORY FOR A CHILD Longer-term (Child) HA -- 2.4E-1 mg/L NOAEL -- 2.4 mg/kg/day 100 (al lows for interspecies and intrahuman variab ili tv with the use a NOAEL from an animal study) Assurrptions -- 1 L/day water consumption for a 10-kg child Princ ipal study -- MacKenzie et al. ., 195 In a 1-year drinking, water study, consumption cf water ccntaainin either Cr(iII) (Cr-C13) or Cr(VI) (k.2Cr4) (0 to I .E7 mg/gq/day for male rats and u to 2.41 mg/kg/day for femala rats) produced no significant differences in weiht gain, appearance, or patholcgical changes in the blood or other tissue. Therefore, a NOAEL of 2.41 mg/kg/day is identified. Chromium (III) > 5 : 1I. . 4 . L ON4EER-TERM HE ALTH 'AVI SOR'Y FOR AN ADUL T Lorqer-term (Adu It) HA -- P. 4E--1 /L NDAEL -- 2.4 mg/k gda UF -- 1.00 ( lows for in tErspec ies and in tr aihuarir, variab i ity with the LSE ofi a NOEL from an animal Study) AsuLmptions -- 2 L/day water consumption f or a 70-kci adlJ t F'rinc i pa l s tudy -- MacKenz ie et aL . , 193 (< tudy desc ribed in I II .A 3. <<< Chromnium( III) I .A. 5. DR I NK: I NG WATER EQU I VALEN'T LEVEL / L II~ETIMEHEALTH DVISORY DWEL 1.7E-1 mki/L Assumptionis -- 2 L/day water consumptiori for a 70--ikg adul t RfD Verification Date = 0/05/86 (see Section 1.A. of this file) Lifetime HA -- 1.2E-1 mg/L IsSuptionS ipostue --- 71- et by drinking ate Principal study - MacKenzie et I . ,1958 (This study was used in the derivation of the chronic oral Rf D; see Section I.A.2. Chr omium ( I I I) IAI.A.6. ORGANOLEPTIC PROPERTIES No data available Chromium( III) > 1 I.A.7. ANALYTICAL METHODS FOR DETECTION IN DRINKING WATER Determination of chromium is by an atomic absorption technique uSing either direct aspiration into a flame or a furnace. < Chromium I II ) >> I II .. WPTER TREATMENT The treatment technolooies that are available to remove chromium Trom wa ter inc 1ude ccaguI ation/f il tratior ,l ime sof ten ing , ion ex hange , and reverse osmosis. ium(Lho I II) >> III.A.?. DOCUMENTATION AND REVIEW OF HAs U..- EPA. 1925. Draft of the Drinkina WaLer LCritria Document on Chromium. Office of Drinking Water. Washington, DC. EPA review of HAs in 1985. Public review of HAs following notification of availability in October, 1985. 6 EntiFc f' i c Ad vi scry nae 1 r eview of H ±1sin JanTuaryr. i? Prep;,rat oni datez. thiS ICRI-ca rmmry--- 06/22/e7 i i . A. 1. EPA CONTACTS Kenneth Bailey / ODW -- (202:382-5535 / FTs 382-5535 Edward V. Ohanian / ODW -- (202 '32-7571 / FTS 32-7571 1iI.BE. OTHER ASSESSMEN-TS Substance Name -- Chromium(III CASRN 16065-83-1 Content to be determined. IV. U.S. EPA REGULATORY ACT:ONS Substance Name -- Chromium(III) LAGRN -- 16065--3-1 Last Revised -- 02/01/90 EPA risk assessments may oe updated as new data are published and as assessment methodologies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the rEgLIatory actions in this section with the verification dates for the risk assess-ments in sections I and II, as this may explain inconsistencies. Also note that some regulatory actions consider factors not related to health risk, such as technical or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions 'you may nave concerning thEse regula story actions to the U.S. EPA contact listed for that particul1ar action. Users are strongly urged to read the backoround inform- ation on each regulatory action in Backiround Document 4 in Service Code5. Chromium( III) _IV.A. CLEAN AIR: ACT (CAA) No data available - -- S Chromiu G IN ) A:. ------ IV.R. SAFE DRINKING WATER ACT (uDWA) 7 IV.B.1. MAX. MLIM CONTAMINA NT L FF L GOAL (MOLE) f or Dr i. : ri g Water alue ( status) -- 1.2 Tq /L, [tota l chiromTiiu]rI ( Propose J 1935) Considers technological or economic fc asii ty? --- NO Discussion -- An MCLG of 0.12 m/L for total c hromium (Cr II I and Cr- VI) is proposed bated on a pr ovisional1'. Di4EL o f Ci . 1 7 mq /L with data on IhUman epo:ure factored in ( 0 . 10 mg /dav in the di et and D igs/d#ay by air) . A DW'EL of C.17 mg/L c t EL Of 2.41im/1:g/dy irn rata [1c:i-year rJrinking water study (Cr VI)], wit- an uncertainty factor of 500 appli UOand consumnption of 2 L of water/day assumed. Reference -- 50 FR 4697 Par t IV (11/13/5) EPA Contact - Kennaeth Bailey / Criteria anid Standrda Divis-in, 0DW / (202) 332-7571 / i-TS 732-7571:; or Drinking Water Hot.l ine / (00)426-4791 <<< Chromium(III) IV. .2. rIMX I MUM CONTAMIINANT LEVEL (MCL ) for Drinkinq Water Value iS tatu) --- 0.5 mg/L [total chromium] ( interim, 1930) Considers technological or economic feasibil ity.'? -- NO Discussion -- Reference -- 45 FR 57332 EPA Contact -- Kenneth Bailey / Criteria and Standards DvsIon UDW / (202)3.82-7571 / FTS 332-7571; or DrinSking Water Hotline / (500)426-479i -ChromiuTm(III) ------ _IY.C. CLEAN WATER ACT (CWA) IV. C. 1. AMI 7 ENT WATER QUALITY CRITERIA, LUT,an HEa I t h Water and Fish Consumption: 1.7E+5 ug/L Fish Consumption Only: 3.433E6- ug/L C-onsiders technological or ecomrinc feibility? -- NO Discussion -- ThIe WfC of 1 .7-E+ ug/L is based on consumption of contaminated aquatic organisms and water. A WOC of 3.43E6 ug/L has salso been estralseC rasco on consumption of contaminated aquatic organisms alone . Reference -- 45 FR 79312 (11/28/S0' EPA Contact -- Criteria and Standards Division, OWRS (202)475--7315 / FTS 475-7315 << Chromium(I I) > 8 Iv.c... a I ENT WTER U.L I TY CR1TER1 A quaC-iqLt ic Or gjarii £ris r eshwater: ACute -- 9. 'E-+2 ugQ/L (hardness deperident) Chronic -- 1. . 2E+2 ug /L (hardness dependcn t) Mar irie: None CLonsiders tcc hnologica) or cnoric feac-ibil it --- N Discussion -- For freshwa-ter aquatic ife? the concemntration (iin ug/L ) of total recoverable trivalent chromium shnuld not exceed the niumer ical vaAILi given by the equations "e**[(.8190 [In (hardness)]+3 ) for acute exposure and "e** (0.190 [ln (hardness)]+1.561 for chronic elposure (t indicatces extponentiation; hardness is in rg/L). For example, at a hardness of 50 mg/L, the aCLLte arid chronic WOC weOL)d be 980 and 12i0) uc/L, re-spectively. Reference -- 50 FR 3074 (07/29/35) EPA Contact -- Criteria and Standards Division, DWRS (202)475-73.15 / FTS 475-7315 . -. << Cnromium( III) >>> _IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) No data available -- Chromium( III) >------ IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available S IV.F RESOURCE CONSERVATION AND RECOVERY ACT (RCRA) IVF.1. RCRA APPENDIX IX, for Ground Water Monitorirnq tatts -- Listed . Reference -- 52 FR 25942 (07/09/87) EPA Contact -- RCRA/Supertund Hotline -0 / FT - 3000 - < Chromium (III) >>-3------ IV.E. SUPERFUND (CERCLA) 9 _ V.G 4. REPRITBLE QUNTI R'GQ) for Release into the Envirornm.ent Value (status) -- See diSCLSsion (Fina 1 1905) cnsiders techknolcii~cal1 or economi c feasibility? - NO Dicussion Thoug h "Chromi (i II I ) , insoluble ma 1 ts" is not spec i fica 1Iv desic:nated as a CERCLA hazardous SuLIstance,. insoluble ch[roilumi (13I.) SaIts would be considered hazardous substances under the CERCLA broad qeneric listing for "ChrOSiun and Comvpounds." There is n corre sponding reportable quantity (RO) for this generic class of compounds. However, the releaser is E till liable for cleanup costs if the designated Federal Un-ScEne Coordinator (CSC) decides to take response action with respect to the rejl ease of an insoluble chromium (III) salt that is not otherwi.e specifically listed as a CERCLA hazardous substance. There are tLwJ O chromium (III) salts which are specifically listed as CERCLA hazardous substances, chromi acetate and chromic sulfate. Both have been assigned final Ros f 1000 pounds based on aquatic toxicity (as established under section 311( )(4) of the Clean Water Act) Ref e ren c e~ -- 51 FR 34534 (09/29 / ) EPA Contact -- RCRA/Superfund Hotline 200)424 -9346 / (202)32-3000 / FTS 322-3000 V. SUPPLEMENTARY DATA Substance Name -- Chromium(III) CASRN -- 16065-S3-1 Not available at this time. Vi. BIBLIOGRAPHY Substance Name -- Chromium( III) Last RFevised - / 7.A. ORhAL RfD REFERENCES van kovic, . a n .d nUSmannm. . 17 Abenzc of [oxic ano car-c inogen ic ffects after adm inisration of hig h does of c hromi oxide pigmen in SLbacLute and 1ong-tErm fceeding ex per imen te in rats. Food osme.- Tox ice 1- 7; -- 347-- 1 U.S. EPA. 1.94. Health Effects AssEEasrmen t for Trival ent Chromium. Prepared by the Environmental Criteria and Assessment Off ice, Cincinnati , OH. DHEA for 10 the Office of Solid Waste and Ernergency Response, Washington, DC. ------<<< oium I I I ) ------ VI.B. INHALATION RfD REFERENCES None ------< Chromium(III) ------ VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ------<<< Chromium (III > >------ VI .D. DRINKING WATER HA REFERENCES Gross, W.B., and V.G. Heller. 1946. Chromates in animal nutrition. J. Ind. Hyg. Toxicol. 28: 52-56. MacKenzie, R.D., R.U. Byerrum, C.F. Decker, C.A. Hoppert and R.F. Langham, 1952. Chronic toxicity studies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am. Med. Assoc. Arch. Ind. Health. 12: 232-234. U.S. EPA . 1985. Draft of the Drinking Water Criteria Document on Chromium. Office of Drinking Water, Washington, DC. SYNONYMS Substance Name -- Chromium(III) CASRN -- 16065-83-1 Last ReviSEd -- 16065-B3-1 CHROMIC ION CHROMILM Chromium ( !) CHROMIUM (III) ION CHROMIUM, ION 11 Chromium(VI); CASRN 7440-47--- (03/0i/51) Health risk assessment information on a chemical iEs inc1Led in IRIS oinl after a comprehensive review of chronic toxicity data by work grrups composed of U.S. EPA scientists from several Program Offices. The summaries presentod in Sections I and II represent a consensus reached in the rev iew proceas. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures precr ibed by that Program Office. The regulatory actions in Section 3V may not be based on the most current risk assessment, or may be based on a current, but unreviewed., risk assessment, and may take into account factors other than health e-ffects (e.g., treatment technology). When considering the use of regulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relatincg to that action, and whether technological factors were considered. Background information and explan- ations of the methods used to derive the values given in IRIS are provided in the five Background Documents in Service Code 5, which correspond to Sections I through V of the chemical files., STATUS OF DATA FOR Chromium(VI) File On-Line 03/Ci/87 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on-: ine 03/ti/S8 Inhalation RfC Assessment (.B.) pending 03 ./ 0i /9i Carc inogenicity Assessment (II.) on -i inec Drinking Water Health Advisories (III.A.) on-line U.S. EPA Regulatory Actions (IV.) on-line 06 / Ki/90 Supplementary Data (V.) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD'i Substance Name -- ChromiumVI) CASRN -- 7440-47-3 Last Revised -- 03/01/SE The Reference Dose (RfD) is based on the assumption that thresholds exist for I ceCrtain tox ic ef fecs sLch as cEu u ar necrosisa but may not ex ist for l.ther toxa Cef fI ects ssuc h as carc inoaleriaci ty. in gerier a] * the ID is ari estll.et wit h un c e rt ii nty spannincg perhapc:s an order of magnitude) of a daily oxposure to thE hunin ppuation (including sensitive subgrcups) that is liei ly to be without an appreciable risk of deleterious effects during a life-time. Please refer to Bavckgrourid Document i ini Service Code- 5 for an elA Fkborataon of these concepts. RfDs can also be derived for the noncarcinogenic health effects of coIuCLnds w hic h ar e:* a Io carc iro genis. There for e, it is ess-rential to r2fer to other sources cf infurmaLi or concernilng the carcinogenici of th is sLtntElCe. If the U.S. EPA haS evalluated'\' this as ubstance fr po. ti al humfiaFn carcirnogen- icity, a summiiary of- that evaluatin will L-e contained in Section II of this file when a re!vQievw of that v an ic completed. < I.A.1.. ORAL RfD LIr-MRY Critical Effect Experim*ntal Doest UF MF RfD No effects reported NOAEL: 25 mg/L of 500 1E chromimLkF as I2Cr04 mu da Rat,* 1-ear Drinking (converted to 2.4 mg Study of chromium(VI) /kg/day) MacKenzie et al. LDrEL: none 1958 *Dose Conversion Factors & Assumptions: 'Drinking water consumption = 0.097 L/kg/day (reported) Chromium(VI) I .A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL R-D) MacKenzie, R.D., R.U. Byerrur, C.F. Dekr, C.A. Hoppert and R.F. Langqhm. 1758. Chronic toxicity studies. 11. Hexavalent and trivalent chromium administered in drinking water to rats. Am. Med. Assoc. Arch. Ind. Healt h. 18: 232-234. Groups of eight male and eight female Sprague-Dawley rats were suppiJed with drinking water containing 0-11 ppm (0-11 mg/L) hexavalent chromium (ac r20rf4) for 1 year. - The control group (i/ receivedcE) distilled water. A second experiment involved three groups of 12 mral es and 9 tamale rats. One group was given 25 ppm (25 mg/L) chromium (as K2CrO4) ; a second received 25 ppm chromium in the form of chrcric chloride; and the controls again rece ived distilled water. No significant adverse effects were en on appearance, weight gain, or food consumption, and thnere were no pathologic changes in the blood or other ti=sues in any treatment group. The rats receiving 25 ppm of chromium (as K2CrO4) showed an approximate 20h' reduction in water consumption. Ths dose corresponds to 2.4 mg chromium(YI)/'g/day based on actual body weight and water ccn suimptioncata. For rats treated wi th C-11 ppm (in rh diet) blood was examirned montly, Sand tissue$ (livr, kidneys aid fEriurs werE;2 xamin:E t ' h S amn d 1 yr. Spleens were also examined at year. T c 25 ppm groLps (and ccr re pon ding controls) were examined si i ry1. except that no animals wer killed at months. An abrupt rise in tissue chrcmiumn concLntr.F aon.s was not-e ai rats treated with greater thsn 5 ppfm. The authors stated that "cpre-ntly, tissues can accumul ate considerab le ouantities of chroCmium before patholoioca ch -anes resuIt." In the 25 ppm treatment CroupL, tissue concentra tios of chromium 2 Lere approximately - tiS higChirF fcr thuse treteci with Ioxavalent chroium than for the tri I ent roup. imif1 arI no-eie C c t lEvel s have been cLservedo i: dog a rid humansIt Anwar al. (1961) observed no significant effects in female doQs (2/dose g.roup) qivOn Ip to 11.2 ppm chromi(VI) (as K2CrD4) in drir i g j water for 4 yeiars. The calculLated doses were 0.2-0. mg/kg of chromiuim( V I) .In human s, no ad verse health effects were dcttec ted (by phyfs ic-al examinEti) ri n a fam ily of tour persons who drank for 3 years f rom a private well con ina ing ch romium (V I) at approximately i mg/L (.03 mg/kg/day for a 70--:g human). Chromium (VI ) I .A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF 500. The uncertainty factor of 500 represents two 10-fold decreases in dose to account for both the expected interhuman ard interspoece ±Es vaEribili.ty in the toxicitv of the chemical in lieu of specific da ano an additinal fac tor of 5 to ccmpersat for the less-tan-lifEtime exposure Curatior of the principal study. MFE = 1 < h 11i U m(VI) I.A.4. ADDITIONAL COMMENTS (ORAL RfD) This RfD is I imited to metallic chromium( VI) of soluble sal ts. Examples f soluble Sal tS i ncude potassium dichromate (K2CR2O7, S odium dicnromate ( Na2Cr2O7) , potassium chromate (K2Cr04) and sodium c hromate (Na2Cr 4) . Trivalent chromium is an essential nutrient. There is some ev idence to indicate that hexavalent chromium is reduced in part to trivalent chromium in vivo (Petrilli and Deplora, 1977, 197; Gruber and Jennette, 17S). The literature available on possible fetal oamage caused by chromium compounds is limited. No studies were located on teratogenic effect= resulting from inqestion of chromium. Chromium(VI) > > .A.5. CONFIDENCE IN THE ORAL RfD -tudy: Low Data Base: Low RfD: Low Confidence in the chosen study is low because of the small number of animals tested, the small nunber of-parameters measured and the lack of toxic affect at the highest dose tested. Confidence in the data base is low because the Eupporting studies are of equal l y low quality, and teratogenic and .eproduc tive endpoints are not well studiEd. Low confidence in the R1-D oll ows. Chromiumk 1 _ .A. . EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EFA. 1S34. Health Effects Assessment for HexavaIent Chromium. Pre- pared by the Office cf Htalth, and Environmental Assessment, Environmental 3 Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Erergency Re.ponse, Wash-ington, DC. U.S. EPA. 1995. Drinking Water Health Advi-ory for Chromium. Prepared by the Dffice of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. (Draft) Agency RfD Work Group Review: 11/21/S55 02/05/86 Ve.rification Date: iC2/O5/8L _I.A.7. EPA CONTACTS (ORAL RfD) Kenneth L. Bailey / ODW ---- (202)382-5535 / FTS 32-5535 Christopher T. DeRosa / ORD--- (5)569-7534 / FTS 834-75!4 I.B:REFERENCE CONCENTRATION FOR CHRONIC INHALAT10N EXPOSURE (RfC) Substance Name -- Chromium(YI) CASRN -- 7440-47-3 A risk assessment for this substance/agent is under review by an EPA work: group. II. CARCINO5ENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chromiium(VI) CASRN --- 7440-47-3 Last Revised --- 03/01/91 Section 1l provides information on three aspects of the carcinogemic rislk assessment for the agent in queStion; the U.S. EPA classification and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-jvidnce judgment of the likelihood that the agent is a human carcinogen. 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 prsented 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. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section 1 for information on long-term toxic effects other than carcinogenicity. << Chromium(YI) 4 EE. FOR C L7'1.F1 CATIN7 'EiC A HT- UM C RN r TY __II.A.1. WE IGH-T--OF-EVI'DENJCE CLAESIFICATON Cl aesi fiAcatOi - -; human carcingen Basis. -- Resul ts of occupation~l1 epiciemialogi; c tudie aof c hi-omi;Ti-i.3se workers are colnsi.ctnt acrcss investigators and studI populatiI : 0 os' respons rl ati onshi pa have been estab l ished for ch romium 5pour'e ar lun cancer. C [rom iu .m-e _ po sed wor ker s - are P pCose ad t L'-t h :: i roi M.L 1U I T lid oh romiurn VI COmpOLInds. Because only chroriumr v ha ben. found to it's carcirnogenic in animal studies, howeverit wa s cnc.ic-':IEd 1.1iat only chr7miuLi VI should be cacsi f ied as a human carcinogen. Chiromiums('QI) :- II7. . -U M A- CARCINOGENXCITY DATA SUfI cient Epidemioloi studies o tuoi of cIrom te pr-o d'du Jct fa r cil ties in the United Stats- (Machle and 2regorius, 1948; Jrinton et al., 1952; Mancuzo and HuMper 1 ,- ancu so, 1975; Faetj e- I 950 Tavlor, 1961; Enter) inc, 197-3: Hayes et al., 197; Hi and Fer-q1on, 1979), GreaBitir (Bidshrup. 13 Bidstrup and C-ise 1956; AlderEon it a. 1 191)., Japan (WaanLb aid Fuuh i 1975; Oh aki et a1. 1972; Sano and Mitohara, 197r; .atch et al. . , 1921) and West Germany (Koral Ius et al. , 1982; bittersh, 1971) have established an asaociatin between chromium (C i x pcisLre and lung Lk Fcacer. M'oNt f these studies did not attempt to determine whether Cr III or Cr VI compounds were the etiologic agents. Three studies of the chrome piciment industry, one in Norway (Lang ard and Norseth, 1975), one in England (Davies, 1978, 1979), and the third in the Netherlands end Germany (Fren-tzel-Beyme, 19-;) also found an association between occupational chromium exposure (predciminantly to Cr VI) and lunq canzer. Results of two studies of the chromium plating industry (Royle, 1975; Silverstein et ad. , 1931) were inconclusive, while the findings of a 3Japanese Study of chrome platers were negative (Okubo and Tsuchiya, 1;97) The resUlt of studies of ferrochromium workers (F'oi:rovskava and Shabvnin., 1772; Langard et al., 1920; Axelsson et al., 190) were inconclusive as to Liung cancer rs;. < ChromiUm(VI ) II.A.3. ANIMAL CARCINOSENICITY DATA Sufficient. Hexavaient chromium compounds were carcinogenic in animal assays producing the following tumor types: intramuscuLtar iniection site tumors in Fischr 3 44 and Bethcesda Elack rats and in C57E' mice (Furst et al, 1976 M1ltcni, 1974, 19776; Payne, 1760; Heuper and a-yn, 195); intra- Flural implant ite tuM0r ior Varia ous chr-omaium V1 componL;ds in Sprague- Dawiev ano zete-da ?ieck rats ,yne, 1960; H-eper 1961; ri;p'er and Pavne, 162)3 intrabronchiamplantation site tuimorI for various Cr VI c"mgcunds in Wistar rats (Levy and Martin. 19a3; Laskin et a ., 1970' Levy as quoted NIOH, 1975) ; and subcutaneous injection sit sarcnmas in Sprague-D;awl rats (Maltoni, 1974, 1976), Chri 5 1I .A. . LAPINCUF FOR CARCINOENICITY A large number of chromium compounds have been assayed in in vitro genetic toxicology assays. in general, hexavalent chromium is mutagenic in bacterjal assays whereas trivalenL chromium is not (Lofroth, 1978; Petrellie and Flora, 1977, 1978). Likewise Cr VI but not Cr III was mutagenic in yeasts (Bonatti et l., 1 976) and in V79 cells (Newbold et al., 1979). Chromnium III and V1 compounds decrease the fidelity of DNA syrithcsais irn vi-t.ro (Loc-b et : 1. 1977), while Cr V! compounds irnhibit replicative DNA synthesis in mammalian cells (Levis et 3 ., 1978) and produce unicheduld DNA synthesis., presumably repair synthesis, as a consequence of DNA damage (Raffetto, 1577) Chromate has been shown to transform both primary cells and cell lines (Fradi2in et al., 1975; Tsuda and Kato, 1977; Casto et al., 1979). Chromosomal effects produced by treatment with chromiumfl compounds have been reported by a number of authors; for example, both Cr VI and Cr III salts were clastogenic for cultured human leukocytes (Nakamuro et al., 1978). There are no long-term studies of ingested Cr VI. There appears to be significant in vivo conversion of Cr VI to Cr III and III to VI; Cr il is an essential trace element. ------C hirom (()i - -- - - 1I.U. OUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORiL EXPOSURE Not available. ------< < Chromium(VI) > - II.C. QUANTITATIVE ESTIMATE OF CARCINOSENIC RISK FROM INHALATION EXPOSURE II.C.I. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk --- 1.2E-2 per (ug/cu.m) Extrapolation Method -- Multistage, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 1 in 10,000) SE-3 ug/cu.m E-5 (I in 100 000) EE-4 ug/cu.m E-6 (1 in 1,000,000) SE-5 ug/cu.m - << Chromium(VI 1I.C.2. DONE-RESPONSE DATA FOR CARCINOGENICITY, 1NHALATION EXPOSURE Speciros/Strain Dos Tumor Reference Tumor Type I enicdC'1 human Route: Occupational expoEure 6 ( in hal atI c, Ade r aIu Deaths f rm Person (y ear) (ug/cu.m LI) Lung Cancer Years 50 5.6 3 34 Mancuso, 2.2T 691 1975 6 3 299 a UbS. . 20./9 5 717 39.C3 5 70 .41. 401 21.29 4 45 < II..3. ADD IT IONAL COMMENTS (RCI N'GENICITY , I NHNLA-TI [ON EXPOSURE The cancer mortal ity in McuFCLo (1975) was assLImed to be due to Cr VI which was further assumed to be no less than one-seventh of total chiomuml. It was also assumed Lhat the mokinc1 habits of chromate workers were similar to those of the U.S. White male population. The unit risks of Langard et l (1 A e snm. Ft a l . ani.d Prc k rsok Hexavalent chromium compounds have not produced lung tLmors in animals 3 by inhalation. Trivalent chromium compounds have not been reported as car- cinogenic by any roLte of adm-,iniStration. The u.nit risk should not be used if the air concentration exceeds SE-1 ug/cu .m, since above this concentration the unit risk may nct be appropriate. ChromiLum(VI) _I.CU.4 DISCUSSION OF CONFIDENCE (CARC I NCGEN IC ITY, INHPLITIN EPCSURE) Results of studies of chromium exposure are consistent across inveSti- and countries. dose-relationship for lung tumors has been t. lished. The assumption that the ratio of Cr II to Cr VI isZay : m lead i.o a 7-fold underestimation of risk. The use of 1949 hygiene data, which may underestimate worker xposure , may result in an overeat ima t ion of rI k Further overestimation of risk may be due to the implicit assumption that the amoking habits of chromate workers were simil ar to those of the qeneral white male population, since it is oeneral ly accepted that the proportion of the general population. smokers is higher for industrial workers than for i---..----- Chromium('VI) >>---- pI.D. EFA DOCUMENTATION, REVIEW, AND CONTTn*TACT CAY ASESSMENT) 1 I... EPAzr DOCUMENTATION Manuo T.FS. 1975. International Conference or Heavy Metals in the Envi- ronment. Toron to, Ontario Canada. U.S. EPA. 194. Health Pssesien t Document for Coromium. Prepared by the Office of Health and Environmental Aesessment, Environmental Criteria 7 and ACnOf ficr. Cinc innrat, . DH. EPA 650/S-E.-KinF. * Chr-omium(r I ) I 1II.D.2. REV IEW 'CARC I N5EN I CITY g:SSESSMIEkT The quanti fication of cancer r-isk in the 1994 Hea I th Assessmen t Documen t has received peer review in public sessions of the E-vironmental Health Com- miittee of the U.S. EPA's Science Advisorv Board. igency Wor Group Ri-L \-/ w: 2 6/ 86 - Verification Date: 05/26/86 II.D.3. U.S. EPA CDNTACTS (CARCINOSENICITYI ASESSMENT) Herman 1. G5ilb / ORD - (202)3c2-598 ./ FTS 25 92 C.hao W. Chren / rO -- (202)392--5719 / FTS -. 2-5719 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURAT I OINS III.A. DRINKING WATER HEALTH ADVISORIES nubstance Name -- Chromium (VI) CASRN -- 7440-47--3 Last ReviSed -- 03/01/22 The Office of Drinking Water provides Drinking Water Heal th Adviscries (HAs) as technical guidance for the protection of public health. Hws are not enforceable Federal standards. HAs are concentrations of a substance in drinking water estimated to have negligible deleterious effects in humans, when ingested, for a specified period of time. Expoure to the substance from o t her media is considered only in the derivation of the lifetime HA. Given the absence of chemical-specific data, the assumed fraction of total intake from drinking water is 20. The lifetime HA is Calculated from the Drinkinq Water Equivalent Level (DWEL) which, in turn is based on the Oral Chronic Reference Dose. Lifetime HAs are not derived for compouncs whic h are potential ly carc-inooenic for humans because of the di fference in assumptions concerning toxa.c threshold for carcinogeni-c and noncarcinogenic effects. A more dcetailed dcescription of the assumptions and methods used in the derivation of HAs is provided in Background Document 3 in Service Code 5. Chromium(I) NC i c hromium HAs are based on total c hromiumnF ( I II 8dn V III.A.1. ONE-DAY HEALTH ADVISORY FOR A Appropriate data for calculating a One--day HA are not available. It is 8 te'cjImInEridjCo *tiha.t the Ton -day HA of 1 .4 mrig /L be LiSCLd aY the One-day HA. .?Chrormiun(K) l iI i . A.2. TEN-DAY HEALTH-r ADVISORY FOR A CHILD Ten--day HA - . 4E+0 mg /L NOAEL - 14.4 mg/kg/day UFL 10C) a I I ows for in terpcic. es and in trahuma variabi lity wi th tie use& cf a NOAEL from an animal stLdy) A-ssuMptions -- 1 L /day water conumption for a 10--I:c chil d Principal Study -- Gross and Heller, 1946 Rats were exposed to drinkincg water containing Dr(VI) (IC2CrDA) at levels of 90 or 134 mq Cr(VI )/L for 60 days (8.3 or 11.4 mg CriY/I)/kg/day, respectively) without adverse eff ects. Therefore , a NJOAEL of 1.14 g /kg /da is identified. < Chrocmijum(VI) 3 > III.A LONGER-TERMI HEALTH ADVISORY FOR A CHILD Longer-term (Child) HA -- 2.4E-1 mg/L NDAEL -- 2.4 og/kg/day UF -- 100 (al.lows for interspecies and intrahuman variability with the use of a NDAEL from an animal study) Assumptions -- 1 L/day water consumption for a 10-kg child Principal study -- MacKenzie et al., 195@ In a 1-year drinking water study, consurmption of water contctining either Cr(II) (CrCl3) or Cr(VI) (K2CrO4) (C to 1.87 mq/kg/dav for male rats and 0 to 2.41 mg/kI/day for female rats) produced no significant differences in weight gain. appearance, or pathological changes in the blood or other tiue. Therefore, a NOAEL of 2.41 mg/kg/day is identified. < KChromium(VI) 1 A. . LONGER---TERM HEALTH ADVISORY FOR AN ADULT Loner-term (Adult) HA -- 8.4E-1 mg/L NOAEL -- 2.4 mio /Ig/day F-- 10u (l3. ow for interE pecies and intrahuman variability with the use of a NOAEL from an animal study) A.ssumptions -- 2 L/day water consumption for a 70-kg adult Rrincipal study -- MacKenzie eat al., 1958 (study described in I .. 3. ) IiChromnium(VI)D II.A.5. DRINKING W4TER E0L[IVALENT LEVEL / LIFETIME HEALTH ADVISORY DWEL -- 1.7E--1 m.,/L Assumptions - 2 L/dav water consumption for a 70-ik adult 9 RfD Verification rate =2/05//6 (see Section I A. of this file) Lifetime H -- I .E-i mn/L Aumptions -- 71. exposutre by drinking water P r.ricipal study- -- Macken--ie et aI . , 1958 (This study WaS Used in the derivation of the chronic oral RfD; see Section .A.2.) III .A.6. ORG5@AO'LEPTIC PROPERTIES No data available Crromi um(VI) III. A.7 ANALYTICAL METHDDS FOR DETECTION IN. DRINKING WAlTER Determination of chromium is by an atomic abs-orption technique Ltsin either diirect aspiration into a fT ame or a furnace. C Cromium V ) 3:= ___III.A..9. WATER~TREATMEN The treatment technolociies that are available to remove chromim Trom water include coagulation/filtration, lime sof-tening, ion exchange, and reverse osmnsis. Chr omiuir ( VI ) III.A 9. DOCUMENTAT I ON AND REV IEW OF HAs U.S. EA. 1935. Draft of the Drinking Water Criteri A Document on Chrc'mium. Difice of Drinking Water, Washington, DC. EPA review of HAs in 1935. Pulbl ic review of HAs fol lowing notification of availadbi l itv in October , 1985. Scientific Advisory Panel review of HAs in January, 196. Preparation date of this IRIS - 06/22/87nummary III.A.iu. .7EA CONTACTS rnnneth Bailey / CDW -- (202)382-5535 / FTS 382-5535 Edward V. Ohanian / ODW -- (202)532-7571 / FT3- __I I I . 2. OTHER ASSESSMENT S 10 SL. tarce Name -- hr Omij umf: ( V I CAstRN-- 7440 - content to be detErined IV. U. S. EPAl REGULATORY ACT IONE Substance Name -- Chromium(VI.) LASRN -- 7440-47-3 Last Revised -- 06/i/0 EPA risk assessments may be updated as rw data are publiSaChed and as assessment methodologies evolve. - Regulatory actions are freqciultl' rot updated at the same time. Compare the dates for the reLulatory actions in this section with the verification dates for tI-e risk: asesm nts in sections I and II as this may ex p l an inconsisnotencie. Al-o not tht , sme FreuL 1 atorv actions consider factor s not related to health risk, such as technical or ecOnomi.c fE?asi L'j.i ty . Such conI.idertis i::-e ar i cated for eac h ction. In addition , not all of the regulatory actions listed in this section involve enforceable federal standards. Plase direct any quetions you may have concerning these regulatory actions to the U.S. EPFA contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatory action in Background Document 4 in Service Code 5. << Chromium(VI) IV.A. CLE AN AIR ACT (CAA) V.PA.1. CAA REGULATORY DECISION Action -- Intent to list under Section 112 Considers technological or economic feasibility? -- NO Discussion -- Chromium VI is. considered a human carcinogen (IARC Group I), and accordino to EPA's p reliminary risk assessment from ambient air exposures, public health risks are significant. There is considerable uncertainty as to the carcinogenicity of other valence 5tates of chromi-um and the proportion OT chromiumiT VI in emission or ambient air Tahpes.The EPA indicated that it ntends to add total chromium or chromium VI to the list of hazardous air pollutants for which it intends to establish emission standards under section 112(-) (1)'-) of the Clean Air Act. The EPA will decide whether to acid total chromium or chromium VI to the l.ist only after studying po-sible techniques that mi ght be used to control emissions and further assessing the public health risks- The EPA will add total chromium or chrronium VI to te li St i7 emission tandards are warranteo Reference 50 FR 24317 (05/10/S5) EPA Contact - Emissions Standards Division, QA*PS (919)541-5571 / FTS 629-5571 11 ------:1< Chreal um(-I.) ------ IV B. SAIFE DRINK: IG WATER ACT (SDWA,) IV B. . . MAYIMUM CONTA@MINANT LEVEL GOAL (MCLG) fror D- rinkin g Water Value (statLs ) -- 0.12 mg/L [total chromium] (Pr opo sed , 1 985) Considers techinolociical or etcrnomic feasibility? -- N Discussion -- An MCLS of 0.12 ma/L for total chromium (Cr III and Cr VI) is proposed based on a provis7ionial DWMEL of 0. 17 mg/L with data on human exposu1re factored in (0.10 rgQ/dav in the diet and f mg/day by air) . DWEL cf 0.17 mgo/L was calcul ated from a NOiEL of 2.41 mci/kg/day in rats [1-year driniing water study ( Cr VI) ], With r. uncertainty factor of 501 app1. ied and conssumptionl of 2 L of water/day aseumec. Reference -- 50 FR 4693.6 Part IV (11/13/85) EPA Contact --- Kenneth Bailey / Criteria and Standards Diva sionq OD / 2:2)322-7571 / FTE 322--7571; or Drinking Water Hotin e / (00) 426--4791 . hromi(V > V. 3-2. MAX IMUM Ct0NT AMINAN-T LEVEL (MCL) for Drinking Water Value (status) --- 0.05 g/L [total chromium] (Interim, 1'80) Considers technological or economic feasibility? -- NO Discussion -- Reference -- 45 FR 57322 E.PA Contact -- Kenneth Bailev / Criteria and Standards Division, ODW / (202)3S2-7571 / FTS 3P-22-7571; or Drinking Water Hotline / (300)426-4791 -- Chromium ( V I ------ IV.C. CLEAN WATER ACT (CWA) V.-1. AMNBIIENT WATER QUALITY CRITERIA, Human Helth Water ard Fish Consumption -- 5.0E+1 ug/L - Fish Consumciption Only --- NoC'n Considers techtnological or econocmic feasibility? -- Discussion --- R:eference -- 45 FR 79318 (11/28/80) EPA Contact - Criteria and Standards Division. LJWRS (202)47--7315 / FTS 475-735. 12 IV.C.2. AMPIENT i r FATERDUALITY CRIERIA i-qual"ti1c Orgarismyts Acute -- 1. E+1 gi/L i1-hour average) Chronic -- 1.1E+1 ug/L (4--day average) Miarine: ACLte -- 1.1E+3 uq/L (1-hour &verA g e) Chronic -- 5. OE+1 ug/L (4-day averagre) Considers tec hnological or economic feasibility? - NO Discussion - Refercnce -- 50 FR 30784 (07/2/D5) EPA Contact -- Critaria and Standards Division, OWR- (202) 75-7315 / FTS 475-7315 - C-- Dhromium(V.) ------ IV.D. FEDERAL NSECTICIDE FUNGICIDE, AND RODENTICIDE ACT (FIFRA) No data available ------< Chromium ( V ) _IV.E. TOXIC SUESTANCES CONTROL ACT (TSCA) No data available (-Chromium(VI) V.F. RESOURCE CONSERVAT ION AND RECOVERY ACT (RCRA IV.F.1. RERA APPENDIX IX. for Ground Water Monitoring -- Listed Reference -- 52 FR 25942 (07/09/97) PA Contact -- RCRA/Euperfund Hotline (-00)424-9346 / (202)3 2-3:00 / FTS 3.2--300 -- Chr-omi um ( VI ) > ------ 13 1,, . G F,.., -- "-- F-- L i t -!'-r .--Z. r---CL A .IV . l-- . -S iFR..f-- - LJf C.LE.'.L .. M)1 _I. .1. REPORTABLE QUANTITY (RD) for Release into the Environment Value (status) --- I pound (Proposed, 1937) Considers technological or economic feasibility? --- NO Discussion -- The proposed RD for chromium is based on potential carcinogenicity. Available epidemiologiical data on inhalation of hexavalent chromium indicate a hazard ranking of high based on a potency factor of 388.99/mg/V-g/day- and assianment to weight-of--evidence group A. This corresponds to an R0 of 1 pound. Reference -- 52 FR 8140 (03/161/87) EFA Contact -- RCRA/Superfund Hotline (00)424--9346 / (202)(32-3000 / FTS 382-3000 V. SUPPLEMENTARY DATA Substance Name -- Chromium(VI) CASRN -- 74 4 0-47-3- Not available at this time. VI. BIBLIOGRAPHY Substance Name -- Chromium(VI) CASRN -- 7440-47-3 Last Revised -- 06/01/90 VI.A. ORAL RfD REFERENCES Anwar, R.A.. F.F. Langham, C.R. Hoppert, B.V. Alfredeon and R.U. Byerrum. 1961. Chronic toxicity studies. III. Chronic toxicity of cadmium and chromium in dogs. Arch. Environ. 3: 456-460. Gruber, j.E. and K.|W. Jennette. 17S. Metabolism of the carcinogen chromate by rat liver microsomes. Biochem. Biophys. Res. Commun. (2) 700-706. NacKenzie, R-D.. R.U. Byerrum, C.F. Decker, C.A. Hoppert and R.F Langham. 1958. Chronic toxicity studies. !I. Hexavalent and trivalent chromium administered in drinking water to rats. Am. Med. A sPoc.- Arch. Ind. Health 18: 232'-4 Petrilli, F.L. and S. DeFlora. 1977. Toxicity and mutagencity of hexavaient chromium on Salmonella typhimurium. Appl. Environ. Microbiol. 33(4): 14 CD f' 1 Petri i , F.L. ard . DFlr i. 1 975. idati on c i ac t ve tri ve t chriumQ to the mutagenic hexavalent form. Mu tat. Rex. - (2--i: 167- 178. U. S. EPA-. 1984. Heal th Ef fec ts Assessie.t for Hexava len t ChromriTUr. Prepared by the Off ice of Health and En vi ronmental ATsesment, Envircnre-ntal Cr iena and Ass essmerit Office, Ci nc innati, OH for the Off ice of Solid Waste ard Emergenc~y Response,. Waehingt on, DC U.S. EPA. 1985. Drinking Wntter Headth Advisory for ohromium. Prepared b the Off ice of 1-eal th a-nd Envi ronren tAl AFsesmeti Environme n nta.l Cri te.i:a and Assessment Office., Cinci rnati OH for the Office of DririDing Water Washington. DC. --- Chromium (VI) - [-VI. INHALATION R'fD REFERENCES ---- - Chromium (VI ) - __VI.C. CARCINOSENICITY ASSESSMENT REFERENCES Alderson, M.R., N. S. Rattan and L. BidStrup. 191. Health ofLwortkrlen in the chromate-producing industry in Britain. Dr. J. Ind. Med. 38: 117-124. Axelsson. G., R. Rylander and A. Schmidt. 1980. Mortalitv and incidence of tumours amonq ferrochromium workers. Dr. J. Ind. Med. 3.7: 121-127 -aetjer A.M. 1950a. Pulmonary carcinoma in chromate workers. I. A review of the literature ard report of cases. Arch. Ind. Hyg. occup. Med. 2(5C: 467-504. Baetjer, A.M. 1?50b. Pulmonary carcinoma in chromate workers. II. Incidence on basis of hospital records. Arch. Ind. Hyg. Occup. Med. 2(5) : 505-516. Eid~trup, P..L. 1951. Carcinoma of the lung in c hrcmate workers. Br. 0 . Med. B3idstrup, P. L. and P. A. M. Case. 1956. Carcinoma of the 1lung in workmen in the bichromates-prodLcing industrv in Great Britain. Br. J. Ind. Med. 1: --- Sittersohl, G. 1971. Epidemioloqical research of cancer cases in the chemical industry. Arch. Geschw ulstforschl . 3.8(3-4): 198-209. Bonatti, S .. M. Mini ard A. Abbondandolo. 1-76. Genetic effect of potasSium d ic hromate in Schizosaccharomyces pombe. Mutat. Res. 33: 147--15. Brinto- , H. P. . E. S. Frasier and A. L. Koven. 1952. Morbidi tv and mor-La ly experience among chromate workers. Public Health Rp. Z79): 2: 5 15 Castn., B.C., J. M yrs and J .. Diaolo. 197~9. Enhace-mnti L cf va: transf orcMatiOn for eval"u Laion of the crc aircngenaic or rutageng i c pot enia 1 c'ff itnorg&aric mnetal Salts. Cancer Res. 39:: 19-19E. Davies, 3 .M. 1979.- Lung-cancer mortaity ini workerz making. chrome pigments. Lnc 1: 34. Davies, j. M. 1979. Lursq cancer mor tality of worI::ers in chromate pigmirent manuf ac tur: An epidem-ioloical survey . 3 . Oil ChemA. cssoc . 62: 157-I1:. -ntetr Id ne, P E . 1 974' . Res pirat rv ca ncer amoci chia c' I: t w rs . . OC C Lp Med.fe23-526. 16: F radklk in, A. A. Jan off, B .P . Lanec and MI KuchnrLE Iar. 197. )I vitro I transformation of BHK21 cells g rown in the presence of ciumt: chromate. Cancer Res. 1058-103. Frentzel--Beyme, R. 1923. Lung cancer iortal ity of wor kers employed in chromate pigment factories. A multicentric European study.SpdemiolOcaical J . Cancer Res. C]in. Oncol. 105: 183-182. Furst:, A., m. Sch]auder and D.F. Sasmore. 1975. Tumorigenic activity of l ed c: hr omat-E. Canc er Res. 3F5 1779-1723. Hayes, R .. , A.M. Lilienfeld and L.M. Snell. 1979. Mortality in ChrOWmiLfm chemical production workers: A proopective study. Tnt. J. Epidemi ol. S(4) HuepEr, W.C. 1961. Environmental carcinooenesis and cancers. Cancer Res. 21: 942-57. Hueper, W.C. and W.W. Payne. 1959. ExIperimental cancers in rats prcduced by chromium compounds and their significance to industry and public health. Ind. Hyg. J. 2: 274- 22. HeLper, W.C. and W.W. Payne. 1962. Experimiental studies in metal carcinogenesis: Chromium, nickel, iron, and arsenic. Arch. Environ. Health. 5:445-462. Hill, W.J. and W.S. Ferguson. 1979. Statistical analysis of eoidermiolooical data from a chromiLum chemical manufacturing plant. J. Gccup. Med. 21(2): 103-106. Ko ralus, U. H. Lange, A. Ness, E. Wustefeld and T. Zwingers. 1922. Relationrhips between precautionarv measureo and bronhial carcinoma mortalitv in the chromate-producing industry. Arbeitsmedizin, Socialmedizir. Preventivmedizin. 17(7): 159-167. (German - Eng. summary) LangQard. a. and T. Norseth. 1975. A cohort study Of bronchial carinomas in wo-r kcrds uc ing c hromate pigcmen ts. Br. J. Ind. Med. 32: 52-65. Langard, S., A. Andersor and . iy3sEth. 1980. Incidence of cancer among ferrcachr-iuLm and ferros ilicon work:ers. Br. j. Id. Med. 37: 114-12 . Laskin, S. M. Kuscnr and R. . Drew. 1 970 . Studi.Es in p*uIelmonry ca. In:n M. . '.aeteneim.Hanna , Jr., P. N C and .R .e Gi rt , Eds - , inhalation Carcinogenesis., . H. rh Pim., NHantatEEc 1(.2* and G..Gib rt. Eds. U.S. Atomic Energy Comm. Symp. Series. Sponsored by the Nat onl Cancer Unstitute and U.S. 4tomic Enrergy Commissin. 18: 321-350. 16 LeviV , . Buntti gnc .l, V. iic hi an-d G. Son:a. 197. EF ffctS; of pc!t.ac ,au d i c hr omate? on nuric lea c ac Cid arId protein synthi tIac: cind Ln prIc.ur s'r u Ftake:ri PHK f ibob 1 as t s . Cancer Re - 38: 110-1 16 Lvy, L.S. arid P. A Marti n . 1983. ThE effects of a ranos of c hrmCiimLki- con taming material- on rat lung. Sponsored by Dry Color Manufac turer-' Asxociation and others. (.Un pub 1 ished Loeb, L . A, M. Sir-over and 3.S. Agq ar wa 1. 1977. I-f i deityef -ynDNA thesis as related to mutagencsia.s and carcinogenesis. Ad. Exp. Biol. Med. 1 103--15. Lofroth , G. 1978. The mu taLer ic itv of hexavalent hroium isdereased 1: microsomal metabolism. Naturvisaenschaten. 55: 2(7-2<3. MachL, W . and F. Gr egori us. 1948. Cance- o-f tie re*spi rat ory system in the United States chromate-producing indLstry. Publin Healta Rep. 63(35 1114-i127. Maltoni, C. 1974. Dccupationial carcinogenesis. Exc.rpta Mad ,nt. Congr. Ser . 32.2 :. 19-26. Mal .oni C. 1 9 7-. Predi c tive val Lue of carcIngenis bioca. s:m . An . N.i A ,ad -c i- 271: 4--443 . Mncuso, T.F. 1975. Consideration of Chromium as an industrial Carcinoc:'n. SInternational Conference on Heavy Mietais in the Environment Toronto. Ontario, Can ad, October27-31. p. 343-356. Mancuso, T.F. and W.C. Hue. . Occupational cancer and oter ealt hazards in a chromate plant: A medical appraisal. . I Lung cancers in chromrate workers r id . Med . Surg . '20(D): 358-363. Nakamur K. , K. Yoshi kawa, Y. Sayato annd. KLLrata. 1973. Comparacae tutdi2s of c hromosomal aberration and mutagenicitv of trivalent aid hexavatint chromium. Mutat. Res. 53: 175-191. Newbold, F ., J . Amos and j.R. Connell. 1579. The cyto-oxic. mutagenic and castoganic effects of chromium-containing compounds on mamma ian cells in culture. Mutat. Res. 67 55-3. NIOSH (National Institute for Occupational Safety and Health). 1975. Criteria for a recommended standard occupational exposure to chromium ()VI U U.S. Department of Health, Education,, and Welfare, Was-hington, DC. Ohaki Y . £.2 Abe, K. Kimur, Y . Tsuneta H. Mikami and M. Murac-. 1978. Lung can4cer in iapanse chromate workers. Thorax. 33: 372-37. Okubo, T. and K. Tsuchiya. 1979-.- Epidemiological study of chromium platers in Japan. Biologic. Trace Eem. Re. 1: 35-44. Payne,F W. 1 Z9 . The role of roasted chrcmite ore in the produc tion of cacer. Arch. Environ. Healti. a: 2-26r . S ane W. 1 . Poduction ofccers i mice r-id ramtsy choiu cmounds. Arch. Ind. Health. 21a: 53-5.I F.L. and S. DeFora. 1977. Toxicity and muTageni t of havalent c hromiuM On Salmonella typhimurium. Appl. Environ. Micrbil . 33(4): 305-,209. 17 Petrilli, F.L. and S. DecFlora. 19-8. Oxidation of arcti.v, t.rivalnt c-hromium to thE? mutacenic hExava enI t form. MLU tat.. ReS. 5-: 167-178. FTc krvs oka, L . V. and N.K. Shabyrtinfat. 1 Cart73 c iogeri c hazardz in tlhe production of chromium ferroa 11 oys. Gig. Tr. Prof. Zabol . 1Q0- 27--26. Raffetto, . ., Parodi , C. Farodi , M. De errari, R . Troianc ad G. Prcnbil la. 1977. Di rect inter-action wit h ce-I UlI ar targets as the mec haniim for- chromium carciogenresi. Tuimori . 63:: 53-512 Royle, -1. 1975. Toxicity of chromic acidin the chromium plating indu'try Environ. Ree. 10: 1-.16. Sano, T. and I . Mi tohara 1 978. OccLIpatiol cance-r amon chromium worki. Japanese J. Chest Dijorders. 37(2): 90-1i1. Satch, K. , Y. F Lkuda, K. Tori i and N. Katuno. 1781 . Epidemiologic study of workers engaged in the manLi factuireC of chromium coipounds. j. Lcu p. Med. 23(12): 835-838. Si Iverstein, M.. F. Mirer,e D). Kotelchuck:1i to. lverstein and M. Z!enrett. 191. Mortal i among workers in a die--cati acd electrpai plant. Scand. Wi-iu. Envi ron. Heal th. 7 (S upp. ): 156-6 6. aylor, F. H. 1965. TIhe rel ationship of mortal ity and dur-ation of employment as reflected by a cohort of chromate workers. Aper. J. Public Heal th. 56(2): 213-229. Tsuda , H. and K. K:atc. 1977. Chromosomal aberrations and morpological transformation in hamster embryonic :ells treated with potassium dichromate in vitro. MLutat. ReS. 46: 87-94. U.S. EPA. 1784. Health Aasessmnt Document for Chromi um. Prepared by the Office of Health and Environmental Assessrment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/2-23-014F. Watanabe, S. and Y. Fukuchi. 1975. An epidemiological survey on lung cancer in workers of a :hromate-producing industry in HOkkaldo, Japan. Presented at International Congress on Occupational Health. -- hromiu (VI) . ------ vI1. . ER I NK3: ING WATER HA REFERENCES Gross, W.S. , and V.G. Heller. 1946. Chromates in animal nutrition. Ind... Hy-g. Toxicol. 28; 52-56. Macen zie, R D. , R.U. Byerrum, C.F. Decker, C.A. Hoppert and R.F. Langham. 1958. Chronic tox icitv studies. II . Hexavaient ano trilent chrmium administered in drinking water to rt s A. Med. Arsoc. Arcn. tIo, Halth, 1a: 232-234. U.S. EPA. 1925. Drinking Water rritTri; Locument on ChrCmium. Offiace of Drinking Water, Washington, E-. (Dra t) 18 Q r])C az~C h~ r 0Qi1i1im U(VT C A SRN -- A 744.- 47-3 I.Last Revised - /18 74410-47-3C CHROMIC ION CHIROM IUM, I ON Chronium(VI) CHROMIUM ( VI ) ION 19 Copper; CiRN 7440-0- ( 12/01/BS) Health risk assessment information on a chemical in icluded in 1IS1 only after a comprehensive review of chronic tonicity dta b work oroups composed of L.S. EPA scientists from several Procgram Offices. The rummari s prevented in Sections I and I represent a cornsensus reached in tre rev procei-S-. ThIe other sections contain U.S. EPA information which i pecific to a particular EPA program and has been subiect to review procedures piescribed by that Program Office. The regulatory actions irn Section IV may rot be based on thic. most current risk assessment, or may be based on a current, but urnrEviewed, risk assessment, a"d may ta-e into accoutiL factrs C~ter (a al.ri h 'f.fect Seg., treatment technology) . When considering the use of regulatory ac tion data for a p.rticular situation. note the date Mthe reg! actien the date of the iiat recent risk assessment relating to that action, and whether technoogical fatts( were considered. Baciground information and explan- ations of the methods used to derive the values given in IRIS are provided in the live Background Documents in Service LOde 5, which correspond to Sections * throurh V of the chemical files.- STATUS OF DgATA FOR Cooper File On-Line 09/07/S3 Category (section) Staus LaSt Revised Oral RfD Assessment (I .A. no data Inhalation RfD Assessment (I.B.) no data Carcinogenicity Assessment (II.) on-line 0?/07/SS Drinking Water Health Advisories (III.A.) no data U.S. EPA Regulatory Actions (IV.) no data Supplementary Data (V. ) no data _I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARC!NOGEIC EFFECTS Substance Name -- Copper CASRN -- 7440-5--S Not available at this time I II. CAFCINOGENiClTY ;SSEScMENT FC1 LIFETIME ECPOUFJRE Substance Na me - Copper CASRN --- 440- Last Revised -- 9/07/ Section I I providE's informatior on three aspec ts of the Car c inf-ci e r ri assessment for the agent i-n question ; the U.S. EPA c 1 assi fc: atFi, n quLL ant - iat i eve e t ii mateS c. f i ± 1-0, or E? C 1 al L.1 F p EL and fro - ri : I in I a t io n, rJ C!TEr. The classification reflects aweight---- f-F-viderce -iudoerrmnt of th e i 1e: ehoo that the agqen t is a huanF carirocn oge. The quEn ti t ta ive ri s j:Stiajir.. r presented in three ways. The slope factor is the renult of application of a low-doEss- extraipolat ion proceCiure and is presented as the ri: per og/kg/dav. The unit risk is the quiantitative estimate in terms of either rid: per ugC/'L drink -'ing UaterF Or' ri k ler u /u m air br eat Lhe.iL Thc_ t.hir-d -formi in whichr- r: .Ik is presented is a drinking wal-ter or air concentration providing cancer riskc of 1 in 10,00, 1 in 100 or . in i,000,00:. Background Document 2 (Service Code 5) provides detai s on the rationale and nethods used to der-ve the c&.rc jiogerri city va luts foudr in iRIS. Us=-ra are reerr-ed to ection' I -for in formati.on on lonw-term toxic effects other thari carcino enici t. ubstance Name --- Copper R N - -7440- . Preparation Date -- 09/01/37 IIA. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINDGENICITY II.A.I. WEIGI-4T-OF-EVIDENCE CLA3SIFICJAIN a Cassification ---. DI not classified Basis -- There are no human data, inadequate animal data from assays of copper compounds, and equivocal mutagenicity dt. II.A.2. HUM AN CARCINOGENICITY DATA Ncne. ,me A__Ii.A.3 ANIMAL CARCINGENICT DATA In d iontic Rqaesearch Las ( ) t- tudi e the car cnogenicity of a copper-con ta:.inng compound copper hydroxyqu i no In , in two strEans cI -ice ESC3F1 and SAKF1.). - roups of 1S male and 1e ema 7 -day--old mice were administered 1i0 mg copper hydroxyauino)ln/ kgm bw ( 6 mg Lu/ kg) suspended In .5 c elatin daily Lntil they wrea 29 days od fe wich they w-re aaminitr 2 ed ppm (505.6 ppn Cu) in the fe-d fr dditioral weaks. No statistically i nifican t increases an tum Ir i n e i ttJre Cbsrved a-n th- treated 7--week-old animals. In the same study, Bionetics Research Labs (19I administered LS Sinle 2 Lbzutarieous inj ct ion of l11a tn r c on Ir o I ) or 1000 mg of copper hytdroxyvqu iol inr/g I bw (1..rCI.6 0 mC1 LuknC) Su p e Td in Q C. ti F to ro LIpE. of 1 23-da-:lId mice of both :stra ins . Af ter 50 days of CIbservation the mie L6C &FI had an inc reasd 2.r inc I Cric c.f r etic:U 1 Lkm CE 1 1 m.ar- comraEE c Cmpared it h on tro I s. No tumors were o bservec in the trea ted male BSAF1 mIc , ano a Iow incidcence of reticUILIM cel mrcomis was cbserved in the treated female mice of both strains. Gilm an-; (1. 62) adrini stered in t ramuscLul ar inj ect ions cr tain. ing 20 mg of cupric xi de (1 mgCUL, C UFr i c If ide (13. fgm CLI), and cuIpr0US LA if ide (16 g Cu) infto t le thead r ic ht thii hs of 2- to :mo-n t c istar rat. After 20 months of obsservations , no in j ec t i-on-site tumf:ors were observed in aniy animal , but other tumors were observed at verv low incidence in the animals receiving cupric uLfi 2/30) an d cuprous 1ul fide (1/ 3) . As the relevance of the organic copper compOunc to the observation of sarcoma induction is uncertain and the incidence of tumors in rats treated i.m. with inorgani c coppCor was very low, data aire considered inadequate for classificationi. CopP.per II.. 4. SUPPORTIN'S DATAI FOR CARCI INOGENICITY Mloriya et al. (1I 8) reported -no increase in mutaLions in E. cli and. typhimurium strains 7A0', T535, 537 and T41538 incubated with up to 5 q copper quinolinolate/plate and in S. tVphimuriuLm TAS'9 and TA!(00 incubated with up to 5 g copper sulfate/plate. Demerec "t al. (19 51) reported dose-related mutaien ic effects in E. coli with 2 to 10 ppm cOppeLr Lfate in a reverse mutation assay. Neative results were obtained with copper sulfate or copper chloride in assays using b. cerevisiae (Singh, 1933) and BEcillus ubtiiis (Nishioka. 1975. Matsui, 1930, Kanematsu et al., 1990). Errors in DNA synthesis from poly( c) templates have been induced in viruses incubated with copper chloride or copper acetate (Sirover and Loeb. 1976). Chromosom)al aberretions were induced in isolated rat hepatocytes when incubated with copper sulfate (Sina et al., 1983). Casto et al. (1579) showed enhanced cell transformation in Syrian hamster embryo cells infected with simian adenovirus with the addition of cuprou- suLITAde and copper SL fate High concentrations of copper compounds have been reported to induce mitosis in rat ascites cells and recessive lethals in Drosophila mel.anoga ster. Law (1983) rorted increases in the percent lethalOs bserved in Drosophila larvae and eggs when exposed to copper by mic roinj ection (u 1. copper sul fate) or immersion (concentrated aqueous copper sulfate), respectively. .B. GUANTITtTATIVE ESTIMATE OF CARCINOTNIC RISK FROM ORAL EXPOSURE Not available. _IIC.NT t ava UA NTITATIVE.E ESTMTOFARIOEIRIKROOF CA INHALAION EXPSuRE Not avalable. 3 SIID. EPA DOCLJMENTATION, REVIEW, AND CONTACTS (CARC1NOGENIC ITY ESEESMENT) -. Cc:pper I I .D. 1. EPA DOCUMENTAT ION U. S. EP A. 19777 . Drinking Water Criteria DocLumen t frLi Copper. Prered by the Off ice of Heal th and ErI rcor)nmtrn tal aEsmiT.en t, I.i ronim- ti Irit.ia and Assessment Office4 Cincinnati, OH for the Office of Drinki ng Water, Washington, DC. ECAO-CIN 417. Bionetics Research Labs. 192. Evaluation of carcinogenic. ter.-toqenic rd mutagenic activities of selected pesLicides and industriial hemvicalC:.1 - I. Carcinognic stLUdy pr pared foi- Nationai LCancer In siti t ut_. NC I -DCCF:-CG- 1.73-i-1 . Castro, B. C. 3 . Meyers and j . A. DiPa 1 . 979. En ha.c emen t of viral trans formation for evaluation of the carcinoqenic or mutagenic poLential of inorganic tieail ats. Carcer Re. 30: 193. Deimerec, M. G., Bertani and j. Flint. 1951. 461 Surve' Of chem icais for mutagen.c action on E. coli. Pm. Natur. 25: 119. Gilman, J.P.W. 1952. Metal carcinogeresis. II. AstLudy on the carcinogenic activity of cobalt, copper, iron and nickel compounids. Cancer Fe. 22: 1 5-166. Knematsu.. N. , M. Hara and T. Kada. 1980'. Rec assay and mutagenicity studies on metal compounds. Mutat. ReS. 77: 109-116. Matsui, S. 198D0. Evaluation of a eaci.1 LL E-Lubtilis rec-assay for the detection of mutagena which may occur in w.ter environments. Water Res. 14(11): 1613-151?. Moriya, M., T. OhtE, K. Watanabe, T. Miyazawa, K. Kato and Y. Shi rasu. 1983. Further mLtagenicity studies on pesticides in bacterial reversion assay systems. Mutat. Res. 116(3-4): 125-216. Nishioka, H. 1975. Mutagenic activities of metal cOmpounds in bacteria. 'utat. Fe . 31: 1 5- 189. Sin .. , .L . Fean, G..R. Dyart, v.. Taylor and M.D. Pradley . 13. Evaluation of the a kal ince iLtion/rat hepatocyte casay a a predictor of carcinogen)c/mutagenic potential. Mutat. Res. 113(5): 357-391. I.Tinqh, 1753. Induction of reverse mutation and mitotic cene conversion by some metal compounds in baccharomyces cerevIsA. Muktat. Res. 117(1-2) rover MA.A and L . A. Loeb. 1976. Tn fiic i t f DNA synthesis in vitro: Screening for potential! metal mutagens or carcinogens. Science. 194 1434-1436 . << .2Copper >> II. D.*2.* REVIEW (CARZCINOSENICITY AE.EESSMENT) 4 The vl Eues irn the 1987 Drini. incg Water Cri teria Doctumen t for CJopper have reC.:VE:d eer arid admi nistrative reviFNW. n Work Group Review: 09/15/87 rif i cation Da t e:0q/ 15 / 87 II .D.3. U.S. EPA CONTAICTS (CARCINOGENICITY AlSSESSMENT) David J7. Reismarn / ORD -- (513)569-7538 / FTS 654-7558 W. Bruce Peirano / ORD -- (513)559-7540 / FTS 6S4-75-i0 II HEALTH HAZARD ARSESEMENTS FOR V2RIED EXPOSURE DURfATIONS I U7btaic Iklae4 --- Copper C-ASRN - 74-40- 50-3 Not available at this time -IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Copper CASRN -- 7440-50-0 No t a v a ilabl1e a t t h is t ime I V. SUPPLEMENTARY DATA ubsanceName -- COpper -50- ' CASRN -- 7440 Not available at this time _yI. R ERQENCES I rbStance Name -- Ccpper I ASRN -- 7440-50-5 * 5 Not available at thisV tifit sYNON'NMS 744- 50-S Copper 6 1,1-Dichloroethane; CASRN 75-34-3 (10/01/90) Health risk assessment information on a chemical is included in IRIS only after a comprehensive review of chronic to>;icity data by work groups composed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections I and II represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment , or may be based on a current, but unreviewed., risk assessment, and may take into accoUnt factors other than health effects (e.g., treatment technology). When considering the use of regulatory action data for a partictular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background information and explan- ations of the methods used to derive the values given in IRIS are provided in the five Background DOcuments in Service Code 5, which correspond to Sections I through V of the chemical files. STATUS OF DATA FOR 1,l-Dichloroethane File On-Line 10/01/90 Category (section) Status Last Revised Oral RfD Assessment (I.A.) pending Inhalation RfC Assessment (I.B.) pending Carcinogenicity Assessment (II.) on-line 10/01/90 Drinking Water Health Advisories (TII.A.) no data U.S. EPA Regulatory Actions (IV.) no data Supplementary Data (V.) no data _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS __ .A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,1-Dichloroethane CASRN - 75-34-3 A risk assessment for this substance/agent is under review by an EPA work group. I I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 A risk assessment for this substance/acent is under review by an EPA work grOup. III. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 Last Revised -- 10/01/90 Section II provides information on three aspects of the carcinogenic risk assessmentI for the agent in question; the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects-a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen. 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. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity. I <<< 1,1-Dichloroethane I!.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINDGENICITY II.A.i. WEIGHT-OF-EVIDENCE CLASSIFI CATION Classification -- C; possible human carcinogen Basis -- Based on no human data and limited evidence of carcinogenicitv in two animal species (rats and mice) as shown by an increased incidence of mammary gland adenocarcinomas and hemangicsarcomas in female rats and an increased incidence of hepatocellIular carcinomas and benign uterine polyps in mice. < < 1.1-Dichloroethane > 11 .. 2. HUMAN CARCINDGENICITY DATA None. 2 1,1-Dichloroethane TI.A.3. ANIMAL CARCINOGENICITY DATA Limited. An NCI bioassay (1978a) provides limited evidence of the U carcinogenicity of 1.1-dichloroethane in Osborne-Mendel rats and B6C3F1 mice. This is based on significant dose-related increases in the incidence of hemangiosarcomas at various sites and mammary carcinomas in female rats and statistically significant increases in the incidence of liver carcinoma in male mice and benign uterine polyps in female mice. The study is limited by high mortality in many groups;, the low survival rates precluded the appearance of possible late-developing tumors and decreased the statistical power of this bioassay. Technical grade 1,1-dichloroethane in corn oil was administered by gavage 5 days/week for 78 weeks to groups of 50 Osborne-iendel rats/sex/dose. A1l surviving animals were necropsied following a 33-week observation period. Due to toxicity, dosing was not continuous (3 weeks on then 1 week off), making the TWAs for 5 days/week 382 and 764 mg/kg/day for low- and high-dose males and 475 and 950 mg/kg/day for low- and high-dose females, respectively. Both a vehicle and an untreated (not in tubated) control group (20 rats/sex/group) were included in the study. A high incidence of pneumonia (approximately 80%) in all 4 groups of each sex was considered to be the cause for the low survival at termination of the study. Survival at 111 weeks was 30, 5., 4,and 6% in the untreated control. the vehicle control, the low-dose, and the high- dose male rat groups, respectively. Survival at termination for the female rat groups was 40, 20, 16, and 18%. for the untreated control, vehicle control, low- and high-dose groups, respectively. In female rats there was a statistically significant positive dose-related trend in incidence of hemangiosarcomas (0/19 for matched vehicle controls. 0/50 for the low-dose group, and 4/50 for the high-dose group). The incidence of mammary gland adenocarcinomas (1/20 for the untreated group, 0/19 for the vehicle control group, 1/50 for low-dose, and 5/50 for high-dose groups) showed a statistically significant dose-related positive trend in those female rats surviving at least 52 weeks; tumor incidence was 0/16, 1/22 and 5/31 for vehicle control, low- and high-dose groups, respectively. (Tumor incidence at termination for the untreated control females surviving at least 52 weeks was not reported.) This bioassay was conducted before the life table tests were implemented, so results adjusted for mortality are not available. No mammary gland adenomas or hemangiosarcomas were observed in the dosed-meale rats. In the same NCI (1979a) study, groups of 50 B6C3F1 mice/sex/group were administered technical grade 1,1-dichloroethane in corn oil by gavage 5 days/week for 70 weeks. Ais in the rat study, the dosage pattern was 3% weeks on and 1 week off; the surviving animals were necropsied 13 weeks after the termination of dosing. The TWAs for 5 days/week for the low- and nigh-dose groups were 1442 and 2885 mg/kg/day for male and 1665 and 3331 mg/kg/dey for female mice. Control groups, identical to those in the rat study and consisting of 20 mice/sex/group were also used. Survival at termination was S0, 80, 80, and 50% for the untreated control group, the vehicle control grOUP, the low-, and high-dose females, respectively. In male mice survival was *5, 55, 62, and 327 in the untreated control group, the vehicle control group, the low-, and high-dose groups, respectively. An increased incidence of hepatocellular carcinoma in ma3e mice was not statistically significant by either pair-wise or trend test (2/17 in the untreated control group, 1/19 in the vehicle control group, 8/49 in the low-dose and 8/47 in the high-dose groups). The incidence of hepatocel lular carcinoma in male mice surviving at least 52 weeks was 1/19, 6/72, 8/42, and 8/32 in the matched vehicle control group, a pooled vehicle control group consisting of mice from this and identical controls from other concurrent experiments, and the low-, and high- 3 dose groups, respectively; this positive trend was statistically significant. In female mize, liver Lrcirnomas were reported in orly the vehicle control (1/19) and the low-dose groups (1/47): no liver tumors were seen in the untreated controls or in the high-dose group. A stati stical1 ly significant increase in benign uterine endometrial stromal polyps (4/46) was observed in high-dose females; these were not observed in any other group. A preliminary report of the NCI (1978a) study was published by Weisburger (1977). 1,1-Dichloroethane >>> SII A.4. SUPPORTING DATA FOR CARCINOGENICITY To determine if 1,i-dichloroethane in drinking water could act as a tumor promoter or a complete carcinogen, Kl*.aunig et al. (1986) exposed groups of 3 5 male B6C3F1 mice to 1,1-dichloroethane in drinking water at 0, 35., or 2500 mg/L for up to 52 weeks following a 4-week treatment with either drinking water containing 10 mg/L diethyl nitrosamine (DENA-initiated groups) or with deionized water (noninitiated groups). The investigators estimated that the approximate weekly dose of 1,1-dichloroethane was 3.8 mo/a/week (corresponding to 543 mg/kg/day) for the groups exposed to 2500 mg/L. Upon sacrifice at the end of either 24 weeks (10 mice/groIp) or 52 weeks (25 mice/group) of promotion. all tissues were examined for gross pathologic lesions and histologic sections of the liver, kidneys and lungs were examined. Neither the initiated nor the noninitiated 1,1-dichloroethane-treated groups showed a significant increase in the incidence of liver or lung tumors compared with initiated or noninitiated controls, respectively. The authors concluded that 1,1-dichloroethane was not carcinogenic to mice and did not act as a tumor promotor following initiation with DENA. These conclusions ma.v not be entirely justified, since the duration of the study may have been inadequate for the development of tumors in noninitiated 1,1-dichloroethane-treated animals. in addition, the incidence of liver tumors in DENA-initiated controls was 70% at 24 weeks and 100" at 52 weeks, and the number of tumors/mouse in DENA-initiated controls at these times was 5.00 and 29.30, respectively. Hence, an increase in tumors or decrease in latency in 1,1- dichloroethane-treated DENA-initiated animals would have to be marked in order to be detectable. Milman et al. (1968) and Story et al. (19@6) investigated the chlorinated ethanes and ethylenes to detect their potential tumor initiating or promoting effects in a liver foci assay in Osborne-Mendel rats. In this assay, 1,1- dichloroethane did not give positive results for initiation (with phenobarbital as promotor), or as a complete carcinogen when administered in the absence of initiation or promotion. Positive results for were seen for promotion with DENA as initiator. The assumption that the liver foci seen in this type of assay are precancerous has not been validated. When tested by plate incorporation in a desiccator (because of volatility) in the presence and absence of metabolic activation systems, 1,1- dichloroethane was reported to be mutagenic for Salmonella typhimurium TA1535, TA8, and TA100, but not to TA1537 (Riccio et.-al., 1983;, mitoma et al., 1984). Negative results were reported for 1,1-dichloroethane in a cell transformation assay wi ALB/c-3T3 cells, tested in the absence Of an exooenous metabolic activation system in a sealed glass incubation chamber (Tu et al., 1985; Arthur D. Little, Inc., 198). When tested in a similar manner in a DNA repair assay with hepatocyte primary cul tures from rats or mice, 1,1- dichloroethane produced positive results (Williams, 1977). The results obtained in these three assays were also summarized in a joint publication (Miilman et al., 1986). Positive results were obtained in a viral transformation assay in which 1,-dichloroethane was incubated with cultured Syrian Hamster embryo cells in 4 a sealed ] ass chamber prior toc addi tion of adenovirus SA7 (Hatch et al. 1983.). Lattanzi et al. (199) determined that 1,1-dichloroethane, like 1,2- dichloroethane, binds covalently to DNA, forminQ DNA adducts. The Covalent Rinding Index (CBI) of both 1,1-dichloroethane and 1,2-dichloroethane classifies them as weak initiators. Chronic bioassays performed by NCI (1978b) on the isomer 1,2- dichloroethane resulted in many of t-he saime tumor types as seen in the bioassays of 1,1-dichloroethane. Significant increases in the incidences of forestomach squamous cell carcinomas and hemangiosarcomas were observed in male rats and an increased incidence of mammary adenocarcinoias was observed in both female rats and mice. In addition, alveolar and bronchiolar adenomas were reported in male and female mice; endometrial stromal po]yps and sarcomas in female mice; and hepatocellular carcinomas in male mice. Based on these findings, as iell as the appearance of lung papillomas in mice after topical treatment, 1,2-dichloroethane was classified as a group B2 chemical, a probable human carcinogen (U.S. EPA, 199r0). Becaudne Of similarities in structure and tarciet orgas, the carcinogenic evidence for .1,2-dichloroethane is cons-:idered to be supportive of the classification of .1,1I-ihlorethan- i n gru C, a possible- hu.manr carcinOgen. ------<< 1,1-Dichloroethane >------ _I.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. - -< 1,i-Dichloroethane >)------ S__II C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. II.D. EPA DOCUMENTATION. REVIEW, AND CONTACTS (CARCINOGENICIT Y ASSESSMENT) 1.,1-Dichloroethane II.D .1. EPA DOCUMENTATION U.S. EPA. 1985. Health and Environmental Effects Profile for Dichloroethanes. 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, Washing'ton., DC. U.. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal U.S. EPA. 1990. Integrated Risk: Information System (IRIS). Online. Office of Heelth and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. 5 1, 1-Dichloroethane II .D.2. REVIEW (CARCINDGENICITY ASSESSMENT) The 1784 Health Effects Assessment for 1,1-Dichloroethane has received Of fice of Heal th and Environmental Assessment review. ---- Agency Work Group Review: 12/07/89 Verification Date: 12/07/89 II .D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Sue VelaZque: / ORD -- (513)5L9-7571 / FTS 684-7571 Krishan Khanna / ODW -- (202)382-7588 / FTS 382-7588 - III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III .A. DRINK ING WATER HEALTH ADVISORIES SLbstance Name -- 1-Dichloroethane CASRN -- 75-34-3 Not available at this time. III.B. OTHER ASSESSNENTS Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 Content to be determined. IV. U.S. EPA REGULATORY ACTIONS Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 Not available at this time. 6 V. SUPPLENENTARY DATA Substance Name -- 1, 1-Dichloroethane CASRN -- 75-34-3 Not available at this time. _VI. BI BLIOGRAPHY Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 Last Revised -- 1.0/01/90 VI.A. ORAL RfD REFERENCES None ------<< 1,1-Dichloroethane ------ VI .B. INHALATION RfD REFERENCES None ------<< 1,1i-Dichloroethane >>---- VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Arthur D. Little, Inc. 1983. Cell transformation assays of 11 chlorinated hydrocarbon analogs. Microfiche No. OTS05093.92, DOcLUent No. 40-5324457. Hatch, G.G.. P.D. Mama'y, M.L. Ayer, P.C. Casto and S. Nesnow. 1983. Chemical enhancement of viral transformation in Syrian hamster embryo cells by gaseous and volatile chlorinated methanes and ethanes. Cancer Res-. 43(5): 1945-1950. Klaunig, J.E., R.J. Ruch and M.A. Pereira. 1986. Carcinogenicity of chlorinated methane and ethane compounds administered in drinking water to mice. Environ. Health Perspect. 69: 89-95. Lattanzi, G., A. Colacci, S. Grilli, et al. 1982. Binding of hexachloroethane to biological macromoleculles from rat and mouse organs. j. Toxicol. Environ. Health. 24: 403-411. Milman, H.A., D.L. Story, E.S. Riccio, et al. 1988. Rat liver foci and in vitro assays to detect initiating and promoting effects of chlorinated ethanes 7 and ethylenes. Ann. NY Acad. Sci. 534: 521-530. Mitoma, C., C.A. Tyson and E.S. Riccio. 1984. Investigations of the species sensitivities and mechanism of carcinogenicity of halogenated hydrocarbons. Microfiche No. OTS0509408, Document No. 40-9424225. NCI (National Cancer Institute). 1978a. Bioassay of 1,1-dichloroethane for possible carcinogenicity. NCI/NTP Technical Report No. 066. DHEW Publ. No. (NIH) 78-1316, Washington. DC. NICI (National Cancer Institute). 1978b. Bioassay of 1,2-Dichloroethane for Possible Carcinogenicity. NCI Carcinoqenesis Technical Report Series No. 55. DHEW Publ. No. (NIH) 79-1361. Washington, DC. Riccio, E., A. Griffin. K. Mortelmans and H.A. Milman. 1993. A comparative mutagenicity study of volatile halog-nated hydrocarbons using different metabolic activation systems. Environ. Mutagen. 5: 472. (bstract) Story, D.L., E.F. Meierhenry, C.A. Tyson and H.A. Milman. 1996. Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital. Toxicol. Ind. Health. 2(4): 351-362. Tu, A.S., T.A. Murray, K.M. Hatch. A. Sivak and H.A. Milman. 1985. In vitro transformation of B2ALB/c--3T3 cells by chlorinated ethanes and ethylenes. Cancer Lett. 28(1): 95-92. U. S. EPA. 1985. Health and Environmental Effects Profile for Dichloroethanes. 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. U. S. EPA. 1986. Guidelines for Carcinonen Risk Assessment. Federal Register. 51(185): 33992-34003. U.S. EPA. 1990. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. Weisburger, E.K. 1977. Carcinogenicity studies on halogenated hydrocarbons. Environ. Health Perspect. 21: 7-16. Williams, E.M. 1977. Detection of chemical carcinogens by unscheduled DNA synthesis in rat liver primary cell cultures. Cancer Res. 37(6): 1845-1851. 1,1-Dichloroethane >>>------ __ I.D. DRINKING WATER HA REFERENCES None ------I = = =-- SYNONYMS Substance Name -- 1,1-Dichloroethane 8 CASRN -- 75-34-. Last Revised -- 10/01/90 AETHYLIDENCHLORID [GERMArNJ CHLORINATED HYDROCHLORIC ETHER U CHLORURE D'ETHYLIDENE [FRENCH] CLORURO DI ETILIDENE [ITALIAN] I,1-DICHLODRETHAAN [DUTCH] 1,1-DICHLORAETHAN [GERNAN) 1,1-DICHLDRETHANE DICHLORO-1,1 ETHANE [FRENCH] 1,1-DICHLOROETHANE I1-DICLOROETANO [ITALIAN) 1,1-DICLOROETANO [SPANISH) ETHANE, 1,1-DICHLORO- ETHYLIDENE CHLORIDE ETHYLIDENE DICHLORIDE HSDB)F 64 * NCI-C04535 RCRA WASTE NUMBER U076 UN 2362 9 1 1-Di chloroethy) erie; CASRN 75-35-4 02/01/91 Health risk assessment infcrmation on a chemical is included in IRIS only a-fter a comprenensive reviEJ of chroric toxic-ity data by work groups composed of U.S. EPA scien tists froi: sever al Prograir Offices. The SL(fmarie2s presen ted in Sections I and II represent a corse nLS r eached in the review process. T he other sectiions contain U.S. EPA in-formation which is specific to a particular EPA progr-am and has been subienct to review procedures prescri bed by that Prcr rm Office. The regulat ory actions in aection IV may not be based on the most current risk assecceert, or may be based on a current, but Unreviewed, risk assessment , and may take into account factors other than health ffects (e. . .I trt-!atment tec hnoi olgy). When consideringj the use of reg-ou latory action data for a particular situation, note the date of the r-eguIatory action, the date of the most recei t risk assesmen t r El ating to that ac tion , and whether tec hno l o giceal factors were con sider ad . Backiroun-d in formation and ex plan-- a tions of the rmethods uSed tCi lerive the va)uS geeiven in IRIS are provided in the five Background Locumen to in Service Code 5, which correspond to Sections I thrcuih V of the cherfica fil .- STATUS OF DATA FOR 1,1-Dichloroethylene File On-Line 01/31/87 Category (section) Status Last Revised Oral RfD Assessment (!.A.) on-line 4/18 Inhalation RfC Assessment (I.B.) pending Carc inogenicity Assessment (iI.) on-line 02/01/91 Drinking Water Health Advisories (I II.A.) no data U.S. EPA ReguLI a tory Actions (IV.) on--line 03/01/BB Supplementary Data (V.) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCAR'CINOSENIC EFFECTS __.FA. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (R f D) Substance Name -- 1,1-Dichioroethylene CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 04/01/9 I . The Ref erence Dnce ( R f D ) is bared on the itS.SUmZt.i on t hat t hrs holC1 E -iSt f or certa in toxic effects such as cellular necrosis , but ma rot exi st for other - cxic c-f fec t.s suc h as carc i noctoni ci -in Iv enera 1, the R fD, is zr estim at- with Lncerta i ty spanning perhaps an order of imaqni tude ) of a daily ex pc:sur e to the human popu I ation ( . rC I ld irg sersi. tivc- subgpruCAps ) that is 1I ke y to bf without an appreciable risk of deleterious effects during a l ifeti me. Please reer to BackI-,round DOCLiment 1 in. r Service Code 5 for an ea borati on cf thCt:e concepts. RfDs can also be derived for the nonccarcinoCenic health effects cf compods whi c h are a J so car-c irceis. T herefore , it is essen ti ai to rcfer to other sources of inforiatior concerg tihe carcinogen icity of this substance. If the U.S. EPA has eva luatec this substance fur potential human carcinogen-- icity, a summary of that evaluation will be contained in Section II of this file when a review of that evalusttion is conpleted. NOTE: The Oral RfD for 1.,1-dichloroethylene may chance in the near future - pending the outcome of a further review now being conducted by the Oral RffD Work Group. I .M. 1. ORAL RfD SUMMARY Critical Ef fect Experimerital Doses* LIF MF RfD H1patic lesions NOAEL: none 1000 1 9E-- c mg/k /day Rat Chronic Oral LOAEL: 50 ppm (con- Bioassay verted to 9 mg/kg/day) Quast et al., 1983. *Conversion Factors: Doses were calculated by the authors. - < 1,1-DichIoroethylere > I A.2. PRINCIPAL AND SUPPORTING GTUDIES (ORAL RD) Quast, J .F., C. G. Humiston, C.E. Wade, et al. 1985. A chronic toxicity and oncogenicity study in rats and subchronic toxicity study in dogs on ingested vinylidene chloride. Fund. Appl. Toxicol. 55-62. Groups of 43 each male and female Sprague-Dawley rats (Spartan substrain) . were administered 50, 100, or 200 ppm 1,1-dichloroethylene in drinking water for a period of 2 years. Control groups of 30 animals/sex were maintained for the same period. Dailvy intake was calculated by the authors to be / 10, Or 20 mg/kg bw/day for males and 9, 14, or 30 mg/kg bw/day for Tmales.I here , were no treatment-related effects on mortality, body or oroan weight, clini- cal chemistry, urinalysis, hematology, or numbers of tumors. The only patho- logic findings were of hepatic lesions., generally characterized by minimal Imid-zonal hepatocellular fatty change and hepatocellular swelling. These findings were no-ed in rats of al 1 female treatment groups. in male rats, only the 200 ppm treatment group showed a statistically Sionificant increase n the incidence of hepatocel ular sweling, but this trend was also observed in animals reeivin 100 ppm 1,1--dichloroethylene. As part of thic same Study, beagle dogs (4/sex/group) were administered .25, 12.5., or 25 mg/kg bw/day in gelatin capsules. Treatment for 97 days had no effect. 2 This study, s well as a review of the available data, indicate that the 5 iver is the most sensitive target organ and, futhErmore, that rats are the most sensi tive species. ThL drinking water exprOsure reported by flucw t et al (1983) offers a more suitable model for potential human exposure to 1,1- dichloroethy]ere than does the NTP bioassay wherein arimals were givaged. It _ is, therefore, appropriate to set an RfD based on the LOAEL of 9 mg/kn bw/day for hepatic lesions in female rats. ,i-Dichloroethylene ' :51< I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 1000 A factor of 10 each was used for use of a LOAEL, 'for interspecies variation, and for protection of sensitive human subpopuIations. MF 1-Dichioroethylerne >t A.4. ADDITIONAL COMMENTS (ORAL RfD) SI1-ichl oroethyene has beer, shown to be fetotoxic, but not teratonenic to rodents after exposure in drinking water or by inhalation (Short et al 1977; Murray et al., 1979). 311-Dichloroethylene D _I.A.5. CONFIDENCE IN THE ORAL RfD Study: Medium Date Base: Medium RiD: Medium The study by Quast et al . (19e3) was conducted LLSing aporoprate numbers of animals of two species, measured several endpoints , and was of chronic duration (rats). Since there are corroborative chronic and subchronic oral bicassays, confidence in the study, data base, and RfD are considered medium. <<< 1,1-Dichioroethylene 1 .A.. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1985. Drinking Water Criteria Document for 1 1-Dichl oroethylene (Vinvlidene Chloride). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water. Washington, DC. i' This document has received a lengthy internal review and has undergocne public comments. R Agency RfD Work Group Review: 01/22/OS Veri fication Date: 01/22/85 1 A. 7. EPA CONTACTS (ORAL RfD) Charles Abernathy / ODW -- (202)J.382-o374 / FTS 382-5374 3 Michael L. Dourson / ORD -- (51J)569-7544 / FTS 6@4-7544 -I .. REFERENCE CDNCENTFATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,1-Dichloroethylene CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride A risk assessment for this substance/aQent is under review by an EPA work group. JII. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,1-Dichlorcethylene CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 02/0i/91 - Section II provides information on three aspects of the carcinogenic riSk assessment for the spent in question; the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalaticon exposure. The classification reflects a weiqht-of-evidence judgment of the likelihood that the agent is a ,human carcinogen. The quantitative risk estimates are presented in three ways. The slope factor is the result of application of a l ow-dose extrapolation procedure and is presented as the risk per (mg/ig)/day. The unit risk is the quantitative estimate in terms of either risk per ug/L drinking water or risk per ug/cu.rn 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 1,00..000. Bac kground Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity. Si,1-Dichloroethylene __II.A. EVIDENCE FOR CLASS IF I CAT ION AS TO HUMAN CARCI NOGEN IC ITY SI .A.1. WEIGHT-OF-EYIDENCE CLASSIFICATION. Clasification -- C; possible human carcinogen Basis -- Tumors obsEerved in one mouse strain after inhalationcx posure is the basis tor thim c lasification. Other studies were OT inadequate oesign. Vinylidene chloride is mutagenic, and a metabol ite is known to alkvlate and to bind covalent ly to DNA. It is structural ly related to the known numan carcinogen, vinyl chloride. 1,1-DiDihlorrethlene>> 4 I I . .2. HUMAN CARCINOGEN ICITY DATA Inadequate. A'n epidemiologic studv of 138 workers showed no carcino- genic ef fect associated with vinylidene chlorid exposure (Citt et al. 1976) . ased on power considerations, this study is inaidequate for assess- ing cancer risk in humans. . 1,1-Dichloroethylene I..3. ANIMiPL CAIRC1NJGENICITY D'TA Limited. Eiqhteen animal s tudies have been reported, which provide information 4 boLt the car-cinocenic potential of viny lidene chloride. Eleven of the StLdies involved inhalation exposure, five were oral, and one each was by skin application and subcutaneous injection. Most were not desiqned for maximum sensitivity to detect carcinogenic efTects. None of the 11 inhalation exposures were for l ifetime; all were 12 months or l e-s. Three of the five oral studies were of lifetime exposures. Of all the ctudies, only 3 one inhalation study produiced a response as a complete carcinogLen. In the inhalation study by ilaltoni et al. (15) both sexes of Swiss mice were exposed to 10 and 25 ppm (MTD) for 4--' days/week for 12 months. tatistical ly significant increase in kidney adenocar-cinoma was noted in male mice. lthough staStically significant increases in marmary car- cinomas in fema le mice and pulmonary adenomas i n both eixes we re reported, dose-response relationships were unclear. A second Mal toni study exposed Sprague-Dawley rats to 1025, 50, 100, or 150 ppm, 4-5 d avs/week for 12 months and observed them until spontaneous death. A statistically signifi- cant increase in total mammary tumors, but not carcinoaiis alone,* was seen 3 only at 10 and 100 ppm. No dose-response relationship was apparent, and the overall interpretation of the mammary tumor incidence is inconclusiVe. Four gavage studies (in rats and mice) and one drinking water study in rats have been negative (Maltoni et al., 1985; Quast et al., 1983; Humiston et al., 1978: NTP, 1982; Ponomarkov and Tomatis, 1980). Only the NTP (1932) corn oil gavage study in Fischer 344 rats and female E6C3F1 mice and the drinking ater study in Sprague-fDawley rats were undertaken for 2 years dosing. The NTP Study was apparently not conducted at the MTD and the drinking water study did not achieve a maximum dose of metabolite. All other oral studies were limited in design and, thus, lacking in sensitivity sufficient to detect a response. Vinylidene chloride did not act as a complete carcinogen when applied topically or s.c. to ICR/Ha mice but did serve as an initiator when toi- 1owed by phorbol myristate acetate treatment (Van Duuren et al. 1979). 1,1-Dichloroethylene > 1 I.A. 4. SUPPORTING DATA FOR CARCINOGENICITY Vinylidene chloride has been shown to be mutagenic for -almonella typhi- muriurr in multiple assays. This activity is largEly dependent on the pres- ence of microsomal enzymes. It has been used as a positive control in stLdies of chemicals that are gases at or near room temperatu-re. Both conventi-onal and host-mediated assays of Saccharomvces cerevisiae have been positive for mitotic oene conversion (Bronzetti et al., 1931). Vinylidene chloride was not mutagenic for VT cells exposed to vapor in vitro (Drevon and Kuroki, 19 79) nor did it produce chromosomal aberrations in bone marrow cells of ICR mice siveningle or repeated i.p. treatment in vivo (Cerna and Kypenova, 1977). CD-1 mice and Sprague-Dawlev rats treated in vivo with labeled vinylidene 5 chloride showed evvidence of DNA a Ikl' at ion and subseqcuen t repai r whic h was specific to liv \er CAnd :idrIey. I..idney in rt and ICuec h highEria il vIat ion than i1ver (Rei tz et a 1 . 90 . Covalent binding of vinylidene r:h-I or i de Sclose Iy corr e I ates with me tioL)O i.te format jon . McKenna e't a I . ( 1.977) observed greater binding in kidney than liver, and greater binding in mice than in rats. Vinylidene chloride -failed to induce dominant lethal mutations in fiicc (Anderson et al., 1977) or rats (Short et al., 1977). Vinylidene chloride is structurally related to the known carcinoqen, vinyl chl oride. ------<<< 1,1-Dichioroethylene II.B. QUANTITATIVYE ESTIMATE OF CARCINOGENIC RIS:K FROM ORAL EXPOSURE II.B.1. SUMMARY OF RISK EST I MATES Oral Slope Factor -- 6E-1 per (mg/kg)/day Drinkinq Water Unit Risk -- 1.7E-5 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) 6E+O ug/L E-5 (1 in 100,000) 6E-1 ug /L E-6 (1 in 1,000,000) 6E-2 ug/L i,1-Dichloroethylene I.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Species/Strain Dose TumOr Reference Tumor Type Administered Human Equivalent Incidence Rats F344, male; mg/kg/dav mg/kg/day NTP, 192 adrenal pheochromocytomas 0 6/50 0.71 0._120 /4 3.57 C.603 13./47 Human equivalent doses were determined by adjusting the administered animal dose' by the cube root of-the ratio of the weight of the animal (estimated 0.43 .:k) to human weight (70 kg) , and adjusting for lenqth of exosLre and lenoth of the experiment. The unit risk estiTm,ate chosen was derived from the highest of four sl ope factors calculated from two studies that did not show a statistical ly 5ignificant increase in tuiTior incidence attributable to oral exposure of vinylidene chloride. The drinkino Wt-ater study in rats (Cua7U t t l. ., 193) produced the lowest slope factor of 0.2 per (mg/kg9 ) /day-. The highest Slope factor Z0.6 per (mg/kgCj)/day] was based on male rat adrenal tumors from NTP (982). Use of data from this study wherein there were no statistically significant increases in tumor incidenca appears justified, since the slope 6 factor dehrived is within a factor of 2 of the sIcope factor based on data from the inhal aticnr st udyk M al toni et al . (1977, 1985) I 1-Dichlorothv] one 7II.B . DDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXF'OSUR'E) iArimal pharmacok inetic data show that metabolite eli imination is dose- dependent and saturabI le at inhailatior, concetratiors of 15.-200 ppm, or approximately 50 mg/kg oral ingestion. Vinvl idere chloride is rapidly absorbed, has limited solubility, and is riot stored in body tissues. 'harmacnki.netics and metaboliST data indicate that the availablce assavs were not of adequate design. The positive Mel toni inhalation study cOies closest to achieving a maximum dose of metablite, albeit less than lifetime expOsure?, but less than maximLm dosincI vis-a--vis metabolites. The water Unit risk based on incidence data from a drinking water study was chosen because route of administratior is appropriate to oral risk: esti mation. The unit risk should not be used if the water concentration exceeds 6E+2 ug/L, since above this concentr at ion tie unit risk may not be appropriate. I 1i-Dichloroethyl ene 3 I-.. -DICUSSION OF CDNF I DENCE (CARI NOGENICI TY, ORAL EX POSURE The estimate is based on a data set in which there is no significant increase in tumor incidence. The confidence that the upper I it is not greater than 0.6 per (mg/kg)/day is hiQh, 3ince it is the largest value by a -Factor of 3 from four rat data sets in two studies. If cirinkino water exposure alone is considered the estimates might be reduced by a factor Of The slope factors for the oral quantitative estimate based on oata from inhalation exposure and based on the negative oral data are within a factor ------K , 1-DichIoroethylene ------ S__II .C. GUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 5.0E-5 per (ug/cu.m) w trapolation Method - Linearized multistage procedure.. extra ri: Air Concentrations at Specified Risk Levels: Rik LevelConcentration E-4 (1 in 10,0)OCf 2E40 ug/cu.m E-5 (I in 100,000) 25-1 E-6 (1 in 1,000,000) C-/CI.Il < 11-Dichlorosthylene _II..2. DOSE--RESFONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE 7 Species/Strain Dine Tumor Reference Tumor Type Admtinist ered HunmiAn EqLiva lent Incidence Mouse/Swiss. male; Route: nhalation M l toni et kidney adenocar- a., 1977, cinoma 1985 ppm fimg/ kg/ day 0/70 iO 0.078 0/25 25 0.195 25/98 < I-Dichloroethylene I I, C. 3. ADDITIONAL COMMENTS (CARCINOGENICITY, I NHA,'LiLATION EXPOSURE) Within each same dose pair there were no statistically significant differences between incidences in the two control and the 25 ppm qroups. These groups were combined for model in. The number of animals survivinq to appearance of the first k idney adenocarc inomaE was used as the denominator for incidence. Human equivalent doses were determined assumiri 0.035 kg as the average weight of the male mice adjLsting for continuous lifetime exposurE in the mice, accounting for metabolisin and pharmacokinetics for mice, and using 70 kg weight and with 1.65 so.m surface area for humans (U.S. EPA, 1985). A slope factor of 1.2E+0 per (mg/kgQ)/dacy was calcul ated using estimated animal administered doses. The unit risk should not be used if the air corcentration exceeds 2E+2 ug/cu.m, since above this concentration the unit risk may not be appropriate. i-DichloroethylenL >>> II .C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Sufficient numbers of animals were used for treatment and control groups. Treatment was for approximately 50% of lifetime. Only two dose points provided data suitable for modeling. --- -. -- < 1--Dich1loroethylene >>>------ _II.L0. EPA DOCUMENTATI ON, REVIEW, AND CONTACTS (CARCINtENICITY ASSESSMENT) II . D. EPA DOCUMENTATION U.S. EPg. 1985. Health Assessment Document for Vinvlidene Chloride. Pre- pared by the Of fice o f Heal th and Environmen ta l Assessmen t Envi ronmental Criteria and As=essient Office, Research Triangle Park , NC. EPI 600/S-5:3-03F. -Dichloroethylene >>> II.D.2. REVIEW (CARCINEN1CTY ASSESSMENT) 8 The v'a)lues in the 19 Health As-essnt Document for V riyl iderne Chloride receivedI 5 e.tensive peer and public review. Lecy rk Group Review: 12/04/86, 01/07/97 Verification Date: 1/07/37 II.D.3-.. U.ES. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) I e-ain C. Parker / ORD -- (303)29-1789 / FTS 574-1739 Steven P. Bayard / ORD -- (202)32-5722 / FTS 392-5722 U III. HEALTH HAZARD ASSESrMENTS FOR VARIED EXPOSURE DURATIONS SIII.A. DRINKING WATER HEALTH ADVISORIES * Substance Name -- 1, i-DichloroethyJ ene CASRN -- 75-5-4 Primary Synonym -- Vinylidene Chloride Not available at this time. _1I.5. OTHER ASSESSMENTS Substance Name -- 1-Dichloroethylene CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Content to be determined. SIV. U.S. EPA REGULATORY ACTIONS. - Substance Name -- 1,1-Dichloroethylene CAFRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 03/01/8 EPA risk assessments may be updated as new data are published and as assessment methodolocies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates for the rEgciu latory actions in this section with the verif ication dates for the risk assessments in sections 9 I aid 11 , aL tis riy&t; e .pl ain iriccnis tenci e . A oC, Ct.e that soIe reC1uilatory a ctions consider fac tore not re 3 ated to heal th r sk uc h as tec hnica o0r ecoionfil c feAsii. h lity. y Lur:Lh tconSiderations are I icated.d for each action. In addition, not all of th regl 1 atory actions listed in this sec tion involve en-iorc able federal staciards. Fl ease Ci rEC t any CLe.S.stions you may havE concerning these regulatory actions to the U.S. EPA contact listed for that particular action-. Users are strongily urged to read the bl-ackground in form- ation on each reguIlatlOry action in Backqround Document 4 in Service Code 5. 1,1- DichorDeth\yIne it>> AIR ACT (CAA) o_IV.A. CLEAN No data available I ----. <:::<1.,1---Dihoroethyene ------ I _ .. SAFE DRINKING WATER ACT iSDWA) IV .' S. I . MAXIMIUM CONTAMINAiNT LEVEL GOAL (MCLG) for Drin::irng Water Value (status) -- 7 ug/L (Final, 1985) Considers technolooical or economic feasibility? -- NC Discussion -- An iCLG of 7 ug/L for 1,1-dichloroethylene is proposed based on an RfD and an assumed drinking water contribution of 20%. The RfD1 was I calculated based on the DWEL of 350 uq/L from an animal study in which liver effects were noted. An additional safety factor of 10 (for carcinogenicity) Ias applied. Reference -- 50 FR 46890 Part II1 (11/13/85) I EPA Contact -- Criteria and Standards Division, ODW / (202)382-7571 / FTS 322-7571; or Drinking Water Hotine / (200)426-4791 < 1.1-Dichloroethylene >)> I_V.B.2. MAXIMUM CONTNAMINANT LEVEL (MCL) for Drinking Water alue (status) -- 7 ug/L (Final, 1987) Considers technological or economic feasibility? -- YES Reference -- 52 FR 25690 EPIA Contact -- Criteria and Standards Division, ODW / f') 32-7571 / T 352-7571; or Drinking Water Hctl ine / (e00)426-4791 I ------<< ± 1-Dichloroethvlene U _IV.C. CLEAN WATER ACT (JCWA) 10 -IV.C. I. AMBIENT WJATER DUALITY CRITERIAq, Human Health Water ard Fish Consumption - .3E-2 ugc/L Fish Consumption Only -- 1.85E+0 ug/L Considers techriological or economic feasibility? -- NO Discussion -- For the maximum protection from the potential carcinogenic properties of this cheriical, the ambient water concEntration should be zero. However, zero may not be attainable at this time, so the recommended criteria represents a E-65 estimated incremental increase of caricer risk over a lifetime. Reference -- 45 FR 793:1 (11/28/80) EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7.15 1,1-Dichloroethylene CIV.C.2. AMSIENT WATER QALILITY CRITERIA, Aquatic Orcanisms Freshwater: AcLt LEC -- 1.16E+4 ug/L Chronic LEC -- None n a rin e: Acute LEC -- 2.24E+5 ug/L Chronic LEC -- None Considers technological or economic feasibility? -- NO Discussion -- The values that are indicated as "LEC" are not criteria, but are the lowest effect levels found in the literature. LECs are oiven when the minimum data required to derive water quality criteria are not available. The value given is for the class of dichloroethylenes, and not specifically for 1,1-dichiorolethylene. Reference -- 45 FR 79318 (11/288:) EPA Contact -- Criteria and Standards Division., OWRE (202)475-73i5 / FTS 475-7315 i-Dichloroethylene IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) No data available 1 1I-Dichloroethylene .-----> _IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) 11 No diatet ave:i]aLIe I - I1-Dichloroethylene .------ __ IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (FCRA IV . F. 1. RCRA APPENDIX IX, f or Ground Wa ter Monitorino Status -- Listed I Reference -- 52 FR 259412 (('7/09/87) EPA Contact -- Jerry Garman / OSW / (202)382-4658 / FTS 392-4658 ------1 1--Dichloroethvlene ------ 3IV.G. SUFERFUND (CERCLA) _IV.G.1. REPORTABLE QUANTITY (RQ) for Release into the Environment Value (status) -- 100 pound (Proposed, 1987) Considers technological or economic feasibility? -- ND Discussion -- The proposed RQ is based on potential carcinogenicity and ignitibility. Available data indicate a hazard rankinq of low based on a potency factor of 4.15/Tg/kg/day and assignment to weight-of-evidence group C, -which corresponds to an RQ of 100 poLunds. Ignitibility is determined by a flash point of OF and a boiling point of 99F. corresponding to an RQ of 100 Reference -- 52 FR 8140 (03/16/87) EPA Contact -- RCRA/Superfund Hotline (800)424-7346 / (202)3.82-3000 / FTS 382-3000 V. SUPPLEMENTARY DATA Substance Name -- 1,1-Dichloroethylene CASRN -- 75-375-4 Primary Synonym -- Vinylidene Chloride Not available at this tims. 12 VI. DI BLIOGRAPHY Substarice Name -- 1 ,1-Dichloroethylene CASRN -- 75-3.5-4 Primiary Synonym -- Vinylidene Chloride Last Revised -- 03/01/90 VI.P. ORAL RfD REFERENCES Nur-ray, F.., . Ni tslchk:e , L. Ramipy and B. Schwct. 1979. Etrvotoxicity and fetotoxicity of inhaled or ingested vinylidene in rats and rabbits. Toxicol. Appl. Fharmacol. 419: 189-2C2. Quast, J.F., C.G. Humiston, C.E. Wade, et al. C83.. A chronic toxicity and Oncogenicity study in rats and subchronic toxicity study in dogs on ingested vinylidene chloride. Fund. Appi. Toxicol. 3: 55 62 Short, R.D., J.11. Winston, J .L. Minor, 3. Seifter and C.C. Lee. 1977. Effect of various treatments on toxicity of inhaled vinylidene chloride. Environ Hea3th Perspec t. 21: 125-129. U.S. E PA. 1985. Drinkirig Water Criteria Document for 1 1-Dichloroethylene (Vinylidene Chloride). Prepared by the Office of Health and Environmen.tal Assessment, Environmental Criteria arid Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ----- 1,1-Dichloroethylene >>------ _VI.. INHALATION RfD REFERENCES Non e ------<<1 ,1-Dichloroethylene ------ VI .C. CARCINOGENICI TY ASSESSMENT REFERENCES fnderson, M.W., T.E. Eling, R.. Lutz, R.L. Dedrick and H.B. Matthews. 1977. The construction of a pharmacokinetic model for the dispositioln of polychlorinated biphenyls in the rat. Clin. Pharmacol. Therap. 22(5.2): 6 5o-Q,7. Bronzetti , G. , C. Bauer, C. Corsi , C. Leporini, FR. Nieri and R. Del Carratore. 1961. Genetic activity of vinvlidene chloride in yeast. Mlutat. Res. 89: 179-185. Cerna .. M. and H.-. penova. 1977. MiLLtaqenic activity f chloroethyens analyzed by screening sytem tests. MLutat. Res. 46(3): 214-215. Drevon, C. and Kuroki. T. 1979. Mutagenicity onf vinyl chloride. vinyl idene chloride and chloroprene in Y79 Chinese-hamster cel is. Mutat. Res . 7(20) 17 3-182. 13 Humis tn, , J.GJ.F. Du tL , C. . , . a.'j-llard, J.E. P -er and R.W. Li we. 1973. ReSU ts of a two-year tcmic ity and oncogen ici ty study with viny i idene c hl oriE- incur por ated in the drinkinc water cf rats. MNCA RCport No. VCD 1,3- TC'-fr l-Dow. Toxico logy Research Laboratory Heal th and Environmental Research Dow Chemical U..S.A. Midland, MI. MIaltoni , C. G. Cotti. L. Morisi and P. Chieco, 1977. CarcinoenicitV bionssavs of vinyl idene chloride Research plan and early resul tS. Med. Lay. Maltoni, C., G. Leemine., P. Chieco, G. Cotti and V. Patella. 1985. Experiaental research on vinylidene chloride carcin!enosis. In: Archives of Research on Industrial Carcinogenesis. Vol. . Maltoni, C. and M.A. Mehlnan, ed. Princeton Scientific PuAblishers, Princeton, Nj. IMcKenna, M.J., P.G. Watanabe and P.G. Gehrinn. 1977. Pharmacokinetics of vinylidene chloride in the rat. Environ. Health Perspect. 21: 99-05. NTP (National Cancer Institute/National To::icology Program) . 1972. NTP Technical Report on the Carcinogenesis Bioassay of Vinylidere Chloride in F344/N Rats tnd BCFI/Mice (GaaQge Study). NPT No. 80-12. NI H Pub. No. 32-17e4. NTP Research Triangle Park, NC. and Bethesda, MD. U.S. Department of Health and Human Services, Public Health Services, National Institute of Health. E Ott. M.G., W.A. Fishbeck, j.C. Townsend and E.J. Schneider. 1976. A Health study of employees exposed to vinylidene chloride. J. Occup. Med. 18(11): 735-738. I Ponomarkov, V. and L. Tomatis. 1990. Long-term testing of vinylidene chloride and chloroprene for carcinogenicity in rats. Oncology. 37: 136-141. Quast, J.F. , C.G. Humiston, C.E. Wade, et al. 193. A chronic toxicity and oncocenicity study in rats and subchronic toxicity study in dog3s on ingested vinylidene chloride. Fund. Appl. Toxicol. 3: 55-62 Reitz: R.H., P.G. Watanabe, M.J. McKenna, J.F. Quast and P.j. Gehring. 1920. Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: A comparative study with dimethylnitrosamine. Toxicol. Appi. Pharmacol . 52: 357-370. Short, R.D., J.M. Winston, J.L. Minor, J. Seifter and C.C. Lee. 1977. Eiffct of various treatments or toxicity of inhaled vinylidene chloride. Environ. HeIlkith Perspect. 21: 125-129. U.S. EPA. 195. Health Assessment Document for Vinvlidene Chloride. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and A-s-ment Office, Research Triangle Par- NC. EPA 600/2-031F. Van Duuren, B.. B. Goldschmidt, G. Loewengert., A.C. Smith, S. Melchienne. I. -eidman and D. Roth. 1979. Carcinogenicity of halocjenated olefinic and hydrocarbonsnliphatic in mice. j. Nati. Cancer Inst. 83 6) 14.3-1438. etthy1 ene ------1 . - ic h i oro ------<<< _VI .D. DRINKINWWATER HA R'EFERENCES 14 NCn.e SYNONYMS S ubs t.ainc e Name -- 1 ,1--Di c l. or ce t hy ee CASRN -- 75--4 Primary Synonym -- Yinlidene Chloride Last Revised -- 01/31/u7 CHLORURE DE VINYLIDENE 1.1I-DCE 1 1.-D ICHLOROETHENE Dichloroethylene, ,1- ETHENE, 1,i-DICHLORO- ETHYLENE, 1 1-D ICHLORO- NCI-C54262 1 RCRA WASTE NUMBER U078 SCONATEX UN 1303 VDC Vinylidene3 Chloride VINYLIDENE DICHLORIDE VINYLIDINE CHLORIDE 15 Lead arid compounds ( inorcian ic ) ; CASRN 743S9-92-1 (05/I/91 ) i Health ri Dk assessment information on a chemical is included in IRIS o after a comprehensive review of chrornic toxicity data by wjork groups c:cmrtpo.sed of U.S. EPA scientists from several Program Offices. The summaries presented In Sec+ions I and II represent a consensus reached in the review process, The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Proqram Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g.., treatment technologyc ). When considering the use of rleuILLatory action data for a particular situation, note the date of the regulatory action, the date of* the most recent risk assessment relating to that action , and whether - technolocical factors were considered. Background information and expian- ations of the methods used to derive the values given in IRIS are provided in the five' Background Documents in service Code 5, which correspond to Sections I thrOucIih V of thce chemical fi3es. STATUS OF DATA FOR Lead and compounds (inorganic) File On-Line 0'3/01/8S Category (section) Status Last Revised Oral RfD Assessment (T.A.) on-line 02/01/31 EInalation Rf0 Assessment (I.B.) no data Carcinogenicity gAssessment (II . ) on-I ine 05/01/91 Srinking Water Health Advisories (III.A.) no data U. S EPA Regulatory Actions (IV.) on-ine 7/1 Supplementary Data (V. no data CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOEENIC EFFECTS .A. REFERENCE DCCE FOR CHRON:C ORAL EXPOSURE (RfD) Substance Name -- Lead and compounds (irgranic) CASR -- 7439-92-1 Last Revised -- 2 1/,1/91 The Reference Dose (RfD) is based on the assumption that thresholds exit for I1 certain toxic effects such as cellular necrosise, but may not exist for other toxic effects such as c&arci noqen icity. In genera 1 , the RfD is an esti mate (with Lncertainty spanning perhaps an order of magnitudeL ) of a dai-.ily Cx posure to the human popu!lation n(inLuding senstitive SuLbgroLps) that. is likely to be Lithout an appreciable risik of deleterious effects durinq a lifetime. PIcase refer to Farkgrouknd Documient 1 in Service Code 5 for an elaboration of these concepts . RfDs can also be derived for the noncarcinogenic health effects of c ompounds which are also carcinogens. Therefore, it is ess:ntiai to refer to at her Sources of informatico concern ing the carcinoeniity of this substance . if the U.S. FEP has evautd this substac for pcioEntial human tcarcinogen- i itv a summary of that cvaluatioin will be contained in Sc tion II f this file ea revie.w of that evaluation is completd. Lead and compounds (incrganic)K> A great deal of information on the heal th nffects of lead has lbeenr obtained through decades of medical observation ard scientific resTrch. hi , information has been a'essed in thedeeopment OT air and wateI- quality criteria by the Agency' s 0 F f ice of Healtlh and Environmental A:vseessmtent (OHEA) in support of recjulatC'rv decision-raing by the Dfficte of Cir GuOal ity Planning and Standards (0A0P0) and by the Office of Drinlking Water (ODW). By comparison to most other environmental toxicants, the deCree Of uncertainty Ia bout the health effects of lead is quite low. It appears that some of hese effects, particul.arly changes in the levels of certain bL ocid en\tmes and in aspects of children's neurobehaviral developent, may occur at b ood lea ylevels so low as to be essentially without a threshold. The cAgency' s RfD Work Group discussed inorganic lead (and lead compounds) at two meetincs (07/0 /S5 and 07/22/95) and considered it inappropriate to develop an FfD for inoroanic lead For additional information interested parties are referred to the 1986 Air Qualitv Criteria for Lead (EPA-500/S-83/,02a-dF) ard its 1990 Supplement (EPA/'00/S-89/049F) or the fol lowing Agency scientists: Harlal Choudhury / ORD -- (513)569-7536 / FTS 684-757.L . Nichael Davis / RD -- (719)541-4162 / FTS 627-4162 Ieff Cohen / 0DW -- (202)382-5456 / FTS 332-5455 uohn Haines / DOAPS -- (919)541-5533 / FTS 629-5533 __I.B. REFERENCE CNCENTRATION FOR CHRONIC INHALATION EXPOSURE (FfC) Sustance Name -- Lead and compounds (inorganic) Not available at this time. Ii.CRCINOGENICITY AF LIFETIE EXPOTU'RTE Substance Name -- Lead and compounds (inorganic) CASRN -- 7439-'-92-1 2 Last Revised - 0/1 Section IT provides information on three aspects of the carcinogenic rihi.: assessment for the agent in question; the U.S. EFA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen. 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 r pcr (mig/Ikg) /day. The unit risk is the quantitative estimate in terras of either risk rp'e ug/L drinking water or risk per ug/cu.m air breathed. The third form in which ris: is presented is a drinking water or air concentration providing cancr risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Bqtqac:: groI'iund DocLment 2 (Service Code 5) provides details on the rationale and methods uSed to derive the carcinogenicity values found i IR IS. Users are referred to Section I for information on long-term toxic effects other thn carcinogenicity. Lead and compound=. (inorganic) > II.A. EVIDENCE FOR CLASSIFICATION AW TO IHUMAN CARCINOGENICITY II.. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen iasis -- Sufficient animal evidence. Ten rat bioassays and one mouse assay have shown statistically significant increases in rena l tumors with dietary and suLcutaneous exposure to several soluble lead salts. Animal assays provide reproducible results in several laboratories, in multiple rat strains with some evidence of multiple tumor sites. Short term studies show that lead affects gene expression. Human evidence is inadequate. Lead and compounds (inorganic) >>.- 1I.A.2. HUMAN CARCINOGENICITY DATA Inadequate. There are four epidemiologic studies of occupational cohorts exposed to lead and lead compounds. Two studies (Dingwall-Fordyce and Lane, 1963; Nelson et al., iS2) did not find any association betwecn exposure and cancer mortality. Selevan et al. (1? 5 ), in their retrospective cohort mortality study of primary lead smelter workers, found a slight decrease in the total cancer mortality (SMR=95). Apparent excesses were observed for respiratory cancer (MR(=111, obs=41, pJ0.05) and kidney cancer (SMR=204. cbs=t, p>0.05). Cooper and Gaffey (175) and Cooper (1i85 update) performed a cohort mortality study of battery plant workers and lead smeltear workers. They found statistically significant excesses for total cancer mortality (MR=113, obs=344), stomach cancer (SMR=169, obs=34)., and lung cancer (SMR=124, b=109) in the battery plant workers. Although similar excesses were observed in the smelter worker5, they were nut statistically significant. Cooper and Gaffey (1975) feit it was possible that individual subjects were monitored primarily on the basis of obvious cigns of lead expoure, while whonthers showed no symptoms of lead poi'oning were not monitord. All of the availab3e studies lacked quantitative exposure information, as well as information on the possible contribution from smoking. All studies also included exposures to other metals such as arsenic, cadmium, and zinc for which no adjustment was done. The cancer excesses observed in the lung and stomach were relatively small (<200) . There was no consistency of site among 3 the varioius 7-tud ieS, and no StudV clhowed any dose--response relationship. Thu , 1the avalabl human evidcrice Is considered to be iraeCuqLiate to re-ute or dermcistrate any potential circ.inogeni.city for humanis from lead cpoLLre. L d ld comipound I.norgarlic ) I.A. ANIMAIL CARCINOGENICITY DATA ?.uffi cie rit. The carcino geni c poten-ti a] of lund lE] to SP im;ril p! os phi a tes and ace ta tes ) ad Ti ni is it-rc cd via t he or al ro U t C? Or 1.)y t j c ti h naG been ieimonst.rated in rats and mice b more than 10 ivestigator. T h no vs chiarac tris tic can~.flcer~ t respons0 is bilateral renal c arcim. Rati givn lead ce tate or SLA bEce C at e oraly I I h ave d evelo ed V !il a. ima . , ad r d C.i Su bac t u ate a1 co produced 1lung adenioias in ice aft Ler i.p. admi nst rat ion Most cf t)eAe inv~etigations found a carciriugen ic response on y at the highe dse. Th ViE lead compounds tested in animals are almost a Lt oluble al t s .ts ] a 1 ic lead l ead O xide arid lc-d tet raky . I ha-ve not been, tested iqua Ltt.E I tC ads oT 1 nhal atcon expo.iurie ha ve nc. o Ecn l oc:a Led i ri the li teraLure A ar It al ( 1973) admin. sterd 10, r 100. and 500 ppm lead as I ad acetate in dietary concentrations to 50 rats'ex/ group fo 2 rs. Control rate (100/sex) received the basal laboratory diet. In a ctlcoi 2-' year fmding uy ratC/group were given diets containir 0, 1000 and 20 ep la as lead acetate. No, renal tumors werec reported in the control gro or I tr-eateoanimtS of either sex re'ceiving 10 to 100 ppm. Mal.-- ratfed 50C, 1000, and 2000 ppm lead acetait.e had an increascd renal tuor ancidenice o-f 5/50; 10/20 , and 16/20, whilI 7/20 females in te 210-rp g Iroupd renal tumors. - Th Aear et al . (1973) study is I imited by the lack oF experimental detai. Th possibility of environmental contamination from lead in the air or drink ing water was not mentioned.. The strains oT rats .Se0 were oct specified in the study, buLt the Health Effects Assessmont for Lead (U. . EP, 9B4) indicates the rats were Wistar strain. The veight gain at 1000 and 2'i00 p pm was reported to be depressed, but deta ils were not g i ven. sprzAk et al. (1985) in investigat ing the interaction OT dietary calcium or lead carcinogenicity, fed 1C Iead subacetate (.500 ppm Pb) to maic Sprague-Dawley rats in the diet for 79 wee-s. Of Lhe rats urviving (29/30) i n this treatmen t group beyond 5@ weeks, 44. '/ had renal tumors. F1-ou rtS had adenrocarcinomas; the remainaing nine had adenomas. iLater a rumors were noted. No renal tumors were noted ariono the controls. As part of a study to determine interactions between sodi um nitrite. ethl 3 urea and lead, ma E Spr ague--Dawl ey rats were gi ven 1ead acetate in thei r driniing water for 7L wecks (Koller et al., 1935)0. The concentratinof l ead was 2 600 ppm. No idney tumors wee detce d amon th 10 cnrrl a'ras Thirtren of. 16 (81c) lead-treate t d ratE had renal tubu Lar carcinoma three uiors Wvere. detc ted at 72 weeks and the remainder detcc ted at th termination of the study. 5nEsch and Kroes (19-9)fed basic lead acetat- at ' . ad . in the dipt to 25 Swi mice/sex/gr-u for 2 years N" r!n4 - tu'id)so1 in the control groip, bit 5/25 male mi CE of 0.15 basic lead acet group I.d renal tumors ( n a carcn coma s c ombined I-in the 1.0% gu, one emale had arensal tumCor. - The authors thought that the I-w In C'n :c In tre 1.0% group was due -) oarl m ortality. Hamsters oive lead subacetate at 0.5% and 1- in the de rhad no iQnifiiicant renal tumor response (VEn Esch and Kroe, 19 ) r.) 4 L eadc eni mpo n d S c. r u ani ) a c: : - II. A.4. SUPPDRT I NB DATA FOR CARC I NOGEN IC i TY Lead acetate a idLces Cel l 1 trans fo rm -ation in Fyri an hamster eimbryn cel l S DiPaolo e t a± q 1779) and a Is e [nt-ances the irc: ioence of s imi an adce iovi rus I induc ti.. Lead oxide sh'owed imi 1 ar eihancecd aderovi rui induc tioi (Lita Et Under certain conditions lead compoundis are - capab l e o) i ncC iri.: c rIY omom al aLerratiorrs In viv aId in t LsuCe Cui t ures . GraIj - l d L-c al 19) 7showe-:.d a re a Eti .n I.h i pbetween SCE arid I La ex p)SUrE C n C 6 teJtJpIe o err. Lead has been shoncr, in a number of DN str-uc Lture and funci Lnb assa/, to affect the molecular procesEs asc:cia ced wa th the rLguLation Of gene expresscon (U.S. EPA, 1986). E------ II.B E . DUTNTITg:TIVE ESTlIMATE OF CARCINOGENIC RISK FROM ORAZL EXPOSURE UNot available.. LuAnMt iying l d' s cancer ri-k involves many unc ertainties. some of whic may be unique to ld.. .-ge, neal th. nutri tional state, body bLrden , avnd .X.posure duration in fluence the absorption. release, and Excretion of l ad. In addition, cLkrrent know Iedge of lead pharmcokinetics indicates that anm estimate derived by standard procedures woUld not. trulv descra e the potential risk. Thus, the Carcinogen Assrasment Group recomra-nd-s that a numerical eatimSte not be used. --- LEd anu compounds (inorganic)> A IC. UANTITATIVE ESTIMATE OF CARCINOGENIC RTK FROM INHALATION EXPOSURE Not available. ------<<< Lead and compounds (inorgaric)->------ A"0 -NT T11 %: 177 rlTQ__ UF.D P OUMENTT ION.,. R E'yiEN, ANCD CONTAT'r (CARINOGENICITY : __m-AK:soESMNT I II.D..l. EPA~ DCCUM1ENTATION U. EP-..P---:. .7O. . -aithtTecI9 -i ssmentT!-Lo ad . Preparac y the UT Tice of-Health.andnironmenal- Asscment, Enviroinmenta~l CII rii ea ris~esmen Tfice, 1incinati, ceH, fr th Ofic of mernc and Reediat -epne achington, 6 / NTIEP Prepared r of H t a nvi ronmn En imentaI l Park .. N , ;or J Off ce of a r eria nd Hfl se ls 11Lnt Of ice, R s rch Tria ngr ' Air Quality Planng EtanddS- an d EPA-6 0/-3/ dF 5 . S. EPA. 79T . Lr I'im ia riar v - F W c f the ' rC c rlDcenli pc t i Et a D f I C-d Z;T-0Cinti-!z Wit-1 Ci - 1 eur-&7dpO tFe . P ep'are(d Lv the OffiC cf Hel th adri .1vi') ient ) £ii'Bfmeri , c r C n g - t li r C riit G (31"CL. L hi r, t or, I'. "f I- t he Office oI i a f O i. f IM ankirlo Watoo i rt f ac c So lid Na-t candC the Off I CE?of Emere ncy ar-d Fem.ic'aa R,'2esponE SLt (Supe- fund ) . OHE A--C- 257. Inr t-rnal RIev cvi - L.id and ciC pDtrnGe .lncrganlc ) +I Ti .D.7. IEV.L-W (. I E l NllC I T YSSS'SE CI-Y Pi EENT The revi R Of iLime Carcilic.C'nLIiC Puta itia Cc o. EEnti.f d I L ; 1 'D L ex poSure has F-eCeiv:LV-d Agl"Cy' FE? "iew The 1 . ir- Q lty Criteria D)CCuiLi. n.,t ior L.cacd haii recaEi vd AcfrliLd y a rd Lternal.- ,to r R i''"'v w Jeview A-geac y Worki. r oup Re'view: C5/04 /88 -/Eor iT ;Lc:a;.ioi-1 Date : U /0U-1/5c2d I '-D- ___II.D.3-. LU..S. ErPA COENTACTSS (CARCINDG3EIITY - A'SEEEIMENT) William iPeplko / ORD -- (202i382--53?8 / FTS 732-5878 James Cooliano / ORD -- (202.).2-59 / FTS 92-589 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURtATIONS III .A. DRINKING WATER HEALTH ADVISORIEs Substance Name -- Lead and compounds (inorganic) CASTRN -- 7 43--9 2 -1 Not available at this time. 11. B. OTHER ASSESSMENTS subetance Name -- Lead anu compourde ior ganic) o-rNfl' -- 74 -- . 2-1 C.ontent to be detemined. 6 IV. U.S. EPg REGULATOF;Y ACTIONS ubc tance NEame --- Lcad arn compourdcfd (inorg aic CASRN 79--92-1 L-aEt Revised -- 07/01/90 EPA rs:: assessmrrents may he updated as new data are pu)Ublished a-Inc as essesmient methodologies evolve. R re 101 requ nt t t Supdaed at the Sctame time. Coiimpar e the dates for tie regul atoryv ac t*ris in this sectio,rn with the verification dates for the risk assessments in sections I and II, as this may ex-plain inconsitencies. Al so note that soie 1elatory actions consider factors not related to health risk, Such as technical or economic feasibility. Such considerations are indicated for each acti.n. in addition , not all of the- regulatOry atctions listed in this Eiection involve Senrforceab) a federal standards. Fl ease direct any qIeSt oris you mr ay- have concerning these regulatory actions to the U.S. EPA contact listed for that particuiar ac:tion-. Users are trngly urged to red thC backgrund i nform- Iation on each reg2uiaLory action iin Backgrund Documc--nt 4 in Ser'.vicIe C-de -c Lead and coupunids ( iniorganic )> IV. A. CLEAN A iR AT (CAA) ___IV.Ai. NIN AIR QUALITY STANDARD ( NAAS) I. AT1 RNA Utl11 ID 0N ConEid-rs technolog ical or economic feasibi lity --- No Discus1in '-- Unoer Section 109 of the CAA. EPA hes set a primary (heal th- ased ) NAAGS for lead of 1.5 uq/cu .m calendar quarter average not to be xeeded (,'3 F4 41281/ 7). The secondary (wel)far,,e---sed) INAAS i s Identical to the primary standard. EPA is currently reviewing these standards to determine if channes are warranted. Reference -- 40 CFR 50.12 U.S. EPA Contact -- Air Quality Management Division / OAOPS / (1%9)541-5656 / FTS 629-5656 ---- L&ad an d c ompounds; ( in o rgan i c ) >------ _IV., SAFE DRI:NKING WATER ACT (SDWA) 3V . i.I YAXIMUM CONTAr: INANT LEVEL GOAL (MCLG) for Drinking W4ter S alue status) - 0.02 mg/L (Propo-sed, 1785) Considers te:hnolociral or conric faibily 1t? - NO Dicusrsion -- Nerolooic.al eff-ects of lead in intar Ls arc adver f7t associated with iblood lead levels of 15 ug/dL a the basis for this MiL-LG. Using a conversion factor of 5.25 to convert from blood lead concentrations to drinking water lead concentratios and an uncertainty -fic tor cf 5, an MCLE f 0.02 mg/L for lead was derived. SReference --- 50 FR 45936 Part IV (11/13/85) 7 EPA Con tact Cri teria and Standarda Divisiorn, ODW / I20'2) 7-- 7571 / r T t2-~/57i :; or t'rinu:irC Waer L1. Afne / 0 Lead and compol-D Ir inorgan ic) _V... 2, MX I MM CbNT AMN MANT LEVEL (MCL for Dribin Water alue (atatu-.) --- C.5 mg/L I--ntei Lona.nders tecInc l ojica1).I or C.:-ec'nom ic Teas i I v -I tr. E: DisCussion - s an, in . ti . s r ure L G L Ih S. EPA is us i nci tahe i . Le previOUSly der'ivEd by L the Plic Heal .h ervice Reference -- 45 FR 57332 (D')/27/80) EPA Co it act - Crieria and Stndarde Di vision, CDW / (2(i)33e,-/ /71 / 1 -TS .22--/ /1 " or Dri rin Wa.-.Er ro lin / t -UUHitI ez----i/ -/i. ------( Le and compunds ( anrdanor aic) > .------ . V C. CLEA WATER ACT i NA) .L . V. .L . AIlS. T WH I EER 1.LJMA i I TY C R. I E: I AH HufLan Sel t h Water and Fish ConsumpTtion -- 5.0E+1 Ug/L Fish Consurmption Only -- None Considers technological or economic feasibility7 --- NO DiScussion -- The criterion was set at the existing drink-ing water tanCaro in 120. .Reference -- 45 F-R 7?318 (11/23/SO) EPA Contact -- Criteria and Standards Division, WRS (2O2)475-7Z15 / FTS 475-7315 Lead and compounds (inorganic) > > IV. C.. AMBIENT WATER DUALITY CRI TERA,, Aquatic Org ani JmsE reen*wa.ar: -- . 2E+i uo/L (I--hU-r -verae) Chronic --- 3E ag/L (4--day averagce MatrinE-: Acute -- 1. 40E+t2 ugO/L (1-hour averagqe) Chronic --- 5.E+- ug/L (4-day averaqe) Considers technological or economic feasibility? -- I ND DiSCuSSion -- The tox ici ty of t his compound in -reifhwrater is hardness- 8 Idtependent . The values5i ven are for a hardness of 100 mc/L CaCO~ - Focr . ror comp ete di cLtion Lee the referenced notice. Ref erence 50 FR 30784 (07/29/85) 3 PA Contact ---- Criteria and Standards Division., OWRS (.202)475-7315 / FTS 475-7.15 -I------Lea*d and ccmrripound a ( in rganic) >------ I Iv.D. FEDERAL INSECTICIDE, FLINGICIDE, AND RODENTICIDE ACT (FTFRA4) No data available ( Lead and ccipoundss (inornic) >, ------ U'- E. TOXIC SUBSTANCES CONTROL ACT (TSCA) ( Lead and compounds (inorgartic) ------ _IV.F. RESOURCE CONSERYATION AIND RECOVERY AC (RCRA) IV.F.1. RC PPENDIX IX, for Ground iater Monitoring Status -- Listed ;eference -- 52 FR 25942 (07/ 09/7) E:A Conta L RCRA/SLLpEr-fund Hotline )424--9346 / (202) 322-3000 / FTS 382-3000 ------< < < Lead and compounds (inoran ------ IV.. UPERFUND (CIERCLA) S IV. G.1. REPORT APLE QUANTITY (RD) for Release into the Environment (tattus) -- pound (Statutory, 1987) Uonsie recrhnological or economic feeaiitv? -- NO -iu - e statu.tory 1-puor a is re tainedpni assesment of its potential carcino enic i ty and may he ?dj usted in a. uture noof cerp:roposed ruit. e-ak ' ahnwn the eva Iuation a . ot-I uana i cmpleted Lead Wis eVa.lUatEd f-or chronic toui city, but Was&E not ran&)ed 7cr . toxicity because 07 insufficient data- I Reference -- 52 FR 2140 (03/16/27) 9 EPA Contac t -- RCR A /S'upCrfunId Hot i rU ()) 42h-/34~ / (202) -. 2-3:00 / FT-S 3 72-3000 V. SUPPLEMENTARY DATA Substance Name -- Lead and conpourdcs (inorganic) C!oRN --- 739-92-i Not available at this rime. V I BLI ID3RAiPHY Substane Nhame Lead and compound i inor jan ic Last Revised -- 12/01/99 YI.A. ORAL RfD REFERENCES N -one ------<<<( Lead and compounds (inorganic) >>----- VI. B. INHALATION RfD REERENCEo None ------< Lead and cOmpOUndS (inorganic > VI .C. CARCINOGENICITY ASSESSMENT REFERENCES Enderson,E.L. , and CAG (Carc inogenic AssesSment Group) 1993 Guantitative approaches in use to assess cancer risk. Risk Analysis. 3:27 -2 5 HA r . H.C. Trochimowicz and i.E. Nax-il. ./ i.. OviL CT .0C sui u les in animals carrxed ou' -as'el 1 L aor-n-C_ try - - earao Te .ing srUcy and response to hemriorrniage study. - arth r.. A. serIin. P. E-nga. r . - and J. Smeets, Ed. EnvironmF-en tai health aspects of lead: Proceed inzg international Sympcsium; October 1972; Amterdam. Tha Neth E..rIds. Commission of the European Communities, LuxeImoerg. p. 19-2'3S. Casto, B.C., 3. Meyers and J .A. DiPaolo. 1979. EnhanceTent of viral transformation for evaluation of the carcinogenic or ifcutagenlc potential of 10 inor tia, c meital' I salts.- CancE-r FRe . -~.: 19-C15. 1Cioper .C. I. M ao , q ity among emp loye Ees of lead bat tr plant.s &ard lead roducA.tc.- nj sS 9 739A7./ -3jori E . ind. n ron. He alth.&5 11: 31-- Cooper, W.). a-d 'W. Gaffv. 1975. Mortality of lead workers. In: roce'dingof th .19774 Coriferc on St anda rds of ccupational Lc-ad E posure J . F . Ccl, c Ed, rebrua ry, 1974. Wa i -.i ngton DC. ,. Occuip. M d. .1 7l: F71.-1 07 Di nt.wal '--FordycL y . nd .F R., L .196 . r a, A fC. i '- t. -- s.*tL oi. f l aI d W r:ErE . or. J. Ind. Ie , .2 : 71 -7.1,:. DiP a 0 o J. ., . L. N el an eud P.C, C. Ias 1 97.. In vi trc' neopl1azst i trans formation of Syrian hiaIister cel l a by l ead arce ta te and its rlCtnv ance to env i ronmen t al carci nogen es . Br. L . Cancer . L.: 52-4. Girandjan, . H.C Wul and . ieuhr. 198-\. Se aitr 4chroma Lid cxc: hane in vraraion in iccuvational lead exour.Enion'e 2 reson~etor RS 7 E-G't0 V Lr'. .0 .I : c c .;p 'ti .- rIE LFI 0f PLS-,I 0 . ~ 1 F- n Cfl v J 19--2_-4 . a sp~--:%,.. ., K.L. Hoover arid L.A. P'Oiri er 1735. Et fec-t cf dietary C lC _um acetate on lead subacetat.e carcinogen ici tyi I in dn1e-s maE SA - e- 0DV4l1 Tr at I C,c i c j a-:Eie . - 'E- 2 7'1 Dawly rts. arcnognesi. 62):279-23.2. .. ol l-r. L. .. NA - vei- I it and d3 .H. Eor. 1r, --.ieoplsia induc-d in . 4i:-a rats fed le-cd acetate ethyl urea and sodium ni ratE'. Txcal. at hol 1 Nelson, D.3., L. Kireiai ian-Schumacher and G. Stotz v. 1922. Effec t.5 OF cadmiurn, lead, and ZInc on macropDhage-med iated cytotoxic i ty toward tumor cells. Environ. Rec. 2: 154-163. Selevan, S.G. . F .. Landricaan. F.-. Stern ano u.H. Jones. 1-8E.. Mortailaty OT sead melter workers. Am. E, EpideTol, 122: S7T.3. van Esch, G.J. and R. Kroes. 1q9. The induction of renal tumors by feedinc of basic lead acetate to mice and hamstsers. -r u. uancer, * r 1 U.S. EPA. 1384. Health E.ffects Assessment for Lea-. -rreparca L ine lT TIce oT Heatrn ano Environmental Assessment Environmental -riterla and HAsessmernt Office, Cincinnati, OH, for the Office of Emergency and Remaedial Response, Washinc ton DC. EPA/540/1-86/055. NTIS PBEP-163996/ AS. U.S. EPA. 1996. Air Quality Criteria Document for Lead. cIlumes III. IV. Preoared by the Office of Health and Envir-onmental AZe-smnt, Environmenita: Criteria and A ssessment Of R'esearch Triang lE Prk- NC, for the Of ice of Hz ua nc 'nr-, n and Sa n dasr d4. EAS/-3 i. U. . P'rEi i na r review of the carcinoQenic poeEtiao iac associ3 ed with oral x posure. Prepare--d by the Office o-- Hcanlth and Env irmental Assessment Carcinogeric Asscissmrn Eroup. Wasngrton DC, for teGfice of Drinking Water, Ofcfie of Sal xowaste and the Cffice of amrenya R-ieedia la espon'e (Super-fund ) .. 3-HE-C-267 . Intarnal Re':vie ------Lead al compounds (anorqanic) ------ VI .Du. DRINKIN3 -WATER HA RERN-Ez 11 nonc TE SuLstance Name -- L.e'ad and COMpOLAFdS ( inoraani tc C03RN -- 7439----1 Last Reviseci -- 0i3/01/5 7439--2-1 Lead ard comlpcitndlsd. p lum LmL 12 Z inc and Compounds; CPARN 7440--6--6 (C2/01/91.) Health risk assessmen t information on a chenica I is inc ludEd in IR1S On lY after a cnmprehEinive reiew of chronic toiici ty diata LIV work or oLupFs composed of U. S. EFA scientists from several Program Offices. The summar esFpresented in Sections I and II represent a cnsErsuS reached :in the revi2ew procesS. ~The other sections contain U.S. EPA information which is specific to a particuLar EPA program and has been subject to review procedures prescribLed by that Program Office. The regulatorv actions in ection IV may not be based on the most current risk crossessment may be based on a current, but LAnIrCeViewed risk assessment , and may take into account factors oither than health effcts (e.g. , treatment technology) . When considering the use Of regu.il a tory acctio.cn data for a particular situation not e the date of theI eQulatory action. the date of the most recent risk asseTsment relat:ing to that acti on and whether technolog ical factors were considered. Backgrnund in formation ari extpl an- ations of the methods used to derive the values given in IRIS are provided in the five Bac kground Documents in Service Code 5., which correspond to Sections I thr ouL V of tI? chemical f i es.- STLTUS OF DATA FOR Zinc and Compounds File On-Line O2/01/91 category (section) Status Last R vised Oral RfD Assessmen t ( .A.) pen in g Inhalation RfC Assessment (I.B.) no dca uarcinogenicity Pssessment (II.) 02/C-/i/9 Drinking Water Health Advisories (III.A. no data UI.S. EPA Regulatory Actions (IV.) no data SuppleTentary Data (V. ) no data I. CHRONIC HEAILTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS I.A. REFERENCE DlSE FOR, CHRONIC ORAL EXPSURE (F -D) utance Name --- 7inc and Compounds eASR-N --- 406- A assessment for thi4 u bstance/aoentc i under review by an EPA work I C -1 .B. REFERENCE CONCENTRATION FOR CHRONIC I NHfALATION EXP'OSURE (F:fC) SLbstarce Name - irc and Ccmpor[unLkds CASRN -- T440-66-6 Not available at this time. I I. CARCINOt3ENIiCITY ASSESSMENT FOR LIFETIME EXPOSURE LAubstance rme --- inc and Compounds CASRN -- 7440-66-6 Last Revised -- 02/01/91 Section II provides information on three sspects of the carcinogenic rii:: assessment for the agent in question; the U.S. EFPA cl4assification, and quant-- itative estimates of risk from oral ex>posure and from inhalation exposure. The classification reflects a weight-of-evidence judoment of the likel i hood that the agent is a human carcinocgen. The quantitative risi: estimates are presented in three ways. The slope factor is the result of appli catin f a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the quantitat'ive estimate in terms of either risk per ug/ drinking water or risk per ug/cu.m air breathed. The third form n wich is presented is a drinking water or air concentration providing cancer r of 1 in 10,000, I in 100,000 or i in 1,000,000. £ackground Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity. <<< Zinc and Compounds> II.. EVIDENCE FOR CLASSIFICATION AS TO HUMPN CARCINCGENICITY AI..l. IDEIGHT-OF-EVIDECECLASSIFICATIONSTO asoication -t nor c assi fiable as to human carc incigenici s-- Based on inadequate evidence in humans ano animals. < Zinc and Compounds >> SIIA. 2. HU.MAN -CRNOGENICITY DATA Tnadequate. There are no reports on the possib- carcinogenicitv of zinc and compounds per se in humans. Case studies have bean used to evalua te the ef fects of zinc administered for therapeutic reasons. TI ere ae reports Lhi ch compare zinc levels in normal and cancerous tiSsue. otuoies f occuatonal exposure to zinc compounds have also been contduted, but have I imitedj value because they do not correlate exposure with cancer ri k. 2 CatSie r eports If chronic therapeutic efpsure fur approximately1of 2 two pat ien ts, 59--year-o)d fema l e and a 26-yer-Ld h--coor;:ygous cickle -ce 1 1 male, t. 10C-150 mg/d, y inc a=. zinculte or 'inc .cetate,respectively, have reported a profound anemia assoc ia ted wi th hypoce ruloplasminemia and hypocupreria (Porter et al . 1977; Prasad et a., 1979) . The conditions werc' corrected by copper supplementation and, in one case, withdrawal of zinc. Habib et al. (1975) reported that average zinc corcen tratiors in normal i and hypertrop-ic prostate tissue: were similar, approxiTatel y 6. S umol /, buit tIe average zinc concentration was loiwer in carcinomatus prostate tissues .6 u1l/g0 ) . These tissue samples were obtained as Fol lowc: normal prostate tiss, ues were olbtaine.,d ait AuitOPSY from 9 menn 25-58 yearas old (averagle agle 356): and both hyperplastic and carcinomatous prostate tissues were Obtained from the biopsies of 23 men 52-67 years 0d (average age 70) and from 9 men 64-91 years old (average age 73), respectively. Several other studies have also shown lower average zinc conricentrations in canc!eroLs vs. nor ma or hypotrophic prostate tizsue (U.S. EFA, 1997). NRC (197B) and U.S. EPA (1997) have reviewed other studies which have rioted both hiih and low zinc levels in other cancerous and noncancerous tissues with no definito pattern. From the.se studi's. it could not be concluded whe-.ther zinc was a carcinogen. oeveral occupational studies have been conducted on workers exposed to zinc compo..inds (Bat chelor et al . 1926| Chmieliwski et al . , 1974a, b Biobrishchev-Pushlin et al!., 1977). No increase in the incidence of cancer was notec; however, the studies were designed to evaluate other endpoints and did not specifically address cancer. Other symptoms such as Ili ght leukocytosis, occurrences of metal fume fever, respiratory disease and hypocalcemia were some of the findings noted in exposed workers. Batchelor et al. (1926) extensively investigated workers exposed tc zinc in a smeltEr. A total of 2-1 workers whose exposure ranged from 2-35.5 years were selected. In most work areas the mean zinc concentrations were generally below 5 mg/cu.m, except in the zinc dust plant where concentrations of up to 130 mg/cu. m were measured. The average level of zinc in whole blood of the 24 exposed workers was 459 ug/100 mL, compared with 337 ug/lO mL in 10 control measurei-ients. No information was given about the control subjects. KiLu i and roprda (1979) oLind that exposure levels to zinc oxide dust in a zinc oxide factory were on average 0.5 mg/cu.m for zinc melters and 2.44-7.15 mg/cu.m for zinc oxide packers; it was not indicated how these values were obtained. Chmielewski et al. (1974a,b) examined a group of workers who were exposed to zinc oxide in a shipyard, this included 20 ship smiths, 20 electric welders, 20 ship's pipeline fitters. and 20 zincifying workers. High concentrations of zinc oxide were found at the stands of the electric welders, who worked in containers (maximum 59 mg/cu.m, mean 12 mg/cu.m) , and the ship smiths, who worked in a superstructure (max imum 50 mg/cu. m. mean 12 m/cu. ) . These workers were also exposed to other hazarduus compounos, Euch as n itroen oxides. Bobrichchav-Pushkin et al . (1977) studtied 1013 workers in the casting shops of three copper alloy productior facilitis in the USSR. Four hundred and -fifty-one workers from the rolling shops were used as controls. The average level of zinc oxide exposure in the casting shop was 2.1 mo/cu.m range of 0.2-5.1 mg/cu. m) well below the USSR's maximally al lowable concentration of 6 mg/cu.m. Workers werer also exposd to other m-tals sucn.a- copper, lead and nickel. - <<< Zinc arid Compounds> IA.3 AiMALT CARCINC=ENxICI DATA Inadequate. In a 1-year study, an unspcc if iCd nU.mber of newborn Chester Beatt vstock mice (sex not repor tec) were administered 0, 1000, or 5000 ppm 3 jinc (apprxF IC m ate. l 0, 1 r 850 mg /kg /day) as z ic sufI fe t.e in drin k i ng water (Wa i ters and PoR 1 eA ). earate g roup of mice received zi-: ol e ate in the diet at an ini t I ci'EC. of r'00,'r0 ppm inC; this dUe wasr. re-C'LJCeO to 2500 ppm of ter months and to 1250 ppm after an additional months because of morta i ty due to arnema An epidemic of e5tromelia caused the deaths of several mice during the first 9 week: conzsequently, addi tional control and test-diet grolups wVee est ablis ithed. There was no difference in body weight ga in between con trol1 and treated gr oups, except the dietary zirc group which became anemic . urviva1 was rot rep:ort in treted compared wih conTIrCol An increase inllprnt the incidence of hepatomis was observed in tretted mice surviving for 45 weeks or loinger relative to cortrols (-riginal and replacement mice pooled) . The' hepatoma incidence in the control 1 lw -dcE drinking w-ter, high-dose drin king water , and test-diet group was 3/24 (12.5%), 3/28 (10.7%), 3/22 (13.6%) and 7/23 (30.4%) respectively. Incidence of mialignart lymphoma in the control , low-doSe driniking water hig h- dose d r-.riking wate, arid test-cdiat group was 3/24 5 4/28 (14.3%), 2/22 (9%) , and 2/23 (.7%) , respectively. Incidence or Lu ng aden0oma in the control low-dose drink-ing water, high-dose drinkin wpter, end test-dit groups was 10/24 (41.7%) * /28 (32.1%) , 5/22 (22.7) a 1nd 9/23 (3 .1:), respectively. None of these were significantly eJ evatted in a LtatiE-ti caI a:nalysis of this data performed by the EPA. In a 14--month study conducted with 150 C3H mice (sex not reported) adminiscration of 500 mg/L zinc sulfate (approximately 100 mg/kg/dav) in -the drinking water resulted in hypertrophy of the adrenal cortex and pancreatic islets (AughevCe al 177 . No tumors were noted; however, on ly the adrenal, pancreas and adenohypohysis were examined. Accurate consumption data could not be obtained due to spillage during drinking. No instances of adrenal or pancreatic hypertrophy were Seen in a control group (number of animals not stated) that received only distilled wa ter. After an intratesticular injection of zinc, Guthrie observed seasonallv- related testicular tumors in fowl (Guthrie, 1964) but no tumors in rate (Guthrie, 1956)). Guthrie (1964) administered zinc chlorida, zinc acetate or zinc stearate to groups of white leghorn chickens by intratesticular injection approximately 0.01 /inj ec tion) groups of chickens were sacr i ficed from 37 weeks to 11 months. Eight of the 111 chickens injected with zinc chloride in January and February developed testicular testoma, while none of the '4 chickens injected with zinc chloride in March developed tumors. None oT the 3-6 chick-ens injected with zinc acetate in March and none of the 14 chickens injected with zinc stearate in January and February developed tumors; no conclusicr about the carcinogenicity of these two compounds could be ma-de because an insufficient number of chickens were tested. No control group was described. Guthrie injected 0.15-0.20 mL of 10% rinc SUifate in to the testis of nineteen 4-month-old rats and 0.15 mL of 5% zinc chloride into the testis of twenty-nine 3-month-old rats (strain not specified). - Guthrie 1956). No testicular tumors were observed in either group at sacrifice 15 mont after in] ection .- No controls were described. Riviere et al. (1959) injeted zinc chloride in distilied water into the testic les of 10 Mistar rats. he rats we're S-ubdivided into several groups;: some rats were unia aer 1 Il castrated and some rats received an inje sctioln of 200 units- e ru m g4 inadotrophin and a subcutanieouS implantation of a 25 mg pel i e tf i S ttti bane r 1'0 m Ltet0sterone. The number of rats in each' f the fco'u r qrou (u-Li l ara l castration +/- hormone treatment andJ untreated +/- hormone treatment was not stated. No control group was described. Testicular tumors (includin interstitial tumors , a seminoma and an embryoma) became apparent 15 months after inoculation (tumor incidence not specifiiedi. Tier e '0or specific date. 4 on the effects of horrnones in this experiment. Halme (1961) expooed tumor-resistant and tumr-susceptible strains of mice to zinc in drinking water. in a 3-year, five-generation study, zinc chiur;de was added to the water of tumor-resistan t mice ( strain not cpec if ied) ; the groups received 0, 10, 20, 50, 100, or 200 mg Zn/L. The spontaneous tumor frequency for this strain of mice was 0.0004%. The tumor frequencies in the generations were: FO=0.8%, Fi=3.5%, F1 and F2=7.6% and F3 and F4=25.7%. Most of the tumors occurred in the 10 and 20 mg Zn dose groups. No statistical analyses and no individual tumor-type data were repo.rted. In the tuior- susceptible mice, strains C3H and A/Sn received 10-27 mg Zn/L in their drinking water for 2 years:. 33/76 tumors were observed in the C3H strain (31 in females) and 24/74 tumors were observed in the A/Sn strain (20 in females). Most of the tumors were adenocarcinomas. The numbers of specific tumor types were not reported. The tumor frequencies (43.4% for C3H and 32.4% for A/Sn both sexes combined) were higher than the spontaneous -requency (15% for each strain), although no statistical analyses were reported. Zinc and CompoLundr.2S II. A4. EUPPORTING DATA FOR CARCINOGENICITY in a short-term, in vivo assay, Stoner et al. (176) injerted strain A/Strong mice (20/sex/dosa) intrapdritonealiy with zinc acetate 3 times/weeK: for a total of 24 injections (total doses were 72, 190, or 30 mg/k) . Controls (20/sex/group) consisted of an untreated group, a vehicle control group administered 24 injections of saline and a positive control group administered a single injection of urethan (20 mg/mouse). Mice were sacrificed 30 weeks after the first injection; survival was comparable for all groups. There was no increase in number of lung tumors per mouse in treated animals relative to the pooled controls. While four thymomes were observed in zinc acetate-treated groups and none in controls, the occurrence of these tumors was not statistically significantly elevated. Urine samples from subjects occupationally exposed in the rubber industry to a variety of compounds, including zinc cxide, were not found to be mutagenic in the microtitre fluctuation assay with Salmonella typhimurium strains TA1515, TA9 and TA100 (Crebelli at al., 1985). The results of short-term genctoxicity assays for zinc are equivocal. Zinc acetate and/or zinc 2,4-pentanedione have been analyzed in four short- term mutagenicity assays (Thompscn et al., 199). In the Salmonella assay (with or without hepatic homogenatesi, zinc acetate was not mutagenic over a dose range of 50-7200 ug/plate but zinc 2,4-pentanedione was mutagenic to strains TA1538 and TA98 at 400 uo/plate. The addition of hepatic homogenates diminished this response in a dose-dependent manner. In the mouse lym phoma assay, zinc acetate gave a dose-dependent positive response with or without metabolic activation; the mutation frequency doubled at 10 ug/mL. In the CHO in vitro cytogenetic assay, zinc acetate gave a dose-dependent positive response with or without metabolic activation, but the presence of hepatic homogenates decreased the clastogenic effect. Neither zinc acetate nor zinc 2,4-pentandione were positive in the unscheduled DNA synthesis assay in rat hepatocyte= over a dose range of 10-1000 ug/mL. Zinc chloride is reported to be positive in the 3almonel la assay (Kalinia et al., 1977), negative in the mouse lymphom assay hAmacher and Paillet, 1990), and a weak clastogen in cultured human lymphocytes Deknudt and Deminatti, 197). Zinc sulfate is reported to ba not mutagenic in the Salmonella assay (Gocke et al., 1981), and zinc acetate ia reported to not induce chromosomal nbberations in cultured human lymphocytes (Gasiorek and 5 Saucnger , 191i) . rree. i et a 1. 1985 ) found zinc c8-ide ( ?. pu r-t (10:'0-5000c Lac;/platie) to b- ncrd mutr.grenic for Sainrinlla in the. re.vecruiOFn Rcs porses in mu tIg)en ic i t v as saEs a re t houg ht to de pen d on t.he frm ( . a 0 inorganic or- organic salt) of the zinc tested. For e -4amfrplI, inorgaitnic salts teid to dissoci ate and { he zinc becomes bound witi LA tcLre media constituerts. Salts that dissociate less readily tend to be transported into the cell and are postulated to cause a posiie response (Thops.on at al . 1 I-] - inc i.S an essential trace eiemen t involved in -umerous '.; ol cal funiL.s nluding growth, taste arid spermatorenesis. it is al coi ac tcr foreveral 'icrliles :uch as those involved in the metabolism of pr- ot ejn a rcd n uc lIc a c Acds .ZI FT iay;' be a mCdi fier of the carcirogenic r ensporse zinc de C f C iCa[y or exUcs svel high levels of zinc may enhance susceptibil-i to carcinoenl eis. 'anerea supplementation with low to moderate levels of irnc may offE ?rprction (Po et al., 1968). C Zinc deficiency enhanced car-cinomaks c- the ersophaus j.nduced by methylPbeny t m (Fn al., 978) but- E d of cancer of the oral ca vitv induced by 4--ni trorui .n i ner-N--oxd (W Paliu s lt al.1979 . In a study that earined I.oth Zinc c- and SUppemn 3 m Ltation, Ma thu (1) found that animals With a deficient diet (5.9 mg/kg ) and animal diet Fupplemented with excesivly h l/s of Ainc in; the diet (200-250 mg/kg) had fully developed carcinmas o f the palIata m1Cosa. W1hile the rats wEre on the specific diets., te p1latial mu s wasIk.-,c i poi n ted wi t h 4 n i t. r- q u in c line JE -7 Limes/ weEk f or 20 weks. In the _inc defi cient group 2/25 rats dCeveloped cancer of the palatial mLcosa 2/25 rats in the excessive zinc group also deve loped this form of cancer. Animals suppleriented with moderate levels of zinc in ti- die- (50 mg/igq devoped only moderate dysplesia. Thus,* zinc's mod-ifying effect on carcinogenc'is may be dose-dependent. - Zinc and Compounds >>>------ II .3. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM OR L EXPOSUi~E None. Zinc and Compounds > ------ II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. -- nc and Compounds >>>------ 11.D. EPA DO CUMENTTION, REVIEW, AND CONiTACTS (CAR CNTN CTY ASSES311ENT) IID .. EPA DOCUMENTAT ION U.. EPI. 1980. Ambien t Water QuaL I it,' Cr iteriE for 7nc. rred by the uffice of Water Regulations and Standards, Washington, DC. EPA -44/5-30-079. J.S. EPA. 174. Health Effects Assessment for Zinc Cand Compounosj. Prepared by the Office of Health and Environmental As.ement, EnvirnmIent-al 6 Cri tera a ind A_EesEsment Of f i c, Ci rc inrAi a Ut cr the** 2f fice f L1 e rcE:nc y ReMcd ial Recpscno Se Wash i n-tcn - - U.S. LP' . 197. SLImCIary \ r:eview of the C'A O iit .. h E e -if: c -ts .D latEdCI w.i th 7 iric aiCd 7i c 'x ide. Hc7.*el . thn Iu -:,e Acse:TSSen t . Environment . Crteria arid Asssment . Office, Reeairch Trianile Par!:, NC. EP'A/600/5-97/(22r. U.S. E IF. 189. Ambiesn t Water Oua lity CvritC-2rie Docurien t ienZdum i for zi nC. Pre pared y the Off i e of Healc:\ 1t h ani Envi roniar L a I stni , n u r: f f vonmenta Criteria and Assecsirent OTffice , Cinrcinnati, OH for the Office of Wat:r Regu a4ti - Inc aI Standards,; Washin gton, DC.. .lIc a-d CofIlound;: + I.D.). EVIEW (CARCINOGENJCITY ASSESSMENT) The 194 Healt ffecta Assesmen t for Zinc (and c ompound) th D 19I7 Health Isue Assesment and the 1790 abd 196 Ambient Water Duality rt jeria Docume rnfta have received 0 ffice ofi 1-ealth Elffcts rA=-s:es:F sriert r e.vJ ew Agency WolIrk 'Group Review: 11./03/9, 06/ 1 5 /90 Verification Date: C06/15/90 DI.D.3. U.S. EPA CONTACTS (LCARCINDGENICITY ASSESSMENT) Rita S. Schoeny / CR0 - - (513)5,q--7544 / 'TS 684-7544 II. - HEALTH HAZARD ASSESMENTC FOR IVARIED EXPCSURE DURATIONS III.A. DRINKING WATER HEALTH ADVISORIES Substance Name -- Zinc and Covmpounds CPSRN -- 706'-6 Not available at this time. I Ci .B. OTHER' ASSESSME NT S aubatance Nlama' -- Zinc and Comrpounds CASRN - 7440-66-- cntCent to be dEter-n)ed. 7 1.1.; tEk U. C. :F; WI..cE i r r ' .Nu Oju )s-t-InC. e II ath. ------Z itc indrC ic:'c potu".idcis CASRN ---- 4 .- 6- Not aval. ab Ie at ti LiE. V. SUPPLEMENT'A 1 RYDAT A SubstanCe Name -- Zinc and Compounds CASRN -- 7440+-66--a Not. availabi at Lhis time. VI BIBLIOGFAPHY S-ubstance Name --- Zinc and Compounds CASRN -- 7440-66-6 Last Revised --- 02/01/1 VI.A. ORAL RfD REFERENCES Non e ------< Zinc and Compounds >------ VI .B. INHALATION R-fC REFERENCES None ------Zinc and Compounds >>> ------ 'VI.C. CQRCINCGENICITY ASSESSMENT REFERENCES Achr D. E. and S.C. Pail 1- 0. Induction of tiuorothymidine- resistant mutants by metal ions in L51 Y /TK+ - cell. Mutat. Res.. 7: Aughey, E., L. Srant, B. L. Furman and W.F. Drydn. 1'977. The effects of oral zinc supplementation in the mouse. J. Comp. Patho. -7:1-14. 8 Batchelor., .. , J . W. Feoh ne, R. M. Thomson and K . R. Dr in [er . I . A c I Ji anf-d !aboratory in vestigation of the ef fect of metael lic zinc! of ::icr-c oid e andF of .inc SulIphJ id e L.pon the heal t h of vor 1:men. n Ind . Hyg. 5 3 -363. i .ummai zed in U. . EPA , 197) brishchv-Pushkin, D . . A. . Or ova, L . A. NatumovaC t a .1 1977. Occupatioctn hyiene and heal status of workers engaged in production of Cofppr Iys . Sig. Tr. Proif. Zabo 1 . () : 10-14. Enq . trans ) ChmielewSki., J., 1.. J1armin, C. Bartnick.1i and R. K1974. EvaluatiOn of occupational exposure to zinc oxide in the mc-ra rinE productic'n shipyard: I Examination of the working environment and the standS unL(fde'r exposure. Biul . Inst. Med. Morsk. Cdansl. 25(1): 43-51. (Summarized in U.?.. EPA. 19a7) Chmielewjski, J. 1B. 3aremin , C. Bartnicki and R. KonieczkI. 1974b. Evaluation of occupational ex posure to zinc oxide in the marine production shi pyar d: 1 I. Exami nation of the iState of health of the wLr:e pc-rexoed to zinc oxid. Biul. Inst. Med. Morsk. Gdansk. 25M.): 53-5 . (ummarizd in U.S. EPA,: 1957) Crbe)i A. PR.,Faoletti, E. FeAcone, G. Aciu iline, G. Fabri Fnd A. Car.ere. 1955. eutagnnicity a tudi Ps in a tyre P1lant: In vitro activity of workers urinr ct and rw Br. j. Ind. Md. 42: 41-47. Dek.nudt, G. and H. Deminatti. 1978. Chromosome studies in human lymphocytes afTEr in vitro expoau-re to metal sal ts. Toxi coloqy. 10: 7--75. F-onq, L. Y . , A. Sivak and P.M. Newberne. 197. Zinc deficiency and methylbenzylnitrosoamine-induced esophageal cancer in rats. J. Nati . Cancer inst. 61: 145-150. Gasiorek, K. and M. Bauchinger. 181. Chromosome changes in human lymphocytes after separate and combined treatment with divalent salts of lead, cadmium, and finc. Environ. Mutagen. 3: 513-518. Gocke, E., M.T. King, K. Echardt and D. Wild. 1931. riutaqenicity of cosmetics ingredients licensed by the European Communities. Mutat. Res. 90: 3. 1956.1uthrie, Attempts to produce seminomata in the albino rat by inoculation of hydrocarbons and other carcinogens into normally situated and ectopic testes. Br. J. Cancer. 10: 134-144. Gut'nrie, 3. 1964. Observations o n the zinc induced testicular t ratomas of owl. or. j. Cancer. 1: 130-142. Habib. F.., G.L. Hammond, I.R. Lee et al. 1976. rIetal-androge'n interrelationships in carcinoma and hyperplasia of the human prostate. J. Endocr. 71: 133-141. Halme I1. On the rAroinogenic effect of drinkino water containing inc . vital~sto-rfe. 5: ,-6. (ar.) (E:.ng. trans. Kalinia.M. G.'H. r oluh in a L . I . Lukahv a. 177 . Zlmone Typhimurium - Te=t system for indication of mutagenic activity of environmental hazards. I . Detec tionj T mu Laneni c EfTE c t of heavy met? aa S2., tS using in vivo and in vitro assays without metabolic acrivation. Ganetika. 1089-1092. 9 c . arns , . Koprd I 97? . 1ypocalcaeia. n subjects a-ftur lonI--t erm e ixp_"rLre to in >:ide. Prac. Lek. 31(5): 2- 4--237. (Suviiar'iz A i rr .. EP , M.thur, A, ,K. W&L Ienius and M. AbullLnset . 1979. Infl uen*ce of Zn on and progreasi.on of or i carc inogenes is in rats. Acta Od on to1 ogica Scand . 37: 3778--4. (Ci td in U..IJ EPA, 19D0) NRC (Natioia R e;earc h uounc il) . 1978. Zinc. Uni ver-5i ty rk P -ress, Bal.timrre 'D. p. 259-261. Porter, K. ., D M.McMaster M .E. Elmew anid A .H .. Love . 1977. Eiii!ii. z crd I o w serLlm-coppcr during zinc therapy. Lancet. p. 744, Prrsad, A.S. , G.J. Brewer, E.B. Schooimakere arind P. Rabbani. 1978. Hypocupremia induced by :inc the r-a py in a dul tI . J . Am. Mled . Assoc . 240(20: 2165- 2169- iv. re M R. , I. ChourCul inkiov aid HM. ue-iri. 159. Teticula tmors in the rat after injection of zinc chloride. C. r. hebd . Seanc. Acad. csri. Pa r-i . 245 26-49-26 1. (Fr-e. (E g Ern . Stoner,7 r G.D. M.B. Shimkin M .C. Troxe 1, T .L. Thompson and L .S. Terry. 1776. Test fur carcingcenici cf m.Ll1-iic compoundS by th pumrlr in strain A mice. -Cancer Rea. 36(5): 1744-1747. Thompson, E... J.A. McDermott, T.B. Zerkle, J.A.A Sara, B.L.. Evans and D.B. Codv. 1989. Genotoxicitv of zinc in 4 short-term mutagenicity assavo. Mu t at,. Res. 223: 267-272. U.S. EPA. 1950. Ambient Water Quality Criteria for Zinc. Prepared by the Office of Water Reglations and Standards, Wasington DC. EPA 440/5--80-079 . U.S. EPA. 1984. Health Effects Assessment for Zinc (and. Compound_). Prepared by the Office of Health and Environmental Assessment, Environmetai Cri tria and Assessment Office, Cincinnati, DH for the Office of Emergencv and Femedial Response, Washington, DC. U.S. EPA. 1937. SummarIy Review of the Health Effects AssociateC with Zinc and Zinc Oxide. Health Issue Assessment. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/ 600/8-87/022F. US. EP. 1922. Ambient Water Quality Criteria Document Addendum for Zinc. repared 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. Wallenius, K. . A. MathL'r and M. AbduLlla. 1977. Effect of different levels o dietary zinc on development of chemically induced oral cancer in rats. Lnt. J'. Oral Surg. 8: 56-62. Walter_, M1. and F. . C. Roe. 1965. A study of the effects of zinc and tir Edmini stered ora toal mice cver a pro longed period. Food Cosmet. Toxicol. -.,,1-,--- 2 Woo, Y.T. D.Y. Lai, j.C. Arcos and Mj. Argu.. 198S. Chemical Induction of Cancer: Structural Bases and i0 log ical Mechani srms. Vol. II0, Natural., Metal F iber and Ilacromol ecul ar Carcinogens. Academic Press Sn Diego. p. . -49 In preparation Not available at this time 10 Nor- e -- c- d-a Cor poun ------ VI.D. DRINKINS WATER HA REFERENCES None? SYNONYMS Substance Name --- Zinc and Compounds CASRN - 7440-o-6 Last Revised ---- C2/01/ 1 7440-66-- Asarco L 15 Elue powder Cinc [Spanish] EMANAY ZINC DUST GRANULAR ZINC - HSDS 1344 J ASAD Lead refinery vacuum zinc Merrillite UN 1436 Z inc Z INC DUST ZINC POWDER Z INC , ashes ZINC, powder or dust, non-pyrophoric ZINC, powder or dust, pyrophoric li Mananeane; CAERN 7439-96-5 (12/0 1/Q7) Healsth risk assesosmnt information on a cheiTical is incl uded in IRIS only aftetr a -com;prehensive review' of chronic to.:i~city d ata by work grouips c5.mp5Qosd i u *. L- i cen- CS-t T rorTi several 'ruor-ae. 0 T-ces i no ufrifi a m-es p-e er c Sections I and II rpepresent a consnssus re'ced iC th e r eview proceE. T other sections contain U.S. EPIA information which i p to a particular EPA program and has been sub ject to review pr oceres precribed by that Program Office. The regulatory actions in ectionl IV ray not bse based on the most current risk asess-mentC. r may be based on a current., bu.t unreviewed, risk assessment, and may take intko account factzrs other than health eftects .. ,, treatment tEc hnol ogy). When corsidering the use of reg u atory action Fata for a particular situation, note the date of the regulatory action, t h dat.e oT the mos ntrece ris aSsessment rel ating to that actic - and whethu r tEchnoloqica. factors were considered. 2.ackground inf'ormAtion and o::plan- 4 tione of the methods used to derive the values given in :R. are provided in ths five Background Documents in Se rvice C.de 5, -which correspond to Sections 7 through of the chem'. ica l f is. STATUS OF DATA FOR Man oanese F IC On-Line 09/26/25 .ateQory (section) Ltatu Ri - - ' a u -c~ -r -- ---tr ------O :ral R-fD Assessment ( I. A. ) - 0 /01/9 InhaLt ion Rf. Asessrent (..) n 12 2arc inocen. ic 'v ASess en T- I. on-line 4- -m/eC? Drinking Water Health Advisories (IITI.) no data Ul .Z-. :- HA Regul ator'/ Ac Ons i I- . no ca.ta uppiementary Data (V. ) no . L-- UNi- . -H H r.HN Hzb- i'I-NC a -R 'M N'i-HlnJ-EN LE1C-r .A REFERENCE DSE FRC--r CHRONIC b-stance Namo -- mang anese Last Revised -- 0/0I/90 She Reference Dose (RfD) is based on the tasumption that thre.holds exist for I cert.in toxi e cts k.ch a c.. ti ar nc.ro is, but may' not ci cL f other Lo. u. eli f c js c h a cs car ci Certa c it . In gFnierat . t I FDaricitE~i Wit- h - ur- rt nt spi-,ri I I per hapos an I C.d r f m-1 a . 1tude ) of a dzi , y ex|- -ure to t.he C pi r i t p. ata r I I n c Ud.~i n sen, i ti v e c ,i ti ub '1rotp's that El i y to C itout in I prec.able risk o dL1eterous effec t: curi n a I i feim e. P e I c r-efe- to La D r-oundo LArt t . a r Ver VicE Cocde S fur an u l.ra ion o theIsu concepts R f can also be derived for the no.carci noe.1c heal tI 1ffec ts of c Om[ipO. u dr.i Whi c h i re a . c arc: .nO4in s: Th e r e-fr c- . i t i s es T:r I L. i. a 1 to r - i r to other £ourLCEs of in formatiCn concern ing the carcingenic oi o Z ' e I.f thi_ , .ubsta1nce if the U.S. EPA has ea cc&val3uatCC this sLuI tEr.ce for patritial i F :r i c iogen- icity, a SuIrmmary of th-at evaluaion 'i Ii be c.ntained i cti I or tis -il.e1 S i' nhen a rev.ie of Phct cvaLation cs coCmpleed . <<'Man~laneE'e I . A . 1. ORAL RfD STUMM'RY Cri tical Effec t Expermeta Dcst UF MF fD CNE f; fEc NOAEL = 0.14 mg/kg/day 1 1 iE-1 H-iumq Chronic LOAEL = None Iqes tio Dat a WHO , I, 73 Schrceder et al , 1966; NRC , 1Ic "Conversion Factors: The NOAEL of 10 mg/day (0.14 mg/kg/day for 7k kg adult) for chronic human consumption of mangannese is based on a compOSite of data from the above three references. WHO (1973) reported no adverse effects in humans consuming supplements of --9 mg Mn/day (0.11-0.13 mg/kg/day). Schroeder et al. (1966) reported a chronic human N'OAEL OF 11.5 mg Mn/day (0.16 mg/kg/day). The NRC (1989) determined "safe and adequate" levels to be 2-5 mg Mn/day for adults (0.073-0.07 mg/kg/day) IT4i important to recoon ize that manganese is an essentia lA ement in huMan nLttri tion. It is al so important to recognize that this oral RFD iS bad0 on a total dietary intake, and this amount of manganese iSnot necesarily acceptable if the intake were from drinking water al on. This CifnYrence is due to the fact that manganese in drinking water is more bioavailabloe than manqanese in food. <<< Manganese I .4.2. PRINCIPAL AND SUPPORT INS STUDIES (ORAL RfD) WHO (World Health Grganization). 1973. Traco elements in human nutrition: Manganese. Report of a WHO Expert Committee. Teciinical Report Service. 532, WHO, Geneva, Switzerland. p. 34-36. Schroeder. H.A., D.D. Balassa and 1.H. Tipton. 1965. Essential trace metals in man: Man.anese, a study .n horr.eoStai. . C*hron. is. 19: 545-571. NRC (Nation4al Rcseatrch Council) . 1929. RercmnYdd D i tary Al oe'Wnc-, 1 J 0th d Food and Nutrition oard, Natiornl Research Council, National Academy Pres, s Washinot on, D-t. p. 230-235. he World Health Oroanization (WHO, 1973: reviewed zeveral investigations adult diets and reported the average daily consumption of manganese to range from 2.0 to 3.8 mg Mn/day. Hioher mangane=E intakes are asociated with 2 di-ts hiqh in wrhe re-'su n renrut-s Jeafv vcoetab) , and tea. iF ro n Mnvtane b- aric e Ju L E t W IC'O con Ic I eLd that 2 tL' 9mig /Cay i s adeq6t 6S f or a d u Is a and to 9 mg/ day i' perfectly safe. EvaluIt~ins of standard diets from the Un i ted States, En end , ard Hod 1 Lrd reveal averace daily intakes of 2.7 to 3.9 mg Mn/day (Schroeder ot i., 1966). Howevc-r d pfn.?pErld i ng On i rId iv i duA 1 diets, a normal o intk" e f may be e-.eni hi her, especial lv from a voetariar diet. Thee I Evel s are con si dered to be safe for chronic FLunan ingestion No si gns o-f toxi City were reported in patients (niumer rot -tspeci fir d iven 30 fmg irang.ane e ci t ra ( 9 mg Mn/day) for mn mnhuig trhe patients al so consumed 2. 5 mg Mn/day. in food, the total mana n-EctakE wOuld be apiroximately 11 . 5 mg Mn/day. The Focid and NLtrition Board of the National Research CurCil (NRC, 1989) determined an "adequate and safe" intake of manganese to be 2 t 5 mg/day for adults. Tihis l eveL was ch o-oser becau=se i t i T C LtCJes an " e trE miiarcg in of E a fc. ty roiri the level of IC m/day, whici can be considered to be swfc. -5*~ Mqainewse7 S_ ... ULCEPTAINTY AND MODIFYINJG FACTORS (0RAL RfD) i F= . The in frmatin LLEd to determine the oral RfDS for mananese was taken from many Iarge popLlations. Humans exert an efficient homeostatic control over mianqnese such that body burdens are kept constant with variatiorns in diet.. There are no subpopulations which are believed to be more zensitive -to manoanese at this level. The use of en uncertainty factor of I i supported by the fact that manganese is an essential element, boing required for normal human growth and maintenance of health. It has also been uaQQCSted that children are less susceotible to manganese intoicaCtion and may require sl ightlv hiqher levels of inanganese than do adul ts. MF =I. U<< Manganiese I .A.4. ADDITIONAL COMENTS (ORAL RfD) A Small-scale epidemic logic study of manganese in drinking water was performed by Kondakis et aal. (1179). Three areas in northwest Greece were chosen for this Study, with manganese concentrations of 3.S to 14.5 uC/L in lrea A, 81.c to 252.6 ug/L in area B, and 1600 to 230') ug/L in area C. The 5 study included only individuals over the age cf 5C) drawn from a ranom sample fbf 0'/ of all households (n=62 49 and 77 for areas A, B, and C, r eszpectiv- aut hos reported that "all areas wer similar respect to social and dietary characteristic but few details w-ere reported. The amount of mananriese in the dliet was not reported. The individuals chosen were Submi tted to a nreurol g;ical ' rramination the score of which represents a -omposite of the presence and severity of 33 symptoms (e.g. S 0 it i Lrbancr r.- mors. dytonia) . 4hole blood ard -air Qanoa.e;= c C ceFn trattions were al o dl Ltermined . The mean concentration MimZnrI ne iS a.ir wa.a. 5 1, .C 10. ug /n dr we.'tfraesA D9 Znd H9 ,ad esp tvely ( for eaef C vs. However, t - concntrati-an manganese in whole bzood did not differ twen the tnre areas. Thee (x) ' nd range cr) cf ne urlog0cores i we followc: Area A. (males: =2. 4, =0-21 ; emals: =. - both x=2 r=0.-2 1 Ara B (m ral? x1 .. r=-6 femoaes: x ; both =.9, r=- ) ; Area C (:ales: x=4 .9 r=029; females: x.,= both x5 r=-29 ) . Whi e there appuears Co 3 ae n o cncres i rn r ther loguicSicaslscore, thi.. di ri should c e in epr eec wit cm.i C. Th authcr-s did not r--ovidme an )ri di vidual dis -. arid the~ large( rnne foGrfeales'i areaCi £3 ind:Icate2C thi~t Li s2.igl i ouilcr ni.;y hae hbe1 n re s ponbl L for the inc rea.ed :1Ea.iK T Lienho Tlen sico' ~e f or a. a r I ANas :icU tul U y LwE'rt.han thIit in area A. The authors irid.iate that the di f fereE::lce in 0 llei E corS fur are.a C vs. A was gi fnca ct FeosEd kMann-i Whilritts z'-2. 36....02 for hoth C C.E combjjrled) . Whil e this firidiign should be ackncwledged , its sign ii c:c:e, part ic:ular-ly with 1rgArd to the concei t ra :ltion of m a n in a , Jc[A drinkitng war, qe inabHe.. This t udc]y ha siE severl 1 f Ilw mo n st. no a b2 y 3.) t he ma l ni mL.:.b r o f iri d.v idu l t 1 tist cd 2) t- :ac < of retter- data; 3) LIe 1ci. 0 irfIOtiltior prciclod n c 7.-%1i aL and c't h'r dietarv and dri nking w t f actCor-s; 4) t-his stuldy cry not have ben truly fnbiFied becatuse the examiriing nIurlists were isted ai authors of i ho paper. In summary, thi Stu dv rai.S c-r some que tin.c a1 o ut accepta ble levClS of (mng a nese in drink inig w ter , but i s iinadequat c e t r v &iiithe batis for Z7 separate water RfD. It may however , serve to c-aut ion risk aS1Esesora agaIn Lt using a ttil oral Rf) ( bLscd princ ipa ly or di LtEar, in ti ), to EStb.l; t iiE h ain acceptable drinl"ing wJater coFcentratLcin wi th:-,t taking iLio C:SideraionCI3F ±issLues scnh as dift terential &ibsor ptiOn. A re port bv, KAL.vaaimura e t a l . (1 41) Jc ribed tcxi ci: ogi c r ez pL)oes in hn.tman cOisumning 1argE EaO-unts cf imainganese dioved Yci ln drinkinCj watr. Th sIorc& Of the mangalese cam7? rom about 400 dry-cell 1atter whxi were buriedi ar a d i F i ng IC i wa i ter wll ;1 Eixte i C; cs f o ma . n r acw1;..tSr-, pro iring WerU reported, with symptoms inca Ludiing ietarg, inc resed mu-gcl tenus, L r tr.mor aId miAentaI disturbanices The most :evere symptoms were seen in elderly people, with children being affected ta 4,lesser oegree. Three individalS died , one frbOM suicide. The caui of death for the other two was not -eported, bt the autopsy of ore individual revealed mngnanese oLcentrt ion n the liver to he 2 to 3 times hi cher than controls. Zinc levels were so increased in the liver. The well water was not anal Vzed until rt 1 month after the oLtbrL:ek, at which time i t conta n ed ;. pproxinmatol y 14 m Mn/L. H cwcver. when re-analyzed i month later, the levels were decreazed by about half. Therefore, by retrospective extrapolation, the concentration of margainese at the time of exposur--e waS probably at least 2e mg Mn/L. Assuming an adult body weight of 70 kg and a water consumption of 2 L/dv, this would be equivalent to an intake of -mg Mn/kg bw/day from drinking water alone. While there is little information concerning manoanese poisoring in hums by the oral route, there is a wel 1-documented association of prolonged inhalation of manganese dusts with psychological and neurological dis=rders. Several 1-oxicitv studies on manganese have been performed in laborat-ry animals. Most of these have been inhalation studies, demionstraing anE fftct on both the brain and lungs. oeveral oral studies have bee. performed in r cdentS th;At dmonstratecd biochemical changes in the brain fol 1 owing doministration I mg MnCL2-4H20/mL in drinking water (approximately 3 9 Mg Mn/kg bw/da) ( Lai et al . , 191, 1932; Leune a l ., 1951) . However , rodents do not exhibi-t the same neurological deficits that humans do fol lowing exposure to manoanese, so the relevance of these biochemical chances has been chal lenged. While primates are considered to be the soecies of choice for r7-de ing the human response to manganese poisoning, only one l imited oral study has be'-n performed in a group oT four riesus mon'keyE (Gupta at al. 199.) Iru tScul ar weaklnesa arnd riclidity Cof the ILwer 2limbs, deveslo pd a-f ter I Bonths of 'xpfOSire t o 6. mg Mn /kg bw/day as MC--4H2). HMi tlogical n i howed2 degenerated neurons in the subtantia nigra and scaint'nuromelanin cranulCE in some of the pigmented cells. Manganese ,> 4 ... 3. CONFDE ENCE IN THE ORAL R D itudy': Hiqh Dat B Mede2: i um RiD f: MLediJum ny tud i es have reported siml. 1 ar f inrdings -ith rega rl to the noria l intake o mianganese by humans. The se data are c cins.dered to be ieup'erior to a ny data obtained f rom animal toxic i tv stud ieS e p e I J y as the phy iolc) Ciic reqLIi reEntrrt's for man ganese' va-. quite a bit among diffr.ent tpcci, with myan r equi ring les than rodents (Sc hr,'oyCer Lt a. , 19 66) . It is again .mphasized that this oral RfD is. baced on a total dietary intake of vangaiqanese and is not in tended to Le LFapplied di rec t ly to drinking w at r. << IiganeseD .I A... EPA DOCUMENTATION AND REVIEN DF TIHE ORAL FcfD Cource Docum-eznt -- This aZsssmnt is not presented in ai existing U.S. EPA docur|1ent. Agency Rv D Nork GroUp REview: 05 1 0: 0./ 1/90 Verif ication Date: 04/21/90 I . A.7. EPA CONTACTS (ORAL RfD) Sue Velazquae- / ORD -- i513)569-7571 FTS 6B34-7571 jUlie Du / 0DW -- (202)362-7593 / FTS 3S2-7ESS _.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- ianganes5e LCASRN -- 7439-96-:' Last Revised -- 12/01/90 The inha-.l.tion Refe renlc e C o nration Cnalocous to the oral RfU and 1 ikewis baoed on the assumption that thresholds -xist for certain toxic effects such as cellular necrosis, nut may not t for other toxic effaecs such as carcinocenicity. The inhalation RfC considErs toxic e4fectS- for both -tne respiratory system (portal -of-entry) and fr eFfects peripheral to the respiratory system (ax trarespiratory effects). t is appropriately epresseU in units of mig/cL.m . In genera, thmaRfC isa etimat ( .i unc&-rtinrt.y span n i ng perhaps an or-der of .agnitd) Cf c di ly nha tion expoaure of h y hurmaLn popuIAlation (inc=Lding sensitiv subgru that i- li'el- to be without an appreciable risk of deleterious effects during a lft are der ived accordi n to the Interim M ethdc fr Dvel opmErnt cf n Reference Doses (EPA/0C0/9-39/066F ALgust 199) developed . EPA scientists a&d peer-rcviawed. For more iformati o dn thc - a iture of these methods and future plIn* See the INFCM]RE Section of 1RIS. RfCs can also be derived for the noncarcinogenic health ef fect I f c'omunds which are 3 r-cin en . Thr-IEor it is 7- %r-:ilntu-c to ref r to other- .oLIcr- cf ni-rit on c(iC ~ ng l c rrc nc. c rii. c:'t.y oi t h ctSubc.t.ds . If te Ui. - as ev.1aluaed t ii Lu talcm for poen l- a] caa rcca i rg en Ic i ty a su i'ifair C tat tlie]) ttt i i 1 ho CDUI".t: TL:d in ti'ri- ct E,f this file vJ ie'ri a i- L-, L-J Cf that eva uationiiS comp I eted Man aan ee I . .. I NIALA2TIN R f C 31UMNiARY Critical f fect E 1fposure tA UF MF f Increased prevalence JIEL Cnr.OCEJ of respiratory C:UqI symptoms and psyvcho- LgEL ; mo/cu. motor disturbances A'EL C2P4 ficl/CL.m LOPEL ( N E CLU.n Occupational m/cumC? to inor L ininanese Roels et a!l q 1987 *Conversion Factors: The LOAEL is based on an 8-hour TWA occupatIna1 exposure The TWA of total i rborna manganes e duSt rainged from .7-.1 mg/cu.m., and the median was 0.97 mg/cu.m. T his is a respiratory an extrarespiratory effect of a partic la ex POSLIre. IMho = 10 CLI . M / day 20 cu.m/day. LOAEL(HEC) =: (:. .97 mg/cu. m x (Myho/Mh) x 5 vdays/7SS = L.324 mg /CLk .m *Maninanese>> I.B-2. PRNCIPAL AND SUPPORTING STUDIES (INHALATION rfC) Roel, H. F . Lauwerys, j-P. Puchat et a2. 1997. Epidemiol oic aL Survy among workers exposed to manganese: Effects on lung, central nervous cvsy:em, and some biological indices. Am. J. Ind. Med. 1i: 307-327. RoeIs et al. (1997) conducted a cross-sectional study in 1411 male wor:ers posed to manganese dioxide, tetroxide and various salts (su late, carbonate and nitrate). A matched group of 104 male workers was =electecd as a control group. The two groups were matched for socioeconomic status and background environmental factors; in addition, both groupa had comparable workload and work shi-ft characteristics. The TWA of total airborne manganese dust ranged from 0.07--.51 mg/cu.m,, respectively, with an overall mean and median Ofr1.33 and 0.97 rig/cu*m. The authors noted that there was an increase in production between 1965 (440 metric tons) and 19S1 (22,000 metric tons) and preLuiiably exposUYr-e with 7i. '5 exposure , parltaS-Lv Yor ndividjuals wVth long employrient durations, may have een lower . The duration of eanploytnt ranged from 1-19 years with a mean of 7 yvears. The particle =ize and purity of the dust were not reported. Neuroloical exanination, psychomotor tests (simple reac tion timie, sort-term memory and hand tremor) , lung function teat (1 orcCd itl capacity, orceC expiratory vc.lume. eak ex uIiratory fl ow rate and maximal expi rato:ry flidow rate at 5 and T : f the FVC) , biood and urine testS ani d a uestinCna ire were used to assess possible toxic e rfecta or ma-neCse epu. The questionnair e was deEied to detect ONS and respiratorv nyptoms. Concentratron-response relationships between length of axposura or urinarv manganese levels and the prevalence of abnormal CNS findings were not observed. A signiificantly hiqher prevalence of coughS during the cold season, 6 dy'p! na durinL: eiCIe C, and recent epIsodEs cT acute2 br-oncii ti s were foLniC 2 th ! xp .ed gr ip Lr, vtr ti , atto ry par 0;ateY- rs we r.. I C ni y ;l t1eed zi n the e;posedi smea:r . Siqnificant ate raations iere fourid in imlC eac Ci ontim v iual ), audi veb.r b al shi r t- te- r ri, uom ry teL.t, ey e- iA n co o rdinatio n, I and Iadr * tEadiries tes; t in the workers exposed to mancanese. In gerieral , this study is Adciriate to cFr ve a risk acss e ssment h o wever , ucr t aj r i limi ta t o ri houl 1 be noCted One shcortcomiing s the I ack Of ad i LStmEnlt for agJe in the p omo t-,r mea r LI . g o en tanda rdi :- tio t waO use in tc? ho rt-- te r m mE'moy t- V ts k, but not in hIe t asures of reaction tiire and tremo10r (hind steacinr and I ey:eIII corir ... ).owev e . ['ce the mean aigce o-:f the cnrtrol o-cjO ?p was higher than ta-it of the cxposed croup, the I ikely efect of a I ack ofr UG adj Ustmenrr t A t o uirieresti mat e the rf fec: t of mrangcanee - Anot he7r 1 imi ta iol of tie Roes et a. study, was the lack of correction for mul tiple tet S. Differences between control and epoed groupS on r'eera nrob-havi.rC] meaSuCres were assessed with simple t tests or chi-squarn tests. W ith alpha = C.05. one in tw;en tV such tests CoL C1 be foutnd staitii c al. y si gnTiCficat. by chance alone. However, it appears that this perce-ntac was well exc eodd, 2.g., 5 or S reactioi time CeiCstu rES were- sign ificant and 7 c f 11. hr -te a-Tmmory measures vre Sig'nificant. Thu, thee flaws in the Rools at al. c Itudv do not ap pear to compromise its Uti J it-V for ris a eccment pu:rpo)SJE. Lased upon the icre-ased pschomotor disturbances, a LOAEL of 0.97 mg/cu . M was iden tified [where the LOAELj(EC)= 0.34 mg/c .] ,hadr et r al.' (181 exain.e d- 0wedr fro~m three nEpartepns 20/plant) xposEd ti m2ng-nese fUMEes. A matched cCnt-Cl groLp Of 2. worlErS was aloexamined. ~-J5I Th e aVear ag1eSIIS l e ngth o10f E.m ploym De nt in1- pla t w-L1vjas z1 yei / arI ., with aomangEse level of 0.24-0 . mg -Q/Cu.m (mean = 0.31 cu. m) in the breathing zone. In plant 2 the air concenrtraion was ..-- U. -0 mg/cum (mn, - 107 C U.m , and the eth o "f eposure ranged from 2years to more than 20 years. In piant 3. half of the workers were employed for less than 10 years * and the-o-Eher half for- more- tha n 15Years. Tne arconcer trat ion ofmnare was c.*@-2.6 mg/cu.Fcm (mean = 1.74 cu . m) . The manganese compounds and the presence Of other compounds in the fumes were not reported. in plant 1, the workers complained of frequent occurrence of colds, cough and-o short '* hyperpyrex i a. The workers of al I three plants often reported insomnia. No other subjective effects were reported by the workers in pl ants 2 and 7., No nhmatoRoical71e .a m1oalterations i a1 er-tti ns:;v,were -: eob observedder-vep in re hemoglbin.l hE:xes Ic i n th RBCicsadosIs and WB'C coun ts. Positive neuroloqical signs (brisk., dep reflexes in the qeg; and/or arms wre observed in 25, 50 and 45% of worikers in plants 1 2 and 3, respec tivel v Tremors were also observed in one end four wor| kers in p ants I and 2 espectively. No positive ne uro l ooical sions were observed in the contro workerS. Ilthoug h sigqni f ican t effects are reported for "deep ref xes" and tremors" it appears that these endpoints were assessed through a non-blind neuroloi cal examinaton. If in fact the examiner was awarE of a su ject'S Exposure condition, then the results are questionable. One may also quest-on t-he sen siiLiVity of a c liCia nEuro l og ical e xamInation for dutectng r-- tj cul b Ce quite subtle neAurotoxic examrination for d. tectin g what could bE cite sutle neurtoxic effects. The findings of Chandra et al . , may be viewed as Supportive Incr eased -serum caLI I evels and urinary mangariese levels were also observed in the welders. The calculated LOAEL(H4EC) from the mF-an Sxpo5Lur lan of pia 0.11 m u . .. Personnel thatwere most -xpse were selected from two Swedish foundrie 15 from ea.ch plan. ) for 1incluion'n a scudy reported by Iregren (1990);. The n ex-posu'1-.,re o ma g nCev r e f o .2-1. Qg c~ (Ean=0.2 mg/cu m for -1-"1 l M 35 years (merinr- 7 ears). E ar li- exposure meas 'u rements made03 in bot 7 :o ~ t o r mdiac u., - hce art-iezl - 0; L Fr. Z, T*. 1.7" E., E1eia -, :5 c/C u or V- ac tories in~dlcate that ther wmer'e' essenti-a~11v no chanzjes irn eic'tr .actry or the past 1 F yearS. Ex posed wor-kers were matched to two workera no exposed to manganese iron other -r for ag., g r c rea and type of work. Evaluaton for neurobehavioral funcion was assesd y 7 c c ..- d :e Fr' a i he SwCci eI Forforn ce a) uc.)a I ".e :CjFI and 2 IliCnuL t dextr -- ' . Af - - furt! kEr ad, u sLTmCe rt for genr C l cr. oi lIve ab i i J react ir: ime. mhe standard devist:in of rection rrie and fing r tapping pd of h r ma n u r t anc . T 1nrerbeviral d'i ff erec b e tIween he two DUp rmind , i tic ally i q i f ic ant eve n L-IJn v erba i test score were used a L aL c t.; e eie. ! 1 C. of t h. refe ren c e gr coup WaSt reLidCC to 30 woe-Ers whe cn r) tro I I ed for ap:pareit difforences in cognitive abi Ii te (the nuMbl 2F Of Ep 'o sed N L[ w ires d id no Jd C t c 'h ) . No si Qni fi c ant c or reai n w.: aIs w i t h in t h E: 1r0 , - ions-ip. e LDrAEL (HEC is therEforE cLlted to 0.7 :i u m CLi il Th is tudy, long with Chandra e -L . (i 191). provide a pattern of n1 eurobehavioral. effects of ow-] evel occupational manOanese exposure consistent with that reaported by Roels et al., 1987.. Mang nese r > . I.B.. UNCE'TiI NTY AD MODFT YING FACTORS ( IN ATIN Rf C I-LIF = 3L0. An uncertaintv factor of 00refl- ects 160 Lo p rotec s enS ind.ividuials and 10 for use of a LOAEL. A additina ictr C. I f a' u'ed to account -for the lEss than chlroni CprlOO of exposure. I. N F - 3 A moifyi i factor of -; in Lused to account for th-e uncetinty of! W xpsure to manganese inh the principal study. During the expoEtue pe riod there was an exponential ancrc.ase in mangianese Lae4 and production withot * accompanying changes in the plant proce;sing area t is therefore asisumed that ambient manganese concentration during the exposUr e period was ow.r than ta measured at the time Cof evaut 1 Lion of neuro lo gcal symptomi :rice the- eXp cUre cannot Le quantitative ly evaluated, a m oEifying factOr Is ed :I *<< Mangarese> .s.4. ADDITIONAL STUDIES / COMMENTS ( INHLT ION RfC) Manganese toxicity can vary depending upon the rou t--e of exposur. "hen ingested, manganese is considered to be among the least toxic of the trace elements. In the normal adult, between 3 and 10% of dietary manganese is absorbed. Tota 1 body stores are then regLlated by a co-mplex homeostatic mechanism involving absorption and excretion. Certain Surb-populations such as the elderly, children preognant women and iron-deficient individual may have increased absorption or altered clearance maechanisme resultinc in an increased potential for excess total body manganese. As detailed in I .A.. and I .(A. 4. toxicitv from ingestd manganese is rarely observed. Undarst and-!ing the inhalation toxicity of mangase requires consider.tion Cf particle doci-metry and subsequent pharmacoki+netic events P Fartic siz wil: dete'rmine the site of deposition in the respiratory tract. bsneral ly, in humanfine Made particles (<2.5 microns) preferentially depcsitL in the pmn-r region and coarse mode particles (>2.5 microns) depC-it in the S ach eo br onchial and extrathoracic region-. Those particles deposEiting in the t horacic ard trachecobrorchi aT regions are predominantlv cleared by the - ilirv eccalacor into the gastrointestinal tract where absorptin wi 11 be it low (abo1ut OW) . For maigoarse , &n eter poss i il tJ ±y CEi StS b rf report (Peri and Good, 1957) suggested that annther eavy mtal al umnum, wa t c transpor ted to the brAn via n as olfactory pathways (e, f or: extra cic deposition). ne could speculate that this pathway may pr . or manganese. raising addS tional di i. f ticul ty in understanding tre dosage. Particles deposited in the pulmonary region will be clered predominantly to the systemic compartrnent by zborption into tc, ro d an 8 , vlymph c ircuiationi. Fr all t hehe factors, j k a(Iu' .n-- 1C. Abrtin f - partrics des:td in the pul monary r-eg ian, r ecogi i r t at t h i s iQ;oI-E ' t Ir echrreLc: ar- iS that are l i:e.l t occur- t some un i quiantLi f I id i eg r-F . Un fortIuae y the lea I effects dat a base on 1anganiese ces riot. in Fc lude ihaaton pha rmaicok Ii t ic: E on the imi.j or Ox ides of mariganese and the cri t ic cc-ipa tiona st..ui:r did not meSure parti c l e Wi.e or e. pec iate the fmZrqartgE5E id a.e E: InvlvIe d. Thf.isT p reu-v enrts quat -- i taL ,t.ive d e t er..I m in at-.i ons uof t he doC.seC. e Iver ed to the rIe pir atoryn tract and etirmates of taract s ite de. T-ir a re no quantita t1: ive data on the i -a I lation absorpti(::on rates of thI differint iang n se com.ipoLiI (Ui.2 , Er 1 4) ( Uina Ft al . (19 9 . I ) n..iEr2ed o L di fference between the absorption of i mic ron par ticl s of nC 12 and Mn J, 20,. Hoiwever, fol lowing in tratrace insti I a tjn of Mn 12 and Mn304, Le [h i Jt-d cleared 4 times faster than the oxide from the lunIg. After 2 wek , imilar levels of manaanrese r einiir,ed : n t he un Li (Drnwnr et l. 1 E 986 . In g iC ra respiratory c earance is faster for c heincals with greater water S Qol.Ub i li. The potential for respiratory syctem toxicity typically is less chemic with faster c erarce. However, water sol u bi Ii v cannot a lways redict respiratory tract cl eran cC since cellular mec hEi iTismscani rev:c'Nve rel ti vl in olLbIe par- ticlEs from the respiratory tract as rapidly as chemiCal dissolution aid absorption Faster brain maiangfl Fiese &l Imjin tI tl -t have been reported in monkeys exposed to manganese via intravdnous or ubcutni inec tio n- r (New I C cilind 2t a., 1787).- It is 1suestedi that th e lwer rat fdin~ L~c b'rain nicnganieLse fol.owing inha)ation procaJbly -e fects replerishmient fromi imanmga nee depositEd_ i t organI, pr. the respiratory csystem. The issuie is further confoundEd since anm Rf C culd only be developed for m--anganese rather than a spe-cif ic Doxide o: f f. man -gne Le. Total manganese exosur5 also becomes an issue because manganese is an~ EQssential element and oral exposures occur. it WoLLd be desirable to know the effective target site doses and aoortion the dose to both the inhalation ard Oral routS Of exposLre. However, given the lack of data regarding both oral :nd inhalation pharmacokinetics under environmental conditions, such Ouantitative apportionment is not possible. in any case, the absorbed doses estimated above are not identical to the targ et site doses. although there is an unmeasured r atI oni i . Un1t the d ata specified above become available, we are left with the conclUSion that ertain inhalation exposuresE such as those in the usccuaEtiona l studies , c auce adverse effects and the NOAEL for humans h as not ben experimen tal v defined iews could differ on what constitutes a NOAEL and a subt iresiobd level wnich woul consider the r-ange 0f usceptibilities in the gencEral populace ad S uncertainty factors have been applied to- account for cetr&apolation issues. defintJi, the R fC is not intended to be an aolutxly accurate value, - i encompasses an oroer of magnitude uncertainty. However, it iu bUasod on inhalation data. To take an oral N"AEL level and extrapolate to !naltion evels. without knowing t-12 quantitttive pharmacol:inetic ralationisb nd inhalation exposures , as G-Ss c i entific val idity . Chronic mangnese poioning in workers has been recoignized sine 1-E7. The primary effects as oiated with manganese toxicity from inhalation expLure in human are sign and sym ptos of NS toxicity (mananis m and pneOnia. Mxanganism i 0VG eevd to resut from disturbanc-s i the extrapy ram~ida. motor ay'-n. Canavarn a-t al. (1934) repored th- ccrence f diffuse c--llr changes i the cerebral ortan Leeb lu gnri of nerve cel tl i and gliosis in t aa ganglia in a mangan ese im iner. The observed CLN Itoxiitv can be divided into twc stagec: a first is dominated by psyc hol ogical disturbanc ec that suoside i FangUbSaes e exposure is termiated the second is predominantlv a neurc.logical dCt urbsnce, which occurs wath continued anganese exposure and is not rE. M, i E F 4angtanese 9 t-s .e t -0b h e e f ci .- r._Er F -:- Q % 'n E..lLw c aC cny h-1.iCCrirlc e eF -f C c-lnt.'C.:. m a -bao aj v l f.-ICre aree s L-ibol e ofic theKo ib . 'I ier tb ILvC 4 Z., i. er f i n t j L.: -Ii II , C! r i ..'i FP [i - I(. - dL[C- D TC tdT: 1 IICE yIT p I: I ex f posu r e i S c c.ii -d. 1 l U e pee- ch and Ca.i t d i sturb ati. ,L trr-. r t0 k- : fce u kotural :itability 6:'Ihoti onl iribtaii 1 tty and hal l;t jicnYaa.oIV .iay ccr. Nuerou investitr have reported NS efftF i. rn wor : ers exposedC- D.Lo Cangenet:.9 du C.1 o fumes iH aw and haur 9EI;Ch-andr-a c 1al. H1- Co al 1 Em r a e t a 1971 Fln Jt al. 1941; 'i r n, Y 0 d 1i I t .t 1 7 Citi A: a t.al , 17/r.: cina-ka and Liebei , .1,--I ) ., 2I- c'tllOIgh i ! i an exhte vi \' udI brL::::.' ovl * os ef fects i nrk er, 3.imi taon i-I i..h' s-tudJ e lpr-c 1Ltdc dLcrbinC3 s qLiafn ti tative doe /rsponIs:e r el a I i i Fe&sieat Mangae e con trations ar e: ote n preserted as a broad rEAagI &nd pa Itcle size disLr ibuticn arid/or c.hemixcal characterization is not reported or adequtee. ly charact Lri zcd. lIn -add i ion the occurrerice of other chemical. at Ihe fctory i ften not eported - Despite the 1imitations of these stLudies, they do provide inform''ti for identifying can E--ffect lev'l; pychological )ir-c - nd/Cr nroLgticl di st urbances appear to b' assUocftiacd wi th l ong -ttrm d ' th: I xposu r toe l. evel 1 of rngnecedin 0..25 mg/cu m ( .I adaw/'J,' and ShaLkkour , 1'94 Chandra et l.. Ls a. (1 A85) repor.d th- relts cf a fertfi iti quStiCniri q i& adminisrter-ed to ire -;act:r workers (n-=8) expoied to mang'nese LuS. i' WaS thE Same ppul 'Ltion of wo:rker for which RoiLs et al. ( - ,port increa ed preval ence of res'tpiratory syTiptors and psvchoctor d i c turb anc The range of manganese leve l s in te breothing aone wa S 0.7-.1 mg/CL/m. with a median concentration of 0.9777 mg/cu.m cs. The partice izE di-st -. ribi as well as the presence of other compounds was not rtd C-.!;ver-agr z; u gh iL' of exposure Was 7.9 ye ars (range of 1-19 years) . A group of wor-r 'n=a- with a similar work load was use as a control gru p. The numr-ber of births xpec ted durin g different age intervals of the workLrs (125, 2 6-45) was calculated on the basis of the reproductive experiencef the contr'L employees during the same period. A decrease in the number of c 'hiren m orn to wori:ers exposed to manganese duS t during the agyes Cf 15-25 dr 2-- w observed. No difference in the sex ratio of the chi Idren was observed. ihE -ame apparent LOAEL(HEC) as was identified in Rols et al.. (197) for psychomotor and respiratory effects is iden tified in this study for human eproductive ef fec ts (0.34 m/cu.m) . Workers exposed to manganese dust have a higher incidence of respiratory effects. An increased incidence of colds, bronchitis and pneuIornia WaS reported in wor:ers exposed to mancanese dust (Lioyd-Davies.. 194; Lod-,y@- Davies and Harding, 1949; Roels at al., 1.37) and _unior hig-h school studznts iving near a rromanganese factory (Nog awa et a., 1973) A S di s-c -uZd in egard to the CN3 toxicity, the study l1imitaEti2na preclude 1 he eh s tb-i shmnt -i a dose--r eSponso rel ationship. Si-mil ar rcspiratory effects wer 1i observed in animals (Lloyd--Davies, 1946 Lloyd-Davies ano Hardin, ; ShiotSuka., 1984 Suzuki et al., 1273). Other effects observed in huans inludenemnatologicai (Chandra et al., 191; Fl inn et % ., 1941; i c an HauIS 1Ir, -9 .), C:arliovascula r Eari C and HrustLc) and I -Epr DucLti ffec (Cook t al 1974; Emaract a. 1971. Lauwerys 25 et a l .195 R 1E Work e Er ST ompyed in thre diffrent factories (30-3D5 w Lkrac a -. ma-".cnd controls bibere s.anined wor neoro-ica ano rs-c & i-' sea ation s (Da. a ahakOur. 1d v 3) . The mean c:oncentr ailonso atmpheic manganese for the thrse plarit were 1.0) 3.C, and 7.0 mg /cLu. Th fpecific manganese compound and other contrI!iriants we're not r EprtI. n 3 increased incidence of headache, involuntary movements, ft i ue and Exhauion.. sleep disturbances, siaIorrhea, sEborrhes, Spech disturban tOce?. 10 gait d t is tLirbance, xagrcr ated refle;E , depr:.i or I lScinatii ,C < d 3rC'1 Ciged reactoir time L':.-re obhEc't-ved in Nor I:e-r E ' C:.-d to flcAriCci! iE:.:tE.. The' i Os t c oCmih3n e f fe-c t vere ;A o C dc , inv .ol un tary ru 'mDVen f cit()u1 u a ri e-h 0 t I. o n. I r c i ci ence of hea i ches; nj. n vol 1 un ta. ry' niC.vefC-n tS ; CL t.L ban c e-b . le p~ech, and gait; and exagge--ratedi reflex e r ee nirifficart 1 V increased with i nicreasing durati or i of empl oIyme'n t ES i I2 fI can t efc- ts w er? O.bserved in al l three plants, thereby indicatini the a e'LEL of 1.0 mg /c m in thi E Study Concen trati on- resporise re atio nhiE.S pe f or the in cide-ce u 3 ivI LI tEy movemets, speec h disturbarcei . gait disturbanc -nd 1l..cinations wrebErved.lip corr lEtion betweenm rC bJnod L ng] ne e i u c' e, level was observed. F rom thee d a A L'EL (HEC- I of . g/um was calcul ted. Ngw. (1973 ) cen-amin ed the possibij that hc z-i h c: :;mpei c manganese levels W cLIoud reSut i n respiratory ef fec ta in jun or hig I zchool Stdt , qLeti onnairce concerning subjective abnormal i ties in the eyes. arLI throa t wa distributed to stIdents. attending Junior high school th a were 100 m er13mEnt=1258) a3nd 7 k (entrQ rolIment Si -:=4) away T fro a ti tt primarily producId ferromanganese. The authors did not not e soc i C.eCoomf ic -ar iaiLlcs were controlled. The cctmcospheric mancanese lcSVel 100). m0 frof: the pln was repor ted to ho c.4 mg/cum. Levels of mnganee in the a nchon wer e not meatreid..rci In aCdi tion, the author s did not atteipt to quanti.fy the Tiounit Cof mang-aes-i thle cild urn were eposed to whienr t heyLt were not. in _ chonol. Othier !avyZ E? tal r. c 1Lu d j.i ng ca.id'Cium wue*re Ft presen t but only manoanSe'nd iron levels were Iigh compared to other cities. Over 9 2 f the studentz Dcmpl eted t: e que tonnaire. A mong the male students in the schoc1 100 m awa' frm the plant. c significant increase in the number of LtuJdet't reporting each of the fowing symptoms was observa..d -putUm a-y in the owinter n arising, clogge neJ nose, nose colds frequrntly in the umm(rricr throat svmptoms (swel 1 ing and s0rEne s), P ast hi story cf s inus erpyrema and an increase in the number of students with familv members having COLghs and =putumL. lasting for longer than 2 months. In the female students 100 from the plant, the incidence of clooged nose, no=e co 1 ds and throat ympEtoms 7in the win te-r was increased. Whern the meai and female students wer? CominM d , a statistically significan L increase In the incidencE F eve :y(mptom and past history of pneumonia was observed. Among students enrolled in the S.choo cated 1i0 m from the plant and living closest to the li ant, more stLkdnts reported hroat swelling and soreness in the summer and past his=tory of Pneumonia than did o ther studen ts. The pulimonary lung function tests revealed statistical ly significant decreases in vital capacity, forced expratory vital capacitv at I second, and the 1-second ratio in the 'tudcnt& att-nding the zchool closest to the plant, Of the students l iving (50m 50-1000 m or uuuC-15Cuu m away from the ferromanganese plant for r.yar, the lowest 1- second ratio was obser-ved in the students iving <'0 m 'way. Distance of residency from the plant did not influence the 1--second atios for students i ving at the pl ace of residency Tor -,3 years. Th -cond rat cc n ce students ivinra <50 m avray for <3 years was not di f erent from th con trc'l1 -tudents. Thee dat-a uggest that a concentration-duration of c? posure rela Cionship may exist between manganese and pulmonary efects. The m -OEL-(NEC) c-al cula td from 'l-lis study is AE-3 mg/cL.mr. n increared incidence of pneumonia was oaberved in men csmplyed at a Pissiu prmanganate manufacuring facilit y durino an c-year per i-o ( -n= 4- L~~'t~cC5 cor.=n wit-:h a con t0T ofu -~res ~.>v.U 1 T1) The ievels ofcanca-ese in "Ee oucr an)e! rain -..----- ' cIt c'... C CT whicl h 4Z--5/, r espeCTiveLV, wasmanganee oogide (a.-4 o rL.cuvm, 13:,..2 m g Mn/CuLk.m), P p roxir7) el G. Iv -D % of t o p ri cl s wer I0. um WInd n 1Z."I !early l I oee L1 iaum. The rajoru e not iclued calcu and h - r e& a lS oD d Ete C t e d in t he a d 'U s . T m ; *a r iu (1 ) 1n .1Z SO d Iu mL ( 0 . % we po0tleve a Is s s oTfi-;u c a 1.clutm an d poc)ta-ss ium i n t he duL we&r e no r2po rt ed. Trace Cmount 11 £ofai l a, iron ano .Li thiTii N- al C' dtit ctE'd . Tic in .d nC-3e o- p.u'o, 'a n thi workers was -. pZrL; C0 C: C.mprr..,d to r Average Of .7C per 100 in U-. I t r i CjIrt up. ill Cc.e "- ee H .. A di octEd I e o ar or ht ur c: ho;: E u ona. r er-s alNU compfaIF inied cf brc c: h'ti h arid ra a L c i'" -i t.J ion. In a continuo ti DI. of the LI cnCiavie's (19iS) tu iy E 6loyd----Ivies arid Ht-Ltd ri (1Hrdn reit- tcd ti rEe uL t5 0f SLu tum arid n) ax :pharnx cu tLurei for Fou r m[e n di ai -i' i as a v ring * - -. 3.10ba r or bir:C i-loj.rlumon i. * i ine Cxcep ti-ri cf oLk of t E he E - .. .Iod-- Zav.'ies and Harding (1949) conclue Lhat it was uik y that bacterial inf ectijon pl ayed a prirnary role i p rodu : ncin th.e c on S o id c. p Zr ri li the * iLtngi and that ianIga ese duaL , -N.i. t t t L tI' j irse c~ 1 f o rli ~ factor e - c aausdc - u thie observed *1-- r-IrSLIiorni.tias. LBas~edn up. r- f hi e ViC!Q Uof E 'sur a to n'rar.i.'r a U' - mcm.2 .i ) a L (I-E)H.-S ).7r-ange o-f mq/ct;.i ai be e-t: m7ed- . SAri . (197 exaxrnired i wrkLjrIs .ia ferro ll p t. WorQci- in two other plants (el ectrode pa Ln, n:1L1; rn iLi rol iing mill, =r-20)2 erved as coritrols. The ferro.l.2 D1 o iarit L worl::crs were exp~~--i cc U. -j t1 mICi . m manianese ; thR c1anIuanese lvel- i n the elec ode a r rnd alil rc 1 i)[ ill wrg./Ouwere - 1- - (1.03 . li n uCL.t"i -. UUU U n/ Li uIM re pec- :tiv eIy. T he waur. : : wer EFCo'.po d toC.L eith i- mangar. n es u.t :Z ~D F um_ The-ianganese coMpouni or C.oi Oi.nd h t h he wur TrF Wre r pCL- 0o ws riot reportd. d f signi- Ticant increase in t -e f olr lw iig Sur r:v Gym-oms wat cjbserved in the fs-rrua loy p1 aLn t work fa1, ErtCgue.i C bd m2O , r ritCbii t y arid r=nod Irmr . One or more sign F ?) of Iii-4i-Fi neur lo ical rim.)ca C i n i:t me1. gj . .,I eQmfr ptoo gi. cal r flxi was obsesr 1 J ' ave-d in 16.8 tanl ri d 5 IT of tIh: w-orr in, T. ferroal ly plant and ectrode plant, respec:tivy - H signif icant crceaze In SyStol ic blood pressure -i tho ut a change in dastolic blod preasLure Wor- a) so r-epor-to in the ferroal lay plant wor:rr 1.Saric anGd HrustriC , / ) r -- id Lucic-alaic (.L77 7 ) reporte r nat in these rouiS of iNor k e- . ng :! L expOs ure and amnEking . Vi:ght have a p i y -Eff4- on the r ccurrence of reEpiratoryv symptoms. Chronic manoanese P EiS.Sc), neui-rp(C latric manl- estetianrs (22.2% hemi-parkinsonism (2.7t) and chorcoathetosis (2.7%) wEFe obeFvd in w 3 workers emp loved i the dry battry indUEtr (mar a l., 1 T workers were exposed to a dLst contaxing 65-70, manoaness dioxide (5.9-42.4 MI/cL.M). Contaminants in the dust included a&mmoniLm chloride, zinc oxide. graphite, acetylene black, aIrmonium hydroxide, cerium thorium nitrate, MraggnesLim nitrate , and mercuric chloride. The partic le size distribrlu tion S ot reported. The psychological manifestations included headache, memOry diStur~bnceS, sleep disturbances, uincontrol lable laughter, sexual imootence or diminihed libido, impulsive acts, uncontrollable weeping, i rritaoibaLit or depression, ard hallucinations, myth L-t E IL. (1c73 obse r-ved 71 vorkrs ex posd to manganese dust OF fLiEs and 71 matched contro ls. The manganes levels in the fumes (primarl as tnanese tetrox ide) were 7 -12- 13.5 mg /cu.m and the majority of the partile were <2 m he available evidence o btained from small la boratorv yL nim I iCia e- at raet± may display some of the neur ochemical changes asciatediwith manganism in humans; however, they do not rFi rangae ofi cE eavioral manifestations described in primates (U.S. EPA,'i. 19 B ) . M aananese accumulation p to be reLatively h in pigmented sub:stani nigra ti5ue5. ince 12 Ut ' 3'IT te? i but '"l rcde-It VhE-t.n trJ ii n aI g riu r po C 1nt ti UL..'rI . i Cr C t 30': c -3 -L5 orI t .Lmx.ng £pc le, di fe rEl ucs in accun'rU. .a cnC ano r -L 1 :./ 7 CaLtSt l E .e-pci-.i L ciri L lId r Ftcu'rI t i fI 3 ip rar..LIh y trac t 'En li n partile si ze, the partic 1 isi::e di str-i bution of te a tmoSi sphicr-ic fn&gIanS E IL, I:Ey to play a role i.. re .rspi ra tor y tract drIa 1E'..1 al rI 2 zof I.-1 mianoanese dL '! w oI ten not repor-ted in the ccupationlsude therefore c~o par i sTn ; L w r t5i dtl an tnQ xp r-h2 n taj Il2aC iaT.i:1 ire di]2LAT1.t. Howeve, the e rimental an im a i cata suppor -he find g. - 1 - P in i in c a w C orkers th at rm anc nlese e-po'' FEr sul ts ir an irirr c.sed inc C de-nC Cf pr iE:-LIII&lFi a 1,e lLotcsU:a , _ ?24 ) gulm ni r y C :cnge -lon (N l.silvania a . 1 . , 1q7 / ., 12 pul monar y emphys'ma E iLul e. - al 2. .. R Lroups Of four f emiale Fa hesu rs imonkeys w.ere exposed to ':1 or - mg/ .Z f iriganes e cl '-.rti c p -s si Ce was * 15 Ciicrol-) for 5 iour-s 'mday, 5 dnlys/we-t for 2 years. i':ngular ervations did not Ieal any behiae,iviraFl .r bn-ormaL neurogicl Isin. -Howaver, the mnywere no- E tt t -L d fr t n [e uCr' hI ira l dysfunction as part of the r-toc.oi and tihe re.i2por t of lac of fsymptcs i ~Jased orl ct :E s-ide (bjsearv'atio-n . ecrontcud C Poa n'E I eV C: Pl mCaTLrCIE 1! Ih E cL'audateC? -,nd gI bu pal lit' .. The r-s .pi r-atory t rc r v r-Et wa not -a min - ird t al., 1954). i . ala. aa e u.|--aCo.e-jLw'ie r ats ( 5 /sec/group) an C S cl L r r L it fEOFi--C- (:-:/oup)I were Contiuus e po.ed to u. . 12 t.113 or i .15 , Mn/cu .m mana InesI E- e -ctCroxl T-i for morth-. In r'a c'9UiV -iuVtent aOIDynaic lameate oI Ene , r t;Ices was- '. 11 microns. The atmospher-e gneratIon stem uSLd was d-?igned to simulate the mancianese tetroxcide levels produced by an iternal com bIuIs to n n egin re burnr rn, gaslie c r ont ai r ing methycc y c--n tactIny i mnanganee trica-bonvl (UlFich et al., 1 Q97Fa) . Etatlistcal s igfi acant increae in hem-ro globin and mean co-r-puscu ar em, ioglbin concen tration wvas freg. at 1.15 m/ cu. m in both species. l.!N h istDpc2Lnc.0 ogic-= c ac traroinU were obse-rved in the lungs, l arynx. pharyn4, trachea, adrena , or kidneys Ut a 1 b No consistent changs in l ung futnct ion, ct romyogra8m activi t and i mb trmor were obeser'ved in r- th monkeys (U lrich et Al. 197 Grop f LtP0 W to three rhSLSu mon keys, Were expose- to mangPnee di o1id du st t conce n ,tr- at 07 Y, m .7 or ma Mn/cu.m for n hours/ ca , 7 v /week or 10 months. Hyperplasia of oeribronchial tissue, pulmonary emphysema and -e Si, exudata in bronchioles and thickening of t e alve.-lar wall were obEsrve in the ex po--sed monkeys. The severity of the ft-fLcts increased with 0FncenFtration (Suzuki et al 1 78). *-: Grus of m-aIe Swi IS C cI ( 9 L/Lroup) werE- ex pce'sd to or 1 .73 Cm Mnc.m r TW r- guan ese dioxid for 7 hours/day. 5 davy/eek for is-32-eeks. The c >41x 2ose .. ' 5ftlan0&nC-'s execuI'i ed sore rearc .n~ int~"l oDUE-f ' l 10 L and 0 Cn O'r J)I EE s -. a ,-4 l Ice. I:'U; Iu L r- Ci F2tfl 05 o t rlO kIt L- t .or 7C p iId -C a UtD 0 -- ,1- 0in - z S7/ o p- Cnd rale 00 ': Lk V F- i I/t'r I0 Lup -e r :xpous'd to autom~oi le e"missicls f ol~50 conseC ti ve days . I cc fua i Led c ro d IndoLene "c I A 'I to which mthylcyl pn tinla r ananeLe t r I. gwa ddsd E ri . hL - r p th rat t 2o e d gu u (.irEraditedndnn irdiaedi wee Fe z1 2- o w- manansediet. t -. 4 1- L a 4 cnrlrupaslot' Ed thi I I Tit The - o+ L w 0group SConsFitd of 7 conro Qr ied a C,27typca aortry dit nd a Ex,,posEid grou--p in en irrdite chmI fdatpalit.MnEse-xps hamsters were fd 0 rmal di et and in r dit 4 n rA cambers. The onccnt - Itin rf mar i' , int4irda ha4rws'1 13 w I,:, L iC -I . .2 !' 2 -t0 Ci''& -- ) . C r: - u I* r a,c E--r-.'nork iC. . ID Jie wer Eo e ts: p fI- ": hA t:ua clo ri re i rator diC)C a ( ilt slo'l 11in I a , 5C d E.?put-o ogi a .. e01 rl.ll u eD E: "Loe~a s:c E'~h C: C Ii-,S e4 L Iic ri ri g of- i. h n ."uhoidd LLA(. :ti epL7': thel' iu in r 1F; e ~r ii l r E o 1%chi l ii c i . t ih -, . ,.. , .,.% V -' -D E.- np c l s I t N-lL:-|... . -1 . I ei r a r c . L U . (': c 's f: E. iC.e t l . . 1 / sI M E C? -. A - .; , - - - , - 1.1, or m Mn/cu .m mananh.EtSte? *:nDIrle J parlI size '. mic0.n': OLA rSd , c'5 /weEk for 4-5 week:. N- c:ng'; in eln ruorph ly LEre o bserved (Camner et al . , 1985). Ma 1 e and femal C Sprgue--Dawey ra :ts (/S E/gr ) C' w''r'k:' d t se to C 68, 1., o~ 21 g/ cu. III mIanm a nese iox l I . U . . u ' I hours;/day 5 days/weel: for 2 wl. :. The MMAD was 3.17 mic:., wih a sigma i of 2.41'Zl7lo N , a 1 CZhe4- i 71"mTL; e'm :D i ,c I -g and whi l C cL.1 3 (.tC an Corp' cular v l L.t C'), w -e Cb, erv . A) ( rice n t r i Ti'- re ate&d' ii cr ie in thf incid ence cf pfnf um.iEU fl ' iS AId an- i'.C r' e.ase 'L in2 wEt LLnq w. i t w rt c bse'rved . T e rever . ty cVf t heR p 'FeUI ti' M I t. h I 1- r S., A &. U cncen tratio n. At A . mCL .. m focal pnIeuImonitis wih in te it . a. nyPerCE... LLk l rlv was :L-b erv, ai.. El'If LSE pIUmonii. ndt. mai Ig-I flir? F1' t r .a lUl Zwii. W'de .. , oser ved in the rats exposed to 13 ag/cu. mn manga /eeK., c 10 d n "E 'n-e - pumonary effects, a LOAEL(HEC) of 7.2 Mg/cU.M was caculaEd (iot'uk.a shivama L- al. a1 /5, ms summriarize in U.. tm E 1-::-_D+ Ii rv0 pumOnary cogriestion in monkeys exposed to 0.7 or 3.0 irg/cu. i nanqanee oxl ours/day for 5 mOnh. h e pulmoary ch" Cngs il thE mofney5S exposed at Cv.7 mg (/cLI.m occurred later and were IeSs severe comparedo th en .. I iu mroup. G"Oups o-f mice were expcsed to manganese ol.xoe at u. / or U mc. f-or 2 hours/ ay for 2 weeks. ReverSibe inf I Lamraorv changCS were observed in both grOups. iwo months after terminataon 0f 4xposurE, the rflammation was not Present and desquamation 0f the bronchial ep ithelium wcas One of the primary ef fects of angoanese exposure ins humans is an increased prevaience of respiratory symptoms (pneumonia, bronch'iiS, c0lds, and cough) l-V-Dv l?+V 5 '1-'46; Iogawa et al. ..- /; 7 d s eT-- al . , 1787 . Re pira- ry effects have also been reported in animals (Nishivama et al. q75: Shiotsuka, 94 uzu ki et al. 1 . t is unlikely that exposure to nancianesc' as ll responsible for the increased prevalence OT respirtory symiptoms. Rather, I,mangneS exposure probably increases suseptibility to infection. This iS spported by several anifmal CStuOdies that have demonstrated a u ino(oxicity ^LT lowing tXsposure co mananese ancI Streptococi . t-.rcLctr o i.boiei l --idimns SC l . jKVU be'ergstrom, .t77; 7 t-airhcxme 20 .!. . ± 1 9 L.loyd-Davies. +:_ ;igisetter et a . 197) ,-ale ano Teffiae gulnea plgs (sample size not reported) werC eposed to 22 cLM. 2 A ianganiEse dioxide (1 Fu. 9 mci Mn /cu..m) for o2x h::our: 87/ jf the carticles mmicrons in iz. roupS 07 guinea pigs were xposed to E rerobact er 020ca 1 day prlcr tomi-anganese e posurE lmmeolately t:reore mangrn;IH exposure, or Im.diately after manganese exposure. Vhe decrease in the clemrance of managaEnese diox-Iide -From the lungs:_, deraein Ilung mac r ophag ond increse in the number Of Lung leukoCytEs observed in animal exposed to Enterobacter 1 day prior to manganese exposureC wri ignif icant wh compared to the manganese exposure-only group (Bergstrom, 1977) 14 - m.i ,. Le C: C, :o El.Cd! to a... ci. D-."-. of T ICi1A,'. . C' c ~I-rtv our . ccom t n;. t conti-Lr group was USeYd . ED I i ctwsing EC:post, r H : 1 1 1hi.Igenr.- i the o_" Ce wer e e ; .sd to St r E-p t. c cc pS .oge.ie -l e . ro c t or ' Tirnut . * c:o c. t-r at- u.iorI--reA cted iricrea ' .- the do Je !rene 1 II FrtaE i t. b* atw.el teri c-. fc r ese-- C. xposed ick arId t I . cD t ro I Ti c e was o bSE ve - ad s o r the regreeio l cr, I ine of Lh is posi Live c.rre 1 ati on (corre l at inn coc- ff i Len t of .1 _i - ldIilS E t a] . 1 ) c l un 1 d Ccl that. ExfoSLl I -C O ? tu T ; LL s IJoL d resu 1 11n a rvlr- tali ty rate tha t: itn -. 107% o F the con tr- s . .her ef fects in I-, rDi rcsne ? -- ex poed l rLi i aI so (ccomparec to tre Control lIXCe) ri ILud 6.e'. CLr. I r 2.' OCCu rrence o-f Str-eptoccccl ba ct -eremiia and a cons is t Cn t concen tr ai Lic-rs:onse rel a i.on hip et weEr the ariou nt of C.3rnC:an ee r tairled il-i t he lui E "' Shanced mo ta .L. . ty rate. red ic ced in i t i al c 1e rance a nd i ul'eq uen t n han c d growth of the :)tru'ptFc.Cc:i. irn addition , Adkins et al. ( 190) observed tlat Fl imUnity aQ inst Streptococci did not coun terac t the toxi ffec ts of mariganese oxide inhalation and consecquerit trep'tococci infection. roups of 2 aFe CD--i mic: Ee L'JC a ex posed to O o( I r 09 i In g an P- d'ic ,o ie, c t.. i L0.c r Mn/cLt. i) JItour d-/ for 1-4 days. Fre I 5 I-iuc'' :. the term in rati n o f fan.laniee exposure, the mice were exp:.'o-d to l Jbol a pi-leuJiinIe aer l .;& Inc: reased mOrtal i ty and decreaC] £Lirvival ti SU 0' wi observed iin th animals exposed to ranganese Tor On 3-mour priodJ J I.- pneumonice 5 hours later. When the piod between the end of can anlse rand administration of K. pneurOnie waC s ex:encd fromn Ito S hours cfer 3 a c -i if icant incr-ase i'n aoi-taL ity. AnCt-her cQY.-urp of cr1 ce wEe c x ci uenza (/P1R/,4 virus 24 or 49 hours r ior to oxposurE to manan7 s e d;i oxide. When the length of timre between xosr tomngnead i-nfl Iuen2za yvrus wa.s inra ,there woAs a- significa&nt inr Lein mrci talit, dced LsurvZt 7 :3LIval ti-'mes, anfd incrEaSed pulmonary ein(Mgtertal. Q -7 Mace were exposed to the duet from a potassiLum permangjnate nufacturing plant (oyd-Davie 1 . he an imal wer exposed to th 70% mngane dioxide du-St 2 times/day for- 1'20 or 70 midnutes for 15-'21 d ays. Up~on expos-ure erminat ion, the =nimals were exposed to pneumococci and/or streptococcus hemlyticu1ks. Cf th 0 mice that were expcosed for ±20-mnute sessions, nine ;ed or, were iIled in extremis after Il davs. Several of the animals that were expoaed for 70 minutes also died. Bronchopneumcnia, s~e ln Of the bronchiale lim, and mononLic lear infiltration were observed in these , an i mal. No hn in susceptibilit! to preLumococcix wee observed in the exposed mica (Liovd-Davies, 1946). Lloyd-Davies and Harding (1949) administered a single intratracheal , ijection; of mangnese dioxide (10 mg MnO2, equivalent to 6.3 mg Mn) or anganese chloride (5 or 50 mg MnCl2, equivalent to 2.18 or 21.8 mg MN. The ratS wer acri f iced from i hour to 13 months (Mno2 or days (Mn2) . rnF 1 01 EpiC ium inflammation k wide=read pnemDnia, and granuloau eactiorn were observed in the at administred manganese dicx i. Pulmnnary edema wobn th roUp xpZSed t o manoancsc chloride. p-amale Hif/IC-R C nice. were exposed to 43.' mci Mn /cu.m manganese dioxide 7 ours/davy. 5 days/Wee: f-or L; mo-nths and were 'ored o unexposed maleE . Th n m were xposed duin i Leational days ±-±o. UEcreased 000y weight and irmpar ed neurobhc virapofrmaneC oe fi:ld rotorod and explration wr- e s L!rv., ed in tae .- i -sp i.inring c , cYraEae in rtotrd performance iWas also c'bserve.d in the offspri of non-expoee ca th''- were' foatEred zo mrganese-expoSed f emal e rS' dr in 1 ac tatn. Trus balanc. Cordination a Lr were affrcted btoh'0by either a cn po -r pA m pu manganese i oxide (iassaro t . 1 ) MUang a nee 15 ___ I .B'.s. ll'r FIDlNCE IN THE INH!ALTION Ru Study: Md iur- D* Zt a Elase. hIEdJ2 1 ilM Rf-1C: Mec-di'U M CInfidnce in the princ -Ii(pal study (Roel! et al. 19 E t7 ) i mFf Idi LII. The LOAEL for retpi rator - and CN :C f e was Hi.ported Ly several ct svi. human Studies iChan r-a e a I 1981 I crren 19T :; iiNc)giw --:a c, al 173; (ad wy- and h-ak our,* 1854) . An a;eqLate number lf m a e r were mtched to an I d . Lteka 0 nu.tiiber vc Etrc1 ri*r . i. iitto sL oif thE' S-tucId pr cc 1 nYl assigning hiher-c nidence to it. N monit o ring data were avai aab lE to characeLri e past manganese I E've1. Thi I e Kpe Ci ly i ;: ci mptan t bcs e t hE produ c tion level at the factory ncrased wi tH tirm7; work- I' therefo r7, m have been xc pose-d to Icwer I eve of nianri.:.i&e. In Ldd it ' or, par ticl C i disti bution , maincaene CL col rp-undj andr, Otr com po'uncdt prnc t- in the facor. ILCv were nD' ro,'rt . c d Confidce in tis data baz ir medu T he Chanra Ct I3 .1 * 9 813 Al '_'dY did noDb cEiArC'Oc tew 2'? Do.iure bo other 'ietal found in elding- rC.s Dr adqualy dcribhe partIic] a it vd c eaindar4l rel iv e.lv few e ELpcsd .cD iacts The pri mal-v oxco c l g C Cf fe0 c of r pIe c a cirb rnc nranese- have been fairly well c hara3c terize.Hevr'imttoncfth ua EH b - n - v I I-L3 £- c I- i *, rI (,,v u I - Iii it E;t 1on , c nt~ t d e p r'c l t heno ei . -hs m eni1t C f a do E -- r e i po n s r e l t h p . A nio-t effect level IasC no.t' b.en idntifi-ed. In caddition., the of fect of man~l~.:EineEi on development and reproducticon havve not been adeqtely t ctudied. Ref cting M.eCium con f idCnC e in the key StUdy and meadiuM COQ1i. dcEE in, tri dIecta Eas, confiJ. dence in t1The inIialation Rf'C Is mediumi EI .5.5. 6 EPA D CU L'ti1.:t T 1UN A 'uID R'E V -N U: MI Wl-T;HEH T LHA DT' -OurCe Document -- This assessment is not oreserted in any sxi sing A.. EPA -thrr EPA Documentation -- U.S. EPA, 1984. Agency Work Group Review: 08/23/90,, 09/19/90 I Verification Date: I9/19/90 . . . F7 H U i -l I t A L AT 1UN i C m Kenneth A. Poiri;:r / 5R -- (513)569-7531 / FTS 684-75,1 richaei i. Davis / ORD --- (9i9541-4162 / FTS 629-4162 I CARCINOCENICITY ASSE SfiENT 7FR LIFETIME EXF SUE ubstance Name -- Manga.ne'se CA=N --- ~439--96-5 L at Revised --- 08/01/90 16 ection I p-ovides Fini ormiatio on t hrac atpeCtE cf the c o risi: aE:mentfor th- agen-' t in ques tion; the L'. EPA:: laificati. nd qucan-z. - t tiv e-tir at.s .-f ri f Is rm cr x osure E nd fr in ht Cti c: orc.LIt Tie cl > a ification ref Icts a weigev i den GTcce _ ,- I-idc-mnt cf tie i 1 i hood that the agent is a human carcinogen T. quatitativ e risk IE: -timts ar- presen ted in three ways. The sJOpe factor is the result of application, ouf a 1 ow--dose ex tr- p'o a tin T- pr-ocedure ancd i- presen-tcd as the risik pcr mQ/RIcd . The Iunit rik si the quant-itative estLimat in terms of ei. ther risk per u-/L ritnking wati or r j.0i*k per LC4/cu .m air breathed. The third ferm; in whi...1h vi.1: is presen'ted i s d rinking vater or air conccentratcion prLvidiIng cancer rS of i i in O- k0,00 or. 1 i 1,000 Q. ,0cg d m F;:I or, 1 i . . L. B$ i:: - C'tf k g(5 r iac: r t - (Service Code 5) provides dtiai d ls on the ratinale ri meth hdc'ed to d.rri4v- the carcint-nici .ty Va .Le found in Il. Users arte referred to Section 7 fo information on long-term toxic effects other than carci nocnici ty. << Manoanese NOTE: Manga ie.e is in c2, efleFiet considE red essen tial 1 t.o human heal t. II . A E-ID ENCE FOR CL AS IFi C AT ION AS TO HUMAN CAR JIOENCITY __ .. P.1. VEI GHT - OF--E VI DENCE CLA 'SSI F CAT I ON ClaSificatin -- D; rot classifiable as to humEin carcinogenicity asis --- Existino studies are inadeouate to LIsess tiA=. erc irngenCicit v manganese. Manganese ___I I.A.2. HUMAN CARCINOGENICITY IDATA None. II.A.3. ANIMAL CARCINDGENICITY DATA - inadequate DiPallo (1964) subCutaneous1v or intraperitorieally injected 'BA/ mice with 0 i mL of an aqueous of solution 1 manganese choride twice weel-±y for 6 months. A larger percentage of the mace exposed subcutaneously ( 24/ / 6 L7) I rd intraperi toneally (l./39; 41) to manganese developad lympho ar coI compared with controls injected wi -th water ( 16/66 24%). In ad it on, tu;ors appeared earli er in the eXP0sed groups than in the contirol cr Cup . h incidence of tumors other than lymphroarcomas (i . qe mamInary ad-nocariznoTac. eu:emias, inj Ec tion situe tumors) did not differ Tigni ficantly between the exp-sed groups and con-rols. A thorough evaluation of the results of this StLudy rwas not possible because the r esults were publi shed in abstract forim. 1tOner 6r al1 ' L' ) C--sc manoanous cul fLTe iC, k mouse 1-7 1-:L .aencTa 2Crn bi Sy Groups of strain /Strong mic (1/sex, .CS wjek d, were exposei d by intraper-i ton0 i tz 0, UL1Tate .or 7 wee:: ia toTal or . Fn ln ,. n anrmaF.r eon s erved for a-n addi ional1 22wee1s afrer t ti pi be c sore sacrifiCe a 30 w0 eks Lung tumor. er-c cbservbed in 12/20 7/2 n 7/ ri mal s in the high, medium, nd loW do10ge gr-oups. rCerpe ctii T ei p trcnt C f miF1 I with tumors was clevated, bu noto signif icnt 'y. at -Cth 7 ig het dose level DFianer Exact test) compared wn a tmer VPe in tne ven icLe. coIntrols. In 17 e- iOt.irn thr' r- e Wa-. ar F appaI-it - r:rce. i ri the avrvia Cle nltiiber cf pulmU riirV a:e. ame pe r f1C e. 0o t.h a t ie mi d n hig h dos ., as c; c0i par-e w I t -al cc2 C C.. ) ut Lthu ar C'F tC, i ~ :s a Ui.2 -ea' :.criU t I v a t thF I vcehi. e cortr ols c (1.iE/ Gx cc5but i-l i - L asI F Jf.::-csig ific.arl JCouy E te high dce (Sutudent's t -tet, p.) In thc' mouse lung adenoma biCias2y c-ertain EpCific .Crte-ri ahou beC me'-t in orde fr for a respnse- tc:o be c on side-red posi ti6v e Shikc1:: in and Stonier 1975) ) ;mCnC l these cr1 er i a are ar inc rese iri the' )e-ri nmber of tum'r pe MOLSE and Sn e.vid ccen t dose-repis e rtc! rel airish. p. Whi 1 e t-e resu lt of thi s :tudy alre su 9gg es t . v U 1 T i- L 3. C in.g erli c:i ty' t e d ; ata c a rl oCt bee co.r n I r'- d c onc 1u si ve 51i rc e the mail rl nber of tunior- per niL-e Lz- J ( sii 1nT 1 cc I.1 y inc reasved at on I v cand ct i a he ev id te c or a co c e-'i-r E s rla-c r i E. c. i .hi. p wU smarg inal.- Frs- t 1978) expsed grou ps Fi F-44 rats (2/se) irtrarusC.u ar y CU or b' g avaa to mrangan es e powdsr, fannriiriE4-es e dixi'd and m Ce s=e I I) ac yl acEtona t e (MiAP) TrFCCaV nieit 0 2c.or S te'd of aithi ' 7 5 il. dri ' of 10 each of rancane Oe Powi der c- mr ai n 6 EMeK C) a. d .id x. d E:- o 0 s a To f 1 C0. MC l S eC p rcw0er by ci\IVSrle Or a i doaes o1f 50 1ilC OT I10rA. 1i: Sddit-Iri , iA le 01T m-ice (25./cg-roui wel - ex:-pneed intratifaii sl- to mr1 U aipag-nEce powderr (singleE 1CDs mg dc.s, ei and a nense dioxi d8eer (%Sf Cach) cr C.1E7--. Thar. an increased inc idence of fibroarcomia at the in ectio. site in al t- (40) nd I CemaIe (24i) r at = e oC'aei s .d i trafluscu l arl y to 1A,% ccuripared wi th V&ehic le controls 4% TalE 4 '. femalr'o) . E~"rA 194) determincd t rhese incr-H'-,e were statsic l ly si icific ant ard notEJ that the study retLi. recardi -c' n organic manganese compound, cannot necessari v 4-extrapol ated to oure manganese or other inorganic manganese compounds. No di ffer'Ence in tumor incidence was 'Found between rats and mica exposed tc mcanganes? powder and manganese dicxide and cont rols. Sunderman at al. (1974 1976) exposed male 34 rats to 0.5 to 4.4 mg manganeSeactio dustscrc intra~muscuet e'a lar!Ly anf-da, Pfoun"d that nJO tUMorst_ were induced at: th injection site. it was further observed that co-administratAion cf manc_Ae- to nickel subSulfide l one.. SubsequEnt studieS by Sundermai at al. (1 0) uggest that manganese dust may inhibit local sarcoma mnduction by i itschi e al. (19@1) exposed female Ac/J mice intraperi tonealy v to n % mg/kg methylcyc lopentadienyl mangonese tricarbonyl (IMT) and found that ag though cell proliferation w-as produced in the lung, Ilng tumor Mncidence did not increase. M -. 'angarese IIA .4. SU'_ PPIRTIN D A TA FOR CARCINOGENICI TY ii None. , II7.. QUANTITAT%22 ESTIMATE OF CARCINIOGENIC R. E FROM DRAL EXPJSRZ Not available. :3 7«Manganese 18 1. C. vUt;I4TTrTlE ESTIMT OF CAZNDEI 'r'N RIS-. 1' *r" lJHI 1 T'iJ I-mt Etailable. ...... - ... - - .::: 11.a n o a tn M~ - -i II .D. EPA DOCUMENTATION, REVIEW. AND CONTACTS (CCNLSENICITY E _II.D.I. EPA DOCUMENTATION U.S. EPA. 1984. Health Assessment Document for Manannere. Offi.e of Research and Developmen t , Office of Health and Envi rormental Asesment Env.ronmentaJ Criteria and Assessment O-ffce, Cincinrati, OH. E 600U/ -0- 013F. U,.S. EPA. 198. Drinking Water Criteria Document for Manganese. Prepared by the OfficTe of Health and Environmental Assessment, Environment Criteria ad Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ECAO-CIN-DOOB. (ExternalI Review Draft). Q II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) The Drinkinc Water Criteria Document for Manrganese has received UHEA revlew. Agency Work Group Review: 05/25/83 Verification Date: 05/25/a 1 .D .3. U.S. EFH CUNTAHCTS (C-RCINOGENICITY ASt-.EblSIIiMi) Cynthia Sonich-Mullin / ORD -- (513)5119-7523 / FTS 684-752 julie Du / ODW -- (202)382-75B3 / FTS 332-7593 _II. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPDRURE DURATIONS IITI.A. DRINKING WATER HEALTH A;DVISORIES S'bstance Name -- MangnesE.- No-t available at tnis 1-ime. 19 . . . OTHER AStEEEMEN7 CAEN -- 743- fkn r Content to be coeternined. IV. U.S. EPA REGULATORY ACTIONS ubstance N am 1-Manganee 4 uASRN -- 7 39-965 >ot available .. t this time, v. SUPPLEMENTARY DATA Substaice Name -- Manganese CAERN -- 7439-96-5 Not avakilable at this time. VI. SI3LIOSRAPHY Substance Name -- Manganese CASRN -- 743.9-96-5 Last Revised -- 12/01/9P0 VI .- r. ORAL Rf D REFERENCES Gupta, S.KW.; R.C. Murthy and ..V. Chandra. 1950. Neuromelarin in Tng.snese- exposed primates. Toxicol. Lett. 6(1): 17-20. Kawamura, R., H. Ikuta, S. Fukzumi, t aM. 191. Intoxication by manganaee in well water. Kitasato Arch. Exp. Med. 18: 145-16q. Kndaki5, X.G., N. ,akria, M. Leotsinidis, M. PrimtI and T. Papapetropoulos. 1929. Possible health effects of high manganese concentration in drinking water. Arch. Environ. Health. 44(3): 175-17S. -ai, j.C..., T.f.. Leung and L. Lim. 19o1. Brain regional distribution of Lutamic acid decarboxylase., choline acetyl transteraae,' and 20 acetyvlcholi-esterane in the rat: EfG-tS of chrc.nic marga'ne e chloride' -dr'inis.ration F 2fter twO year s. 3.- Neu och.~im. 2C14 ) : ''-- ;-2. a , .C ...... Leung, O.F. Guest, .N. DCvisn and L. :Am. 19E2. h effect: of chronic manarigiese chloride treatment expressed am ago--depondent transient changes in rat brain synaptosomal uptake of amines. J . rochem. 1S 3):.244-247. Leung., T.K.C., J.C.K. Lai and L. Lim. 1981. The regiona distribution of monoamine oxidase activities towards different substrates: Effect in rat brain of chronic admini5tration of manganese chloride ardor f aginq. J. Neu roc he . 3 ( 203u -- 0. NRC (National Research Cotuicil) . 1909. Fecommencl-d Dietary 2C]OFaces, 9th rev. ed. Food and Nutrition Board, National Research Coun::il, N,.tional Academy Press, Washington, DC. p. 230-235. Schroeder, H.A.1 j.j. Bala-a and I.H. Tipton. 1966. Essential trac metal I in man Manganese, a study in homecstasis. J. Chron. Dis. 19: 515-571. WHO (World Health Organi::ation). 1973. Trace eiments in hunan nutrition: Manganese. Report of a WHO Expert Committee. Technical Report Service, 532. Wr'., eneva ._i tzrerland, p. 74-36. -...... <.. Ma r-, g aflne2e *. :------ __VI.B. 1NHA-!_T.IN RID REFERENCEE Adkins, B., Or., S.H- Luginbuhl, F.3. Miller and D... Gardner. 1?o. increased pulmonary susceptibility to streptococcal infection following innalation of mananese oxiCe. Environ. Res. 23: 110-120. Badawy, A. B.N. and A.A. Shakour. 1924. Chronic manqanese intoxicaztion (neurological manifestations) . In: Proceedings of 5th international Symposium: Trace Elements in Man and Animals. p. 26 4 -.. 63. Bergstrom, R. 1977. Acute pulmonary toxicity of manganese dioxide. Scand. . ork Environ. Health, 3: 1-40. Bird, E.D., A.H. Anton and B. Bullock. 1984. The effect of manganese inhalation on basal ganglia dopamine concentraionE in rhesus monkey. N. uro toxico"oIgy,y: (i O-65. Camner, P., T. Curstedt, C. Jarstrand. A. Johannsson, P. Robertson anc A. Wiernik. 1985. Rabbit lung after inhalation of manganese chloride; A zomparison with the effects of chlorides of nickel, cadmium, cobalt, and copper. Environ. Res. 38(2): 30i-309. Canavan, M.M., S. Cobb and C.K. Drini:er. 1934. Chronic manganese : poisoning. Raport of a case with autopsy. Arch. Nurol. Poychiatr. 32: Chandra, S.v., S.S. snui , r,.S.. btrivastava. ;. Singn ano V.4.. Supta. 15 . An exploratory study of manganese exposure to welders. Clin. Tuxical. 13: 407-416. Cook:, -. G., E. Fann and 6..A. Brait. 1974. Cnronic manganese intoxication. 21 Hr-cni. I ! U-.r c. -. .. " 7-: - - D rw D .. rb rg and R.F. c fma. 17. u 1 rnICar y C C IarnC C of E-o.lblotL b I fi2 and in: ;uLe itfo rmis of maoanLs. a. Toicol . Environ. Heal th. ... i.) - .' . .. . Erir A. . , I -. GhA wab.i D D . . c J -Mad .. : r LA and CH.H I.-El --a Frma . 1 7j Chronic manganreistIeO DCpOisoning-i)_ si the d....r bttery inus try. r. J . In d Med 28; 7E-C2. FI in , R.H. . P .. ieal aid W.D. Pi ul 141. ioIdustrial ratng r.e poisoning . J. I rid. Hyg . Toxi ct . 2.: 37 337 I reg re-n, . 1I 99 0 c hI n i .. al t est peIf- i n- 5 m f: v ouI Cry ri :e r xoDL!; to low levels of mtnganese. N e u-0tox . Toratl. 12: (ir pro . Ke .ic, B . ind YV. i--uLE1er . .19 54 . H aatolIocji l invest-y ' ao ig tinc-r on -W'orker c exposedt c licmanganese C?us--J~ L. wilLn. -n.ri. r iyg. Cccus:. . 100. .9 : aa as r; o------+ L.auWeryC. H. * d -i. '..o iS, I - . J 4aEt et li. 1t ... D. s-et .tl y f fUaile L'oriycrs txp Co 2Sd to mercu:-r y vapor or tO maannEse dtos: A qLlestionnir scuoy. .- k n T. ind. red. 7: 171-176. Lloy -- UaVla"-- I-i. -7- c. iaa-c r- se pie-mIn iti . r. 3 . 'ni . .rc:o . 111-135. L Iy "-Davisd, - D--. and H.E. Hardiri . n7 9-i. ... angar-;ee pnEu.mo itis . -ur- er c lin ical and e xperimenta 1 observations J.. Ind. Med. Maitter, R.Z. R. Ehrlich, J.D. Fenters and D.E. Sardner. 1976. r oten tiatIng effects of manganese dioxide on experimen-cai respiratory infections. Environ. R !s 11: S--91. Masssaro, E.J.., R... D 'Aostino, C. Stineman., J.ES. Maranti an B.A . Lown. 1980. Al terations in behavior of adult offspring of femal mice ex;osed to Mn02 dust during gestation. Fed. Proc. Fed. Am. Soc. Exp. Bi . 3.9: 623. (Abstr.) lHen *j t- * LL C. ih 1- K. Bre an d G.. C olles. . Choi ff1r- flOU1 flC poisoning: Individual susceptibility and absorotion of iron. Naurology. 19: 1000-100S. Moore, W., D. Hysell . Miler et al. 1975. Exposure of labor tcrv animals to atmospheric manganese from automotive emisSions. Environ. R(ces . 9: 74-294. .orga:n~ - G._ . , .H. L.own, L. . C tineman, H.Ei. E Dgostino and Ld- F ascsaro. 1925. Upak-e, distri .butJion and behavioral effects of ina a a Cto osurt mangan ese manrariose dioxide) in the adu t mouse. Neurotoxicoioyv. (1: Newland, M.C.,.. x., R\. Hmada, S. Oberderst:er and B. Wi.s. C9 o . Te clearance 0f mar-r ngua 3. n es8 Z e ClDre in the pr imate. Fund . Appi. Toic. : N ish i y m a , K . Y S u u i N. Luj ia *i -i. Y an o , T. Mi yc i an d K . tJ ; i s hil . 1 7 . N - . NT.. U. Tu"itz J1 v Effect of long-term inhalation of manganEse dusts. . Con ti-cuOus observation of the re-piratory orcans of monkeys and mice. Jpn. J. Hy.. aU.(i): 117. 22 N- na,-; K I.. E. Klobay ashi, M. S kErito ct a)l. I 77-. Ep duemi o c l cs S di , c 3 on di Ltrbnce of rspiratory system caused by Rmanganse air polluio. Reprt - Effcts on. res.paratory-yh -cc yst~emi of junior tun.Jp . nub. Health. 2: 31-25. (ap. 3 Perl, D an;d P. F. Good. 1987 Lptak of a I LIiuiLmfTI into cen tra3 nervCus - ystemri-,AI alcng nasal--olfactory pathways T he Lanct. May 2: 102. m 1 -2Rodie~r, 2 1- '7 3J. 1955u. .MaLr! i liese poiso1 riin .ri C n Mo car m rear-..... -.. J. FInd. M d Reels, H., R. Lauwer yS J . F . PBu C cht et a 1 . 1987. Epidi(olgC C.i cal .urI among workers exposed to manrariese: Effects on lun, c-entral nervOus syste and sone biological indices. Am. 3. ind. Mied. 11 (3) 307-328. Saric, M. and 0. Hrustic. i975 Ex5posure to air borne maroaneEe anrd r r tja ier-i blood pressure. Envi ron. Ree. 10: 314 --318. I eAric, M. and S. LUCcic-Palaic. 1977. Possible synerg i sm of Ex posure to airborne manclariese and s moking habit in cccurrence of rcspiratory miptom. In : In -a 1 ed Particles. IY , W. H . Wial ton, Ed . Perg a mqoLn Pre s s, N-e '(cWr: Yrk, Lp. *a ric , H. A- Mar-iacvIc arid t. Brui. 1977. * ccupaticnalexposurEto Tanganese. Br. . Ind. Med. 34: 114-118. Schuler P. , H. Cyanguren. ,. Mat Urana et al. 1937. Mangancse poisoning. Environmen tal and medcal study at a Chilean mine. Ic. Med. Surg. 2: 7Shiotsuka, R.N. 1984. Inhalation toxicity of mancianese -dioxide aria a rraqn-esiuiT oxi Jde-mangane se dixide mixture. GRi. 85(7): 34. 3 myth, L .T., . C. Ruhf , N.E. Whitman and T. Dugan. 1973. Clinical imancianiT and ex pOSuLre to manganese inr, the production and processing of ferro-mancanese alloy. J. DccLUp. MEd. 15: 11-109 UZUkI, Y. N. Fuj ii, H. Yano, T . Ohki ta, A. Ichikawa and K. Nishiyama. 972. Effects of the inhalation of manganeze dioxide dust o fmonlkey lungS. TklUshima J. Exp. Med. 25: 119-125. Tanaka, S. and J. Lieben. 1969. Manganese poisoning and exposure in Pennsvlvania. Arch. Envi-ron.. HEalth. 19- 674-6S4. rch, CE.. and W. Eusey. a 179. vUalut ion of the chronic nhalati4on toxicity off a manganese Oxide aerosol: . Inttroducticn, xperimntal design, and acrasol ge-neration methods. Am.. Ind. Hyg. AEso. 3" 4 -^ " ) . '-a44 ? Ilrich, C.E.. W.' ineart. W. BUS=-EV and M.M.A. Dorato. 197Mb. Evaluation of the Cnronic inalation toxicy of a manganese cxide aerosol: II. Clinical obser1tion. flgmatology, clinical chemistry and histopathology. Am. Ind. I. o. J . 4 (: . 3-32C Urich, .E., W. Ri nehart and M. Brandt, 197c. Evaluation of the chronic ii of a mancanese oxide aerosol: II. Pulmonary f ni. In, - ectrom.voc rams imb tremor, an tie mranoanowe data. Am. Ind. HygJ UE.EPA. 194 th A)se ssnt Documnt for MIangan1est. Fnal FRport. 23 Offi of Heal th arid Er-:i ronmnrtal AsE-ent, Environer, n.Iai C rtr ia and * ,ccL1?-.=it ... TfTC.& siC;.~.iin.ti. L. rP4 5'.0../8 p- .>-t .-.. U.. EP. 1 ' . Intrimn IIrEn Methd for Develpnt of In haa t i R ef ce c.ro nc 7 E, -1 on . ffice of Health iand Er vir -m nrial . s] essmj. i.n En 1 -- nIn tal Crteri and Ifsessi t 0ff ice, Roaet'rch Triang1 n Frk NC. EA- ?0/ C55 . Pie vd t 0./66. (..RGNih Da i)m-- VI.C. CARCINOGENICITY E ENT REF-ERENE DiFaolo, J.,A. 1964 - The -- 4E. en t iat i-on of l ymp'hoa a rcoE: s .r in, SC: C by m ann M. 1-1i ou chloride, red. r-c:... . . tract; -Llrt., H. 17/s..E. cUoG -- gic T af fec t c1 orn organoran anese cr!ipound On - r *-A49 ra t ari d i s Q aC Gb mi- .L p I Z E- Dilr; C Z i:.. Orn . N l . .. nt 1 C nrcsr Tn -M . 60 (5): 11-117. 'nail.n. i . and G. L . trconer. 1.75. L'rng ttimors in ice|: An p ec 2 Jat2in 2.it carci nogn i Liaay . Adv. Can-cer Re. 21: s--38 ct'ner . G. . , N.F. Shi) kin . I . T.; ro i . 1 . L . 'hompor an .. d L . T erry. 1S/ . est for carcinogenicity of metie 11 c compound a by the pulmonary tumor rEspore in rtrain A mice. Cancer Res. 76: 174-1747. inderman, r.W. 9 Jr., .3. Lau ard L.. Lraliey. - z1,. Inhibitcr eT--Tect CT ran; anese c up8L1On muscl.e tutflOrlgeaiS by rniche± SLICuITiOE, usrnC~?r rxCS. 7 , - ~~ .-,l c-I ..-- -- l -- E-- --a Z t --- Sunderma, r . .F . , r ., . S.. .asprza: . . 4ingne- .. 4. 5. J:n--'a. .i. be;cmOnz C. Onkelinx and P.J. GoldbltI. 1975. Effects of mancanese on carcino-- ceniity and metabol sm of nickel SLOSu T O. 11 'ncer 17 * Cb 77.--180. Dunderman F .r. . We, C. rd . Ailpass ard S.ED. Taubman. .1.5. Manqanese inhibition of s=arcoma induction by benzo (a)pyrene in Fi-cher a s. Proc . Am. Assoc. Cancer Res. 21: 72. (Abstract) u.S. EPA. 1334. Health A sessment Document for Manoanese. Office of Research and Development, Office of Health and Environnmental AEsessmert, nv ron-rmeral Criteria End Asesment 'ffice, Cincinnati OH. r.r 5uu/0-57-- r: t-.. 17t5 Driniing Water Criteria Document for Mangcane e, Erepared Ly n U ace of Health and Environmental acesamen t, Envir-nmenm:a Criteria and ssesanent Off ice, Circ innati, OH for the Office of Drirking Water. WaShington, DC. ECfAO--IN-DCI . (Ex terra I Review Drat) titchi H. P. P.J. Hakkinen and .P F. E:hrer . 191. Modificati'n of 2Lung 2 eumor devel opm-ent in : mice. icxicolog y. : - ----- +:' -anqanese ------ V I .D. DRINKING WATER HA REFERENCES 24 SYNotlYMis SubStance N - aanee CARrN -- 74996- Last Revisred - 0972>/E ~7439-96-5 COLLOIDAL MANGANESE MAGNACAT MANGAN Manganese MANDAN NIiTRIDOVANY TRONAMANG 25 Dichloromethane:; CASRN 75-09-2 01/01/91) Health risk assessment information on a chemical is iFiciLded in IRIS only after a comprehensive review of chronic toxicity data by work croLPs composed of U.S. EPA scientists from several Program Offices. The summarief S presented in Sections I and II represent a consensLis reached in the review process. The other sections contain U.S. EPA information which is specific to a particLlar EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g., treatment technology) . When considering the Use oF regLlatolry action data for a particular situation. note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background information and explan- ations of the methods Used to derive the values given in IRIS are provided in the five Background Documents in Service Code 5. which correspond to Sections I throuoh V of the chemical files: Oc STATUS OF DATA FOR Dichloromethane File On-Line 01/31/87 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on-line 03/01/S8 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment (II.) on-line 01/01/91 Drinking Water Health Advisories (III.A.) on-line 03/t1/88 U.S. EPA Regulatory Actions (IV.) on-line 08/01/90 Supplementary Data (V.) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD ) Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Last Revised -- 03/01/22 I The Reference Dose (RfD) is based or, the assumption that thresholds exist for certain toxic ef fec ts such as ceI 1Ll 1ar necrosis, b ut ray not exist for other toxic effects such as carcirnoqenicity. In cjeneral , the Rfl) is an estimate (with uncertairity spanning perhaps an order of magnitude) of a daily exposure I to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Please r-efer to Background Documen-t--ti in Service Code 5 for an elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of compounds which 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 hLman carcinoger- icity, a SUmmary of that evaluation will be contained in Section II of this file when a review of that evaluation is completed. e D cc<< Dichloromethan I . A. 1 . ORAL RfD0 SUMMARY Critical Effect Experimental Doses* UF MF RfD . Liver toxicity NOAEL: 5.95 and 6.47 100 1 6E-2 mg/kg/day for males mg/kg/day E 2-Year Rat Drinking and females, Water Bioassay respectiv'ely National Coffee LOAEL: 52.53 and I Association, 1922 52.3.2 mg/kg/day for males and females, respectively *Conversion Factors: Doses reflect actual values and not nominal ones. DichIoromethane I I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) National Coffee Association. 1982. 24-Month chronic toxicity and oncogenicity Study of methylene chloride in rats. Final Report. Prepared by Hazleton Laboratories America, Inc., Vienna, VA. (Unpublished) The chosen study appears to have been very well conducted,* with 85 rats/ sex at each of four nominal dose groups (i.e., 5. 50., 125 and 250 mg/kg/day) for 2 years. A high-dose recovery group of 25 rats/sex, as well as two control groups of 35 and 50 rats/sex, was also tested. Many effects were monitored. Treatment related histological alterations of the liver were evident at nominal doses of 50 mg/kg/day or higher. The low nominal dose of 5 mg/kg/day was a NOAEL. The supporting-data base is limited. A NOAEL of 87 mg/cu.m was reported in one inhalation study (Haun et al., 1972). [The equivalent oral dose is a bout 28 mg/kg bw/day (i.e. , 97 mg/cu. m x 0.5 x 0.223 cu . m/dAy/O .35 kg; these ex posure values are for rats).] < ichorom-hane __I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100. (10 x ih) The 100-fo16 factor accounts for both the expected intra- and interspecies variability to the toxicity of this chemical in lieu of specific data. 2 MF = 1. Dichlorormethane I.A.4. ADDITIONAL COMMENTS (ORAL RfD) None. < < Dichloromethane I A.5. CONFIDENCE IN THE ORAL RfD Study: High Data Base: Medium RfD: Medium The study is given a high confidence rating because a large number of animals of both sexes were tested in four dose groLps,, with a I arge nuriber of controls. Many effects were monitored and a dose-related increase in severity was observed. The data base is rated medium to low because only a few studieS support the NOpEL. Medium confidence in the RfD follows. Dichl c ro ethane I.0.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1985. Drinking Water Criteria Document for Miethylene Chloride. Office of Drinking Water, Washington, DC. Agency RfD Work Group Review: 06/24/65, 07/08/65, 11/06/35 Verification Date: 11/06/85 _ A_I.A.7. EPA CONTACTS (ORAL RfD) Krishan Khanna / ODW -- (202)382-7588 / FTS 382-7589 Michael L. Dourson / ORD -- (513)569-7544 / FTS 684-7544 __I .B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Not available at this time. _. UARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE 3 Substanc.e Name -- Dic hloromethaine CASRN -- 75-i9-2 Pr imary Synonym -- Iethyl en Chloride Last Revised -- 01/01/91 Section II provides information or three aspects of the carcinogenic risk assessment for the agent in question; the U.S. EPA classification, and quant- itative estirnates Lf risk from ora) exposure and from inhalation exposure. The classification reflects a eight-of--evidence judgment of the likelihood that the agent is a hurran carcinogen. The quantitative ris k estimates are presented in three ways. The slope factor is the result of application of a low-dose extrapo]ation procedure and is presented as the risk per (mg/kg) /day. The unit risk is thie quantitative estimate in terms of either risk per Lg/L drinking water or risk per ug/cu .rm air breathed. The third form in which risk is presented is a drinking water or air concentration providing cancer risks of 1 in 1I0000 1 in 100,000 or 1. in 1,000,000. Eackground Document 2 (Service Code 5) provides details or the rationale and methods used to derive the carcirogenicity values found in IRIS. Users are referred to Section I for informaition on long-term toxic effects other than carcinogenicitv. < II .A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Based on inadequate human data and sufficient evidence of carcinogenicity in animals; increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in male and female mice, and increased incidence of benign mammary tumors in both sexes of rats, salivary gland sarcomas in male rats and leukemia in female rats. This classification is supported by some positive genotoxicity data, although results in mammalian systems are generally negative. Dichloromethane II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Neither of two studies of chemical factory workers exposed to dichloromethane showed an excess of cancers (Ott et al., 1983; Friedlander et al., 1976; Hearne and Friedlander, 1991). The Ott et al. (1983) study was designed to examine cardiovascular effects, and consequently the study period was too short to allow for latency of site-specific cancers. In the Friedlander et al. (1978) study, exposLLres were low, but the data provided Some suqQestion of an increased incidence of pancreatic tumors. This study was recently updated to include a larger cohort, followed through 1964, and an investigation of possible confounding factors (Hearne et al., 198. 1997). A nonsignificant excess in pancreatic cancer deaths was observed, which was interpreted by EPA (1987a) as neither clear evidence of carcirogenicity in humans, nor evidence of noncar-cinogenicity. An update of the Ott et al. (1993) study, based on longer follow-up, indicated possible elevation of liver and biliary tract cancers (TSCA section S(e submission no. 9eHQ-019-0772 FLWP et seq., 1989). <<< Dichlorometnae > 4 II . A.3. ANIMAL CARCINOGENICTTY DATA Sufficient. Dichloromethane administered in the drinking water inducr-d a signi-ficant increase in combined hepatocellular carciriuma and neoplastic nodules in feirale F344 rats and a nonsignificant increase in combined hepatocellular carcinoma and neoplastic nodules in male B6C3FI mice (NC", 1982, 1983). Two inhalation studies with dichloromethane have shown an increased incidence of benign mammary tumUior s in both sexes of Spr-ague--Dawley (Burek et al.., 184) and F344 (NTF, 1986) rats. Male Sprague-Dawev rats had increased salivary gland sarcoma (Burek et al. , 1784) and femal e F314 rats had increased eLkemia incidence (NTP, 1786). Both sexes of B6C3F1 mice developed liver and lung tumors after dichloromethane treatment (NTF', 1986). In a 2-year study by the National Coffee Association (1982, 1983), groups of 65 F344 rats/sex/dose received 5, 50, 125, or 250 (mg/kg)/day of dichloromethane in the drinking water. Control groups consisted of 135 rats/sex. In female rats the incidence of combined hepatocel lul ar carcinoma and neoplastic nodules was statistically significantly increased in the 50 and 250 mg/kg dose groups when compared with matched controls (0/1.34, 1/85, 4/83, 1/85, and 6/e5 in the five dose groups 0, 5, 50. 125, and 250 (rg/kg)/day, respectively). The incidence of hepatocellular carcinoma alone was not significantly increased (0/134, O/65. 2/83, 0/85, 2/25). The combined incidence of hepatocellular carinomna and neoplastic nodules in controls and the 4 dose groups (472 rats: 4 with carcinoma and 8 with neoplastic nodules) was similar to that for historical controls (419 rats; 5 with carcinoma, 19 with neoplastic nodules). Male rats showed no increase in liver tumors. In the same National Coffee Association study (1982, 1983), B6C3Fi mice received 0, 60, 125, 185, or 250 (mg/kg)/day of dichloromethane in drinking water. Treatment groups consisted of 50 female mice and 200, 100, 100, and 125 male mice (low to high dose). One hundred females and 125 males served as controls. Male mice had an increased incidence of combined neoplastic nodules and hepatocellular carcinoma (24/125, 51/200, 30/100, 31/91, 35/125). The increase was not dose-related, but the pairwise comparisons for the two mid- dose groups were reported to be statistically significant (U.S. EPA, 1935a). The hepatocellular carcinoma incidence alone for male mice (which was about 55 to 65% of the total) was not significantly elevated. Female mice did not have increased liver tumor incidence. The EPA (1985b) regarded this study as SLggestive but not conciuSive evidence for carcinogenicity of dichloromethane. A gavage bioassay of dichloromethane conducted by NTP (192) has not been published because of high mortality, much of which was attributed to gavage accidents. Inhalation exposure of 107 to 109 Syrian hamsters/sex/dose to 0, 500, 1500 or 3500 ppm of dichloromethane for 6 hours/day, 5 days/week for 2 years did not induce neoplasia (Durek et al., 1984). Sprague-Dawley rats (129/sex/ dose) were -exposed under--the-same conditions. Female rats administered the highest dose experienced significantly reduced survival from 18-24 months. Female rats showed a dose-related increase in the average number of benign mammary tumors per rat (1.7, -2.3, 2.6, 3.0) although the numbers o-f rats with tumors were not significantly increased. A similar response was observed in male rats, but to a lesser degree. In the male rats there was a statisticalliy significant positive trend in the incidence of sarcomes of the salivary glano (1/93. 0/74, 5/91. 11/B8); the incidence was sigi-ificantly elevated at the high dose. There is a qutCestion as to whether these doses reached the MTD, particularly in the hamsters and the male rats. In another study (Dow Chemical Co., 1982) 90 Sprague-Dawley rats/sex were exposed by inhalation to 0, 50, 200, or 500 ppm dichloromethane for 20 months (male) or 24 months 5 (female). No salivary tumors were observed! but there was an exposure-related incr eae.a in the total numnber Of berign mammary tumors in fem-nale rats, a though the increase was not statistically signif icant in any individual exposure group. GroLips of 50 each ma le and female F344;/N rats and BiC3F1 mice were ex posed to dichloromethane by inhalation, 6 hours/day. 5 days/week for 2 years (NTP, 1 9B86) Exposure concen trations were 0, 1000, 2000, or 4000' ppm for rats and 0, 2000, or 4000 ppm for mice. Surviva 1 of male rats was 1 ow however, this apparently was not treiatment-related. Survival was decreased in a treatment- related fashion for male and female mice and fema)le rats. Mammary adenomas I and fibroadenomias were significantly increased in male and female rats after survival adjustment, as were mononuc lear cell leukemias in female rats. Among treated mice of both sexes there were sigri ficantl y increased inCidences of hepatocel lular adenomas and carc iomas, and of alveo arbronchioJ ar adenomas and carcinomas, by life table tests. A^denomas and carcinomas were significantly increased alone as well as in combination. In addition, there were significant dose-related increases in the number of lung tumors per animal mul tiplicity _in both Sexes of mice. Two inhia lationi aEsays usi ng dogs, rabbits, guinea pigs, arid rats showed no tumors, but were not conducted for the lifetime of the animals (Heppel et al. 1944; MaEwen et al.. 1972). Theiss et al. (1977) injected Strain A male mice intraperitoneally with 0, 1860, 400, or -300 mg/kg of dichloronethane ia to . 17 times, over 5 to 6 weeks. Survival of the animals was poor. The animals remaining 24 weeks after the first treatment were ki 1 led and examined for lunc tumors; pulmonary adenomas were found. -KDichloromethane ya _ II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Dichloromethane was mutagenic for Salmonella typhimurium with or without the addition of hepatic enzymes (Green, 193) and produced mitotic recombination in yeast (Callen et al., 1780). Results in cultured mammalian cells have generaliv been negative, but dichloromethane has been shown to transform rat embryo cells and to enhance viral transTormation of Syrian hamster embryo cells (Price et al., 1979; Hatch et al., 193). Although , chlorinated solvents have often been suspected of acting through a nongenotoxic mechanism of cell proliferation, Lefevre and Ashby (199) found methylene chloride to be unable to induce hepatocellular division in mice. ------< < Dichloromethane ------ __I.B. QUANTITATIVE ESTIMATE OFr CAPRCINOGENIC RISK FROM ORAL EXPOSURE DIa.n i . SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 7.5E1-3 per (mg/kg.)/day Drinking Water Unit Risk -- 2.1E-7 per (ug/L) Extrapolation Method -- Linearized multistace procedure, extra riSk 3 rinkng Water Concentrat ions at Specifiedi Risk:. Le-vels_: 6 Risk Level Concentration E-4 (1 in 10 0) 5E--2 ugt/L E-5 (1 in 100,000)' 5E+1 ug/L E-6 (1 in 1,000,000 5E+0 ug/L Dichloromethane II .B.2. DOSE-RESPONSE DATA (CARCI NOGENICITY. ORAL EXPOSURE) Tumor Type -- hepatocellular adenomas or carcinomas (NTP') and hepatocellular cancer and neoplastic nodules (NCA) Test Animals -- mOuSe/B6C.F1 (female, NTP; male, NCA) Route -- inhalation (NTP); oral/drinking water (NCA) Reference -- NTP, 19B6; National Coffee Association (NCA), 1993. Dose S D 0 sfl Human Aid min is tered Equivalent Tumor f ppm) mig/kg/day (mg /kg )/day Incidence Reference 0) ' 3/ NTF', 1986 2000 1582 122 16/48 4000 3162 244 40 / 48 0 24/1125 NCA4. 1983 4.5 51 /200 125 9.4 30 / 100 165 14 . 0 31/99 250 18.9 35/ 1,25 < Dichloromethane >> 11.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The slope factor is an arithmetic mean of slope factors derived from NTF'(1986) and the National Coffee Association (1993) data, 2.SE-3 per (mg/kg)/day and 1.2E-2 per (mg/kg)/day, respectively. The use of liver tumor data from the NTP inhalation bioassay was considered valid since dichloromethane is rapidly absorbed following either inhalation or inoestion. Dose conversions used the mean body weight for female mice at the midpoint of the bioassay, and an estimated inhalation rate of 0.04u7 CU. r/day. To obtain estimates of unit risk for humans, an inhalation rate of 20 cu.m/dav was assumed. Dichloromethane was considered to be well-absorbed as a vapor at low doses. No pharmacokinetic or metabolism data have been Used to modify the oral unit risk estimate. becaLse such analyses have not yet been carried out. The unit risk should riot be used if the water concentration exceeds 5E+4 ug/L, since above this concentration the unit risk may not be appropriate. << DichIoromethane > II . B .4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of animals were used in both assays. Risk estimates were based on the more sensitive sex in each study. The two risk estimates 7 were within a factor of 5. - Dic.hloromethane -II C. OUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 4.7E-7 per (ug/cu.m) Extrapolation Method -- Linearized -multistage procedui-e, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 iF 10,n000) 2E-2 ug/cu.m E-5 (1 in 100, 00) 2E+1 ug/cu.m E-6 (1 in 1,q000000) 2E+0 Ug/cu.m << Dichl1oromrethee III.C. 2 DO SE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- combined adenomas and carcinomas Test Animals -- mrouse/B6C3F1, female Route -- inhalation Reference -- NTP, 1986 Dose Tran sformed Human Administered Animal Equi va Jen t Tumor Type (ppm) (mg/kg) /day (mg/ kg )/day Incidence Live r 1582 3156 16/46 4000 316 2 712 4'0 4 6 Lung 3/45 2000 1582 / 30 / 4 6 4 0 C0 3162 41 /46 << Dichlorometthane II.C.. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) Thr unit risk of 4.7E-7 per (uo/cu.m) , which incorporates information on pharmacokinetics and metabolism of dichiorometharie, is approximately nine-fold lower than the previous applied dose estimate (U.S. EPA, 197a,0). Internal dose estimates were based on the metabolism of dichloromethane by the glutathione-s-transferase pathway, as estimated by the model developed by Andersen et al. (1987). The internal dose was corrected for interspecies differences in sensitivity by using the surface area correction factor. Calculation of a slope factor from the unit risk is inappropriate w'hen 8 pharmacokinetic models are used. (When dose-response relationships are -fiur ed on the basis f i nternal or netabol IIed dose, a slope factor ir terms of per (mg/kg)/day represents a back calculation usting different absorption assumptions than the pharmacokiretic models. This introduces possible contradictions.) The unit risk should not be used if the air concentration exceeds 2E+4 Lg/CLu.m, since above this concentration the LIfl-t risk may differ from that stated. Since the unit risk is bas.ed on a pharmacokinetic model , the risk may change with alterations in exposure patterns. Thus, the unit risk presented here nay not be applicable to acute, high exposuLres. < Dic hi oromethane >>> II . C. 4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALAT I ON EXPOSURE) Adequate numbers of animals were observed and tumor incidences were significantly increased in a dose-dependent fashion. Analycis excluding animals that died before observation of the first tLmors producmed similar risk estimates, as did time-to-tumor analvsis. The use of animal and human metabolism and pharmacokinetic data reduces some of the uncertainty typical ly associated with dose-risk extrapolation. A great deal of uncerta inty still exists, however, in the estimriates of internal dose generated by the model of Ande&rsen et al. (1987). Important uncertinties remain regarding the pharmacokinetics , pharmacodynamics, and mechanisms of carcinogenicity for dicl-orc-methane. ----- C Dichloromethane >>---- II .D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) II.D.1. EPA DOCUMENTATION U.S. EPA. 1985a. Health Assessment Document for Dichloromethane (Methylene Chloride). Final Report. Office of Health and Environmental ssessment5 Washington, D.C. EPA/600/S-S2/OO4F. U.S. EPA. 1985t. Addendum to the Health Assessment Document for Dichloromethane (methylene chloride). Updated carcinogenicity assessment. Prepared by the Carcinooen Assessment Group, OHEA, Washington, DC. EFPA/600/S- o2/OO4FF. U.S. EPA. 1987a. Update to the Health Assessment Document and Addendum for Dichl(oromethane Methylene Chloride): Pharmacokinetics, Mechanism of Action and Epidemiology. Review Draft. Office of Health and Environmen tal Assessment, Washington, DC. EPA/600/S-7/030A. U.S. EPA. 1?7b. Technical Analysis of New Methods and Data Regarding Dichloronethane Hazard Assessments. Review Draft. Office of Health and Environmental A-ssessment, Washington, DC. EPA/S00/S- 27/029A. < D'ichlorometi-e I_.I.D.2. REVIEW (CARCINOGENICITV ASSESSMENT) The Addendum to the Health Assessment Document, the Update to the Health Assessment Document and Addendum, and the Technical AnalyEis of New Methods 9 And Data for dichlorosmethane have received Acency and ex,: tern al review, inc Ludirin . reviw by the Science Advi sory Board (SAD). AIthouah the IaEst t.-Wo documents are not yet final i- ed and the SAD commente are not yet incorporated these dr not ali ter this docurmient's analyses or c.onlu Iisions. Agency Work Group Review: 11/12/86, 12/04/36, 04/06/89 .erification Date: 04/0/89 II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Lorenz Rhomberg / ORD -- (202)32-5723 / TS 2-572 Dharm V. Sinch / ORD -- (202)382-5898 / FTS 382-5898 Ill. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III.A. DRINKING WATER HEALTH ADVISORIES ISubstance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Last Revised -- 03/01/88 The Office of Drinking Water provides Drinking Water Health Advisories (HAs) as technical guidance for the protection of public health. HAs are not enforceable Federal standards. HAs are concentrations of a substance in drinking water estimated to have negligible deleterious effects in humans, when ingested, for a specified period of time. Exposure to the substance from other media is considered only in the derivation of the lifetime HA. Given the absence of chemical-specific data, the assumeRd fraction of total intake from drinkina water is 20A. The lifetime HA is I c ikV+W4.+YPD~o/Ko43(JY9 X/.Z -_<[Ywt Level (DWEL) which, in turn, is based on the Oral Chronic Reference Dose. Lifetime HAs are not derived for compounds which are potential ly carcinogenic for humans because of the difference in assumptions concerning toxic threshold for carcinogenic and noncarcinogenic effects. A more detailed description of the assumptions and methods used in the derivation of HAs is provided in Background Document 3 in Service Code 5. <<< Dichloromethane > I.1 .A.i. ONE-DAY HEALTH ADVISORY FOR A CHILD One-day HA -- i.33Ei mg/L LOAEL -- 1 mg/kg/daym26 UF -- 1100 (allows for interspecies and intrahuman variabil ity with the use of a LOAEL from an animal study) Assumptions -- 1 L/day water consumption for a iO-kg child Principal Study -- Kimura et al., 1J971 10 Sinr 3e raL d csics cf di c hI cr omet hane wer e adm in isterE:.d to yoInI ad u l t Sprague-DLal.jey rats. An approximate dose cof 1.3 g/'g vas th- l1owestc do 0 to induce the f i rst obser vabI E, gross signs of tox ica t y Dichloromethane > III.A.2. TEN-DAY HEALTH ADVISORY FOR A CHILD Ten-day HA -- 1.5E+0 mgi/L NOAEL -- 15 mg./kg/day UF -- 100 (allows for interspecies and intrahuman veriabi lity with the LIse of a NOAEL from an animal study) Assumptions -- 1 L/day water consumption for a 10-kg child Principal Study -- Bornmann and Loeser, 1967 Male and ferrmale Wister rats were administered dichloromethane in drinking water for 13. weeks at a dose of 15 mg/kg/day. No treatment-related effects were observed. D i h1chloromethane IIII.A.3. LONGER-TERM HEALTH ADVISORY FOR A CHILD Appropriate data for calculating a Longer-term HA is not available. It is recommended that a modified DWEL (adjusted for a 10-kg child) of 0.5 mg/L be used as the Longer-term HA. Dichloromethane _I . A .4. LONGER-TERM HEALTH ADVISORY FOR AN ADULT Appropriate data for calculating a Longer-term HA is riot available. It is recommended that the DWEL of 1.75 mg/L be used as the Longer-term HA for the 70-kg adult. <(< Dichloromethane III .A.5. DRINKING WATER EQUIVALENT LEVEL / LIFETIME HEALTH ADVISORY DWEL -- 1.75E+0 mo/L Assumptions -- 2 L/Ciay water consumption for a 70-kg adult RfD Verification Date = 11/06/35 Lifetime HA -- None Dichloromethane is considered to be a orobable human carcinogen. Refer to Section II of this file for information on the carcinocenicitv of this suostance. rrincipal Study (DWEL) -- Nations: Coffee Association. 1982 (This study was used in the derivation of the chronic oral RfD: see Section I.A.2. < Dichoromethac ine> II. A. S. ORGANLEPTIC PROPERTIES 11 No datE a vai lable . Dchloromethaneo _III .A. 7. ANALYTICAL METHODS FOR DETECTION IN DRINKING WATER Analysis of dichloromethane is by a purge-and-trap gas chromatographic procedure used for the detection of volatile organohalides in drinking water. Confirmatory analysis is by mass spectrometry. << Dcic hloromethane >> III.A.8. WATER TREATMENT The available information suggests that adsorption by granular activated carbon and air stripping are feasible technologies to remove dichloromethane from drinking water. << Dichloromethane _III.A.9. DOCUMENTATION AND REVIEW OF HAs U.S. EPA. 1985. Final Draft of the Drinking Water Criteria Document on Dichloromethane. Office of Drinki-ng Water, Washington, DC. EPA review of HAs in 1985. Fublic review of HAs following notification of availability in October, 1985. Scientific Advisory Panel review of HAs in January, 1986. Preparation date of this IRIS summary -- 06/24/S7 III.A.iO. EPA CONTACTS Krishan Khanna / ODW -- (202)382-7588 / FTS 382-7588 Edward V. Ohanian / ODW -- (202)382-7571 / FTS 382-7571 II 1 .B. OTHER' ASSESSMENTS Substance Name -- Dichlorom-ethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Content to be determined. IV. U.S. EPA REGULATORY ACTIONS 12 Substance Name -- Dichloromethane CASRN -- 75-097-2 Primary Synonym -- Methylene Chloride Last Revised -- 08/01/9U EPA risk assessiments may be updated as new data are published and as assessment methodologies evolve. Regulatory actions are frequently not Updated at the same time. Compare the dates for the regju lator',' actions in this section with the verification dates for the risk assessments in sections I and II, as this may explain inconsistencies. Also note that souie regIu 1 atorv actions consider factors not related to health risk, such as technical or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning these regulatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the back ground inform- ation on each regulator-y arction in Background Document 4 in Service Code 5. < IV.A. CLEAN AIR ACT (CAA) No data available ------:< Dichloromethane >>----- _IV.B. SAFE DRINKING WATER ACT (SDWA) No data available Dichloromethane > ----- _IV.C. CLEAN WATER ACT (CWA) _IV.C.1. AMBIENT WATER QUALITY CRITERIA, Human Health Water and Fish Consumption: 1.9E-i ug/L Fish Consumption Only: 1.57E+1 uo/L Considers technological or economic feasibility? -- NO Discussion -- Methylene chloride is classified as a carcinogen, and under the assumption of no threshold for a carcinogen, the recommended WOC is zero. However, if zero cannot be obtained and exposure is via ingiestion of water and aquatic organisms, 0.17 uO/L is associated with an upper-bound excess lifetime risk of 1.0-5 [other risk levels to consider: 1.CE-5 (1.9 ug/L) and 1.1E-7 (0.019 ug/L)]. If exposure is only via ingestion of aquatic organiss, the WGC associated with an upper-bound excess lifetime risk of 1..E-6 is 15.7 uo/L. The criteria are based on halomethanes as a class. Reference -- 45 FR 79315 (11/13/B0) EPA Contact -- Criteria and Standards Division, OWRS 13 202)4T5-7315 / FTS 475-7315 Dir hi oromethane . 1- . C. AMBIENT WATER DUALITY CRITERIA Aquatic Organisms F reshw'jater: Acute LEC -- 1.1E+4 Lg/L Chronic -- None Marine: AcLIte LEC -- . 2E+4 U/L Chronic LEC -- 6.4E+3 ug/L Considers technolocical or economic feasibility? -- NO Discussion -- The ValufeS that are indicated as "LEC" are not criteria, but are the lowest effect levels found in the literature. LECs are aiven when the minimum data required to derive water qLality criteria are not available. Reference -- 45 FR 79318 (11/13/80() EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 < _IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) No data available ----- :<->--- Dichloromethane >------ _IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) IV.E.1. TSCA, SECTION L Status -- Advance Notice of Proposed Rulerraking (ANPR) (1985) Discussion -- Initiated priority review under TSCA., sect. 6., of risks from cancer which mnay be associated with certain exposures to methylene chloride. Receipt of a positive NTP bicassay triggered an accelerated-analysis under TSCA, sect. 4(f). Based on its preliminary analysis, the Agency decided that methylene chloride should be classified as a B2 probable human carcinogen under its Interim Cancer Guidelines. TSCA, sect. 4(f), requires that the Agency initiate appropriate action under sect. 5, 6, or 7 within a 10- day period of receipt of health effect information which triggners a ect. 4(f) decision. The sect. 6 ANPR initiated appropriate action. Reference: 50 FR 4 2005 (I0/17/85) EPA Contact -- Chemical Control Division., OTS / (202)322-3749 / FTS 322-3749 14 -- Dichloromethane ------ _IV.F. REZOURCE CONSERVATION AND RECDVERY ACT (RCRA,) IV.F.1. RCRA APPENDIX IX. for Ground Water Monitoring Status -- Listed Reference --- 52 FR 25942 (07/09/87) EPA Contact -- RCRA/Superfund Hotline (800 )424-9346 / ( 202)732-3000 / FTS e32-3000 ------Dichlor--methane ------ I IV.G. SUPERFUND (CERCLA) I IV.G.i. REPORTABLE QUANTITY (RO) for Release into the Environment Value (status) -- 1000 pounds (Final, 1995) Considers technological or economic feasibility? -- NO Discussion -- The final adjusted RQ of 1000 pounds is based Upon a chronic toxicity score of 10. This substance hIs recently been identified for assessment of carcinogenicity, and the RD will be reevaluated when that is completed. Referenceassessment -- 50 FR 13456 (04/04/25) A Contact -- RCRA/Superfund Hotline (B00)424-9345 / (202)382-3000 / FTS 382-3000 _./V SUPPLEMENTARY DATA 3 ubstance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylenae Chloride Not available at this time I BIBLIOGRAPHY 3 ubstan Name -- Dichloromethane 75-09-2 15 PrMimary Synonym -- MethylIene Chloride Last Revised -- 09/01/90 VI .A. ORAL RfD REFERENCES Haun, C.C., E.H. Vernot, K-.I. Darmer Jr. and S.S. Diamond. 1972. Continous animal exposure to low levels of dichloromethane AMRL-TR-130, paper No. 12. In: Proceedings of the 3rd Annual1 Conference on Environmental Toxicology, Wriaht-Patterson Air Force Base, Ohio. Aerospace Medical Research Laboratory. p. 199-208. National Coffee Association. 192. 24-Month chronic toxicity and oncogenicity study of methylene chloride in rats. Final Report. Prepared by Hazleton Laboratories America, Inc., Vienna, VA. (Unpublished) U.S. EPA. 1S5. Drinking Water Criteria Document for Methylene Chloride. Office of Drinking Water, Was hirigton, DC. - Dichloromethane ------ VI.B. INHALATION RfD REFERENCES None ------<<< Dich oromethane ------ VI .C. CARCINOGENICITY ASSESSMENT REFERENCES Andersen, M.E., H.3. Clewell, III, M.L. Gargas, F.A. Smith and R.H. Reitz. 997. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol. Appl. Pharmacol. 87: 185 -205. Burek, J.D., k.D. Nitschke., T.J. Bell, et al. 1934. Methylene chloride: A two year inhalation toxicity and oncogenicity study in rats and hamsters. Fund. Appl. Toxicol. 4: 3-0-47. Callen, D.F., C.R. Wolf and R.M. Philpot. 1980. Cvtochrome P450- mediated genetic activity and cytotoxicity of seven halogenated aliphatic hydrocarbons in aaccharom yces cerevisiae. Mutat. Re. 77: 55-63. Dow Chemical Company.. 1982. Methylene chloride: A two-year inhalation and oncoenicity study in rats. Toxicology Research Laboratory, Health and Environmental Sciences., Dow Chemical Company, Midland, MI. Friedlander, P.R., F.T. Hearne and S. Hall. 1978. Epidemiologic investigation of emplovees chronicall exposed to methyvlene c-il oride. 3. Occup. Med. 20: 657-666. Green, T. 1.973. The metabolic activation of dichloromethane and chlorofluoromethane in a bacterial mutation assay using Salmonella typhimurium. Mutat. Res. 118(4): 277-252. 16 Hatch, G.G. P.PAL Mamay, rl.L. Ayer, B.C. Casto and S. Nesnow. 1983. Chemical enhancement of viral t rariormator .in Syrian hamster enbryo cells by cIaseoIs and volatile chlorinated methanes a.nd ethanres. Cancer Res. 4: 194 5-1950. Hearne, F.T. and B.R. Friedl arder. 1981. Fr l ow-up Of methylene chloride study. J. Occup. Med. 2:,: 6 60. Hearne . . , F. Grose, J .W. F'ifer and B.R. Friedlarder. 1986. Methvlene chloride mortality study update. Eastman Kodak Company., Rochester., NY. June 16. Hearne, F.T. F Brose, J.W. Pifer, B.R. Fiedlander and R.L. Raleigh. 1997. Methylene Chloride mortality study: dose-response characterization and animal model comparison. J. Occup. Med. 29 (3): 217-226. Heppel, L.A., P.A. Neal, T.L. Ferrin, M.L. Orr and V.T. Porterfield. 1944. Toxicology of dichloromethare (methylene chloride) . I. Studies on effects of daily inhalation. j. Ind. Hyq. Toxicol. 176: 763.--769. Lefevre, P. A. and J. Ashbv. 1989. Evaluation of dichloromethane as an inducer of DNA synthesis in B8C3F1 mouse liver. Carcinogenesis. 1i(6) 1067-1072. MacEwen, J.D., EH. Vernt and C.C. Haun. 1972. Continuous animal expocure to dichloromethane. AMRL-TR-72-22, Systems Corporation Report No. W-7105. Wright Patterson Air Force Base, Ohio, Aerospace Medical Research. NCA (National Coffee Association). 1982. Twenty-four month chronic toxicity and oncogenicity study of methvlene chloride in rats. Fi nal Report. Prepared by Hazleton Laboratories, America, Inc., Vienna, VA. Unpublished. NCA (National Coffee Association). 1983. Twenty-four month oncocenicity study of methylene chloride in mice. Final Report. Prepared by kazleton Laboratories, America, Inc., Vienna, VA. NTF' (National Toxicology Program). 1982. Draft technical report on the carcinogenesis bioassay of dichloromethane (methylene chloride) in F344/N rats and B6C3F1 mice (gavage study). Research Triangle Park, NC and Bethesda, MD. Unpubl ished. NTP-82-061. NTP (National Toxicology Program). 1986. Toxicology and carcinog enesis studies of dichloromethane (methylene chloride) in F344/N rats and S6C3F1 mice (inhalaltion studies). NTP-TRS-306. O!tt M.'G., L.K. Skorv, B.4. Holder, 3.M. Bronson and P.R. Williams. 1983. Health evaluation of employees occupationally exposed to methylene chloride: Mortality. Scand. J. Work Environ. Health. 9: 8-16. Price, P. ., C.M. Hassett and 3.1. Mansfield. 1978. Transforming - activities of trichloroethylene and proposed industrial alternatives. in Vitro. 14: 290-293. Thiess, .C., G.D. Stoner, -.B. Shimkin and E.K. W:eisburger. 77. Test for carcinogenicitv of organic contaminants of United States drinking waters b pulmonary tumor response in strain A mice. Cancer Res. 37: 2717-2720. Toxic substances Control Act. 1789. Section S(e) submission no. SeH-l92- 772 1-FP et seq. U.S. EPA. 1985a. Health Asse=sment Document for Dichloromethane (Methvlene 17 Chloride) . Final Report - Office of Health and Environmental Assessment, Washington, D.C. EFA/60 /8-82/CO4F. U.S . EPA. 1935b. Addendum to the Health Asscessment Document for I Dichloromethane (methylene chloride) . Updated carcinogeri±city assessment. Prepared by the Carcinogen Assessment Group, OHEA, Washington. DC. EPA/600// 92/004FF. U.S. EPA. 1987a. Update to the Health Assessmet Document and Addendum for Dichloromethane (Methylene Chloride) :Pharmacokinetics, Mechanicr. of Action and Epidemiology. Review Draft. Office of Health and Environimental A=ssessment, WashinQton, DC. EPA/6.00/8-r7/0C3..7-i, U.S. EPA. 1907b. Technical AnAlysis of New Methods and Data Re-arding Dichloromethane Hazard Assessments. Revi ew, Draft. Office of Health and Environmental Assessment, Washi ng ton, DC. EPA/600/B- 87/029A. ----- << Dic hloromretfE------ane VI .D. DRINKING WATER HA REFERENCES Bornmanri, G. , and A. Loeser. 1967 . Zur Frage einer chronisch-to ischen Lebensm.-Unters. Forsch. 1 6: 14-18. Wiw Lrn von Dichloromethan. 2. imur a E.T., D.M. Ebert and P.W. Dodge. 1971. Acute toxicity and limits of solvent residue for sixiteen organic solvents. Toxicol. Appl. Pharmacol. I19: 6499-704. National Coffee Association. 1962. 24-Month chronic toxicitv and oncogenicitv study of methylene chloride in rats. Final Report. Prepared by Hazleton Laboratories America, inc., Vienna, VA. (Unpublished) U.S. EPA. 1985. Final Draft of the Drinkina Water Criteria Document on I Dichloromethane. Office of Drinkinq Water, Washington, DC. S YNONYMS U Substance Name -- Dichloromethane CASRN -- 75-09-2 Primarv Synonym -- Methylene Chloride 5Last Revised -- 01/>3/7 Aerothene MM Chlorure de methviene Dichlormethan, uvasol Dichloromethane 1,.1-Dichloromethane. rreon 30 I Methane dichloride Methane, dichloro- 18 Methylene bichloride Methylene Chloride Methylene dichioride Mettvlenu chlorek Narkoti I NCI -C50102 R 30 Solaesthin Solrnethine WLN: GIG 19 Nickel, soluble salts: CSRN 7/4O-02-0 (06/03/91) Health risk assessment information on z chemlical iS irZ lUded in IRIS on iX' after a comprehensive review of chroni c toic i ty da.a by work-p rou pS c: om pored of U.S. EPA scientists from several Program OffAcem. The cummaec preTented in Sections i and II represent a consensu reached ii the review procesE . The other sections contain U..S. EPA information which is specific to a particular EPA program and has been subject to review procedurvE prescribed by that Program Office. The regulatory actions in Section IV may not be based on the most current risk assessment, or may be based on a current butb unreviewed, risi assessmG'nt, and ma' take into accouint factors other than h.-i th ef fectr. (e. g. , treatmeti technology) . ileri Considering the u.se of regulatorv acti on data for- a particular situaition, note the date of the r&egLratory action, the date of the most recent risk assesEiant relating to that action. and whether technological factors were considered. Background infor-mation and explan- ations of the methods used to derive the values given in IRIS are provided in tne Tive FacKrrouno DOcuments in Service Code 5, which correspono to ec ._iona I through V Of the chemical fi-leS; STATUS OF DATA FOR Nickel, soluble malts File On-Line 09/30/S7 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on-line C/i /9 Inhalation RfC Asessment (I.B.) pending Carcinogenicity Assessment (1£.) Message Drinking Water Health Advisories (III..) no data U.S. EPA Regulatory Actions (IV.) on-line 06/i1/90 Supplementary Data (V.) on-line 09/90/37 _I. CHRONIC HEALTH HAzARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS -. A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Nickel, soluble salts CAERN -- 7440-02-i-D Last Revised -- 05/01/90 The Reference Dose (RiD) is based on the assumption that thresholds exist for 1 ccrtain toy D c efeci 1 tic..-as C.:. I u Ar n:crD ., but 1ay not eLLA1 62or ft.Ir L.'icL V-1 LT.fU-' iLc'.sC- uuc E 's c.r- L.Picger Ic.'tv - . E E? .nlcaI .I , *i.F o. a a c st ointr ' 4.withl LncCL?ttailtv E2.jal~IliiXQgiperitapo an orcder o5f magn'imt ude) of a dua CA ;e2psure to the hLm f i c u r . 1 at. d c (. . rL 1 Lud-rig s, c- Fi C. I t iv e su ruc. 1DLt ;. E 1 1' toi ii: Ce.. C 'JF: wii I t h u t ana pe il:: e r 2 s if d ee I ate r i ouE eff ec ts du r in c a ifet irne F E1CaSe rEe r to E.:ckQru.ld Dcuieni. . i irice -ode 5 for #: n E.labotion of th krrse concepts. FfDs car a so be der- i ved for the nonca: rcinogenic rhe) thm f C!C t c-f compounds which -are I so carci noC-en c. T 0Ler efoie , tt i s ecscsn tial tcU refer Ic c!thmer CojUrces rf in fcormiat ion concerii a r-g the cac irol enici tV of .i j u j : tInce . If t L he U . S . 'EP'A b ;a v a ISted thi S u L bh 1taet F) for p teF: i J.i riUMt-an car c:in. Fit cn : city a sUminmary of that i-val u a tion will be 1 cn1- tea. ed in ZCecin II c. ti f il whe'n a revi-w f that ealtion a C, con lted . NicI::ei. so) Ib salts NOTE: The Cra RftD for nickel (sol ub a salts) may change in the near fLILtre pen di rig the tcmc o'f a fur-ther r-ev now being cond uC ted by the Oral LC' r k C3 Ero.u p. I.A__ ORA RfD £JfMM;ARY Critica3Sf EfTot ExperimFnta] Dlo'ec4 UF IF RfD Daecreased body and IJDAEL: 100 ppm diet 100 -5 2E-2 organ weights (5 mg/ko/day) mg/ki:g/dav Chronic Rat FPeding LOAEL: 1000 pp diet Study (50 mg/kg/day) Ambrose et al., 1976 *Conversion Factor's: 1 ppm = 0.05 mg/kg/day (assumed rat food conSLmp tion) << Nickel, sClLuble salts __I.Ai~ .2. PRINCIPAL AND SUPPORTIN3 STUDIES (RAL RfD' Ambrose, A.M., D.S. Larson, J.R. Borzellecca and G.R. Hennigar Jr. 1976. Long-term toxicologic assessmnent o nickPi in rats and dogs. j. Food Sci. Technol. 13: 181-187. Amborse et al. (197 ) reported the reSiLl tS Of a 2-year feeding study u-ing rats 51Ven diCkC S Lfate Ze-cimydrate in concentraticns of , 10'u 1000 or 2500 ppm as nickel Ni (estimated E , 5, 50, and 125 mg Ni/:g bw) in the diet. coy weignts in the high-dose male no Taal6e ra cc were SIgITI cantly deci-eased compared "ith- controls, ody weight was also reduced at 1000 prii this red'uction wE's sin if icant for females at week. 6 and from week 2 Y t U 104.. whereas mal es F howed body wEight reduc tions only at 52 weeks. 'GroLp of temale 'a on the 1000 or 2500 ppm nic kel diets (50 and 125 mg Ni/kg bw) had nignI fTca tl ' -iger ILa|~t--t-bdVci/ weight ratios and -ovJirE I aver--'C)dv wih rai ta cnro, N f i c an -t e -f c wF '-ier-E reportd at 100 ppm Z'M IN if, D -J I- e E I-nforDF--,-L0r: t mg 1E15Lt ' h. ) .ose p-pNU ' mwU d1/ : .- ) ni 1-hpre iL sLudy Li' 'e Cer 1'0 (5'mg U,;- ppia C: Lk ZzF Ni/k i n bw)c o r t doSe- is - I,oaL. - T - IF:D'z thi Studv -year L' vv h as poo-- r ,-ic. pc:i- icul rl in con lrcl rats of btDh Ce: (det: f * 4/50) ti raisd *-jimei conFCern 0 ALbout t'h- interp-Lre:taition of the reslt of thiS SLdv A subchrnrFi-C ktdy conductEd "y Ari±can Biogeics Corp. rp U.S. 19826 . So toLin 5 i -Ai/ .- C to o e a lH L.,L wiicn supports t-Cle -YIproSe e .. 1a7/.) 2 chron ijc NOA.EL of mg/g/day . U.I.U -P (17 report. d that the d0-day tLUdV u admini EEre w n;ijcktelo chilzride in ater ( '. 35,5 and 100 mg /kc/day) waS by clav to both mtale a;d female C-D rts (3O animal s/sx/rop ) . ThE data (gernerated in tiics study included clinical pathology ophthalmoogic aluations,I so rumI 0 hiochoreistry, body and organ we ic ht c.hanges, an d histopatholoCic evaluations of sal cted organs (heart, k idney, liver). The b.od w 2-eig4ht and food cons Umpt i on va 1 Les were cons:i ste nt 1y l uower than Co ntro is for the 35 and 100 mg/kg,/day dosed males. Female rats in both high--dose groups had lower body weights than controls, bUt foo consumption was unaffected by the chemica l. Clinical siqns of toxicity, suchi as lethargy, atax a , irrequ 1 ar brcat hingi , cool body t&mpera cture salI at..'t i on , ard di scl1rcEd o extremities, were senprimar the iGO mg/kgq/day grou; theSe is were ess severe in the 3$mg i/i'c/da y group. The 5 mg/kg/day group did not show any significant clinical signs ocf toxicity. There was 100 mortality in the hiuh- dose group; 6/3,C males and S/30 fema] es died in the mi di-dose g-roLp (35 mg/kg/day). Histopatho- logic evaluation indicated Lhat the deaths of 3/C males and 5/2 fe'males in the mid-dose g-oup waers due to gavagEs erors. At sacrifice, kidney liver, aI-d enEp wei ghts or- 1 es treated a.t the 35 mg/kg/day dose v a nd rigIi t Ik.i diiy weiq hts fo r femIe treated at the e mg/kg/day doe level were signi ficantly Iower than controls. Based on the r-esLIltS obtaainEd in thi= ctudv, the 5 mg/:g/day nic:ei dome was a NOEL, whereas the 397'5 Tg/kg/day was a LOAEL for decreased body and organ weights. Nic , solubCleSl sal ts - I .. 3. UNCERTAINTY AND rODIFYINGrACTORS (ORAL RfD) UF = 100. An uncertainty factor of 100 is used: 10 for inte'rspecies extrapolation and 10 to protect sensitive populations. The nickel dietary I study by Ambrose et al. (1975) identifying a NDAEL of 100 ppm (5 mg/kg/day) is supported by the subchronic gavage study in water (U.3. EPA, 19w) which indicated the same NOAEL (5 mg/kg/day). The uncertainty factor of 100 ia therefore appropriate, since two studies support the NOAEL of 5 mg/kg/day. MF = 3. A modifying factor of 3 is used because of inadequacies in the reproductive studies (RTI, 1937; Ambrose et al., 1975, see Additional Comn't-. =S section). Durirg the gestation and postnatal development of F1b litters in the RTI (1987) study, temperatures were abouC 10F higher than normal at Certain times, which makes evaluation of this part of the reproductive study impossible. In the Ambrose et al. (1975) study there were some statistical 3 design limitations, Such as small sample size and use of pups rather than litters as the unit for comparison. <('Nickel, soluble salts > > I .A.4._I ADDI TIONAL C rMMET (ORAL RfD) 3 Ambrose et al. (1976) also reported reproductive toxicity of nicl:,a I ut the study had some statistical desi-gn limitations, such as small sample size and use of pups rather than litters as the Unit for comoarison. Furthermore, 'the results were equivocal and did not clearly define a NOAEL or LOAEL. Toe I f act that nickel was administered in a laboratory chow diet containing milar . powder., rather than in drinicingj water, in this study caused pr oblecs in quantificatiori of nickol x posure when apPl ying thete data to di n- inr water In a 2-generation tudy (RTi. 1987), nickel chloride wsa dministered in drinking water to male and female CD rats (30/sex/group) at dose levels of 0, 50, 250, and 500 ppm (0, 7.3, 30.3, and 51.6 m/k-g/day, estimated) for 90 days prior to breedina (10 rats/so>./group compr-sed a Satellite subcnronic 3 n db - '.p).p t i he 50 ppm dose e1 .her-I L wa s a i I i.c n . dii r a the P-inP- ro maternal body wei C.hts , al on1 with a-sol ute nd rela tie iver Ut Thus 2.250 5 ppm (30.C mg,/kw/da ws a NlAEL i c) r F- r re le is ist path 1oy was performed for Ii ver, b-idydv lung h ea r t, p''tuitar-' adarre nali, nd iproduci-ive organs to make thI assessment. Tthi N0OAEL is -iger tI-an the NOAEL de rived from the chronic Ambrose et al. (197e>) and suchronic gavage (U.S. EPA, I @O6) assays. Th e nuLmlber of live, pp/itter was_ significan-tly decreased, pup. :) mortAlity,T was1IF sEignlr-i f j ia-%n tly, inrc r -,z easd , a nd avo erage pup body weg twas sin fc tl decreased in compar-ison with-- con )t rol fo1 r t-h e F 1E la gencmra t i.on ( postnar~jLkta d.,.1ay t la f e t er e n w 3 ve (R 1 19 7.Cm i 1-4) at the 500 : ppm j dosT.e. Fib Ii. tters o f P- zero dms e posed to 500 ppm nick el In tIe 5 a nd 250 ppm doe group , increased pup mortality ard decreased live litter size were observed in the F-b litters. However, these effects seen with Flb l itters are qutestioriable because the ro0m temperature tended to be 16F hiclher than normal at certain times gestation-postnata days) aloni with much lower levelc C-f hLLdiiC;i ty . Atim evid'enc ied in the 1 i ter-atLre , tefliperatures that are 1F above nor-mal during fetal odJveliopfiIt cause adverse effects (Edwards. 1933) Therefore thee above resu 1ts seen at the 50 and 250 dose evels cannot be considelred a g enuine advers% effects. 7 i mles and females cf the RTI (1987) stcudyi were randomily mati o ptnaz ldav 70 and1 Ctheir offSpri-ng (F2a and F2b) were eva u LuItd through postrata l dy 21. This phase inc luded teratologic eval uations of F2b fetuses. Evaluation of the data indicated that the 500 ppmn dose caused esdinificant body weight depression of both mothers and oup S* and increased neonatal mortality during the postnatal developmtent period. The intermediate dose. 250 ppm nickel, produced transient depression of m;aterna weight qai n &rd water intake during gestation of the F2b litters. The 50 ppm nickel exposure caused a significent increase in short ribs (117'). However, since his ef fect was not seen in both of the hic her dose groups, the reported incidence of short ribs in the 50 ppm group is not considered to be of bicIlogical sigrificance. Schroeoer and Mitchener (1971) conducted a 3-generation study in which five mating pairs of rats were provided drinking water containing 5 mg Ni/L (estimated as 0.4371 mg/kg bw). Results of this study indicated significant increases in neonatal mortality and number of run ts born to expsecd rate compared with controls. The major weakness of this study, however. is that U the end resul-t is based on a total of five matings. The miatings were not randomized and the males were not rotated. The Schroeder and Mitchener (1971) study was conducted in an environmental ly controlled facility where rats had acce-s to food and water containing minimal levels of essential tracemals. ecUaSe of the interaction of nIckel with other trace map 4 ls, the restricted expoz=u.e to trace metals (c hromium wcs est imated as inadequate) may have contri buted to the tox icity of nicel Nicke,i< . soluble saltsS 2: I.A.5. CONFIDENCE IN THE ORAL Rf-D Study; LCw DLa Ba e: Medium RfD:D - Mediumd . he chronic tudy (aimbrcee er al., 17) wasS properly dCignec and provided adequate toxicologic endpoints; however, there was high m;ortal ity n the controls (44/50). Therefore, a low confidence is recommended for the study. The data base provid;e d adequate supporting eubc hron ic at udies, one by 4 garge and the oth ier in dr iing n 1 a u. te r FP::o aniama i s cf t hC R-I ( I =SP su bch trD1 a c studyJ . f rred iLti cni id c, rn r ce i Cve i in t. he daab t a v reco n ded e a the. rei aFrf-. - a i- iLie n t c-he j Are ma F ir iri c reproducti. i ve sv S. Ci y dat- Li T hc. R1) is adEquately sLpp.)rted by te r L sbCc hr-on ic and rpro du c t v-e d i. es, aid 0uI t . 1 Cd dit i on l & C U C L. r .' L Lu Ci CS 6 -E F\'i; j. 1 trr L-1 a iMEClcJ i un con i i derc &e in. i the RfD is recomrreonded , - 6. EPA DC1MENTAT ION AND RE IEW O THE CRORAL RFD U. S. EP.. 1 3. Healt AS w .t Dci n t fpr Niicie . Prepared bv the Off icem -f Hea l t h and Esviromntal A srss Eert o Evironmental oCri.tceria and Dssesment Office Research Triang I aFar:: NC. -ternar RceviewrI ztraft. U .5. FA. 1985 . Drink in- Water Cri e-ria Doc -umnr(r t for- Nr- ke 1- Quean tif ica= tior of To xc ocgical E fcts Chipteir On . Prep-ri rI:.. c Off i fc HEalth ar nd Envi rormer ta l A-sesr5 menrt, , Eni ronimlenl 1 Cr1 teria aid Assessmen aet Cfi j.:, Oinc nrat i OH'r- ffic ho f c rin:ir.g Wc Narn ri r hingi tcn. , DC. E 60 r 01 / - o4-193-i. Ex-ters jive Agncy- 3ide Rev J.iew, 1.7 Agency RfD ' Wrk Group Rev: a L4/16/87, 5/20/87 *7/16/87 -erification Date: 07/16/87 I .A.7. EPA CONTACTS (ORAL RFD) Haril.a ChoiUdhury / ORD -- (513)569-7536 / FTS 6S4-4o7536 Christopher T. DeRosa / ORD -- (513)569-7534 / FT- L84-7534 _I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Nickel, S01ble r. ts CASRN -- 7440-02-0 A r ais- ssessment for this substance/agent is undoer review by an PA wo rI cgroup. .II. CARCINOGENIC±TY ASOESSMENT FOR LIFETIME EXPOSURE Substance Name -- Nicke: , soLuble salts CARN --- 7440-c2-o The U.S. EPA has not evaluated soluble a ts of nickel, as a clas S compoLds, for pot4ntial human carcirroqen icity. ! Hwever. nickel ref inery dust 5 ard pci. Ia C. :.J C kE:: c iLES -- r; C i e C arr :. 1 - I n:r C i I AbUt f -4Li6ed - havE' be: e e .?Can auui aed . idar-A.es o f t-ie t--'v z. u t r:tn .-AJ C 0 n ,, III. HEALTH HAARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III A. DR I NKI1 WATER HEALT H ADI SOI ES Substance Name-- Nickel, soluble salts CA viRaN--- 7440-02-- i Not avilbl t thstime . I II .. OTHER ASSESSMENTS Substance Name -- Nickel, solubie salts CASRN -- 7440-02-- sontent to be determined. IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Nickel , soluble salts ASRN -- 7440-02-0 Last Revised -- 06/01/90 EPA risk assessments may be updated as new data are publishEd and as assessment methodoloqies evolve. Regulatory actions are frequently not updated at the same time. Compare the dates Ior the regulatorv actions in this section with the verification dates for the risk IssessITients in ction L and II, as this may explain inconsiotencie. Also note thit some regulatorv a.ctions consider factors not reasted to heaslth risk, such as technical or economic f easibil ity,. SucI considerations are indicated for each action. addition, not all of the regulatory actions 1-isted in this section involve rnforcealc federal standards. Please direct any questions you may have concerning these regulatory actions to the U.S. EPA contact lited for that particu jar action. Users are stron ly urged to read the backorcund inform- ~un on tacn regu. ..oi- acton in t'ackgroluno Uocurient 4 in :Servlce ...ode 3. N scluble saltE .'fv K;!. iw"r Ir1 ACT CA ; ND oata available 6 - -~-- - -. < [Nic-i:: l , ,olub) .alt ------ WATER ACT (SWA I A F DPR I NK ING S ta available I ------. << Nic,a -::el so lub e t - - - I _IV.C. CLEAN WATER ACT (CWA) UNodata avalable -- -- - Nickl. uble saI t -- I IV.. FEDERAL INSECTICIDE. FUNGICIDE, AND RODENTICIDE ACT (FIFRA) 3 No oata available ------Nickel. SouIble salts K>>- IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available ------< Nickel 5oi.LLbae salts >>>------ U IY.F. RESOURCE CONSERVATION AND RECOYERY ACT (RCERi) IV.F.i. RCRA APPENDIX IX, for Ground Water Monitoring U Status -- Listed Reference -- 52 FR 25A42 (217/09/87) ERA Contact -- RCRA/)uper fund Hot ine (00) 424-9345 / (202 322--300C / FTS 3S2-3000 -Niqck, solu bl e sal ts I __U. ., EUPERFUN!D (CERCLA) No daLt availablE I 7 . UPPL~NEMNTrRY -TA, 3 _..Sb t n N I m - I' Ni c c., 1 sol ub 3 tos CASR --- 744.::--C2-u L at evoed -- 09/~3~ /i7 The information contained in this sectio- (subsections and 8) has been o etr acted from the EPA Cheinical1 Prcfi les Da tabase, w hic has been coufmp ild from a number of sconidary sources and has riot undergone fcrmal Agercy C ,'eiew. The c:omplete refe rce'rnice listings for the ci tat.ons in this s. Iionj 5 are provided in Service Code 5. The user i s urOed to rad Eac: kcg roLrid Docuernt 5 i se -- v cE Code 5 for furthEr information on the sources and 1limi tat ionns of the data presented here. < Nickel, soluble salts .A. ACUTE IHEALTH HAZrR INFORATION To*xicity --- Numerous caaes of dermatitis have been reported (Claytun and C Iy tn 191-- S2) 3 cMdicI Cord itions Denerally A1 gravated by Exkposure -- Not Found 6igns and Symptoms of Ex. posure -- Symptoms include nausea, vomiting, diarrhea. central norvous system depression (Weiss, 190. 990 p. 1105) coughing, shortness fbreath, - chest pain, fever and weakness upon inhaI ation (Rumac: 1975 to rresen'i~) .. ----- << Nickel, soluble salts ------ V.B. PHYSICAL--CHEMICAL PROPERTIES Chemical Formula -- Ni Molecular Weight -- 58.70 Boiling Foint -- 5139F, 2837C (Merck 1983) specific Gravity (HD=1) -- .90 (Sa, 1979) Vapor Pressure (mmHg ) -E 1 t 110 C (Sax;. 1979) Melting Point -- 2§31F, 1555C (Merck 193) SV esity (AIR=1) --- NotFnd vap tion Rate (Butyl acetate=1) --- Not Found Ioui lty in Waster--- In[luble (Wast, 1979 I ,1 ,-'i' ir tater_1b1e -- WmE* -J Fl ash Point (Vethod d ) --- Not Flund Flammable Limits --- Not Found Appearance and Odor -- Silvery metl (Weas, 1979) ).ustrous White met 3 (Merck, 1983) .onrditions or MatE-rai. to a-voii --- FinelV divicd i nickl I (cgc: . Raey', r-i:i i cata vstu) may beccme hot enough to iqnite if exposed to air r- moisture Student, 1 I3). p!. Mlateri.als cont$ni ninq potassium pe-r(c.iIOrate- witL-i nickl1 and ti tan ium pwd-erS and in fusiona l ear-th gi vIe ex p1Iere osI sonduri n a fri. c t i. est.t j.o ane ro-ac to. e xp los i ve I y w4t I hyd r ot iern and F'Fran ey nickel aboVe 210C (NFPA, 19 78) Al.so, aL ruminum ali umrlni-um trichloride.; ethyn. 1 e hyd rogern: metharol nor -meta l ox d ants; s L fur compoundi (Sax, 1.94, p. 1790 ) and se 1 er ium m(e tal (Weis, 1930, p . 1 1.5 ) are in c cmp atib le with n i c:e e Haat-dous Decompoiti on -r ryproducts Not Fouri Use -- Nickel is used in ni Ckel -plating for various all oya ouch as nw Ei lver , Chinese 2ilver*, and German ilver; for coirns , e I ectrotypes, lighting-rod tips, electrical contacts and e-1lectrcds, Spark plugs, machinery pa-ts; as a c ata St for hydrognation of oroanic suListance.s- in marfacturin of Monel metal, stainless steels, and nickel-chrome r esistarrce- w2ire; and in alloyn for electroni.c arid spac: e appliicat ions (M erci 193). I. I FLIOGRAPHY Eub;ance aName -- Nickel, solubieI saits CASRN -- 7440-02-C L at Re2vised ---- :04/01/90D _VI.A. ORAL RfD REFERENCES Ambrose, A.M.. D.S. Larson, J.R. Borzelleca and G.R. Hennigar, Jr. 176. ong-term toxiciloqic assessment of nickei in rats and dogs. J. Food Sci. Technol. 13: 181-17.- dwards, M.J 1986. Hyperthermia as a teratogen: A review of exper imen ta Studies and their clinical significance. Teratogen. Carcinogen. Mutaqen. 6: 563:-582. RTi (Research Triangle Institute) . 1985. Two-generation reproduction anld fertility Study of nickel chloride administered to CD rats in drinking water. nterim report: Ninety day toxicity study of nickel chloride administered to CD rats in drinking water. Roport Hubmitted to Office of Solid Waste, U.. Environmental Frotecticn Agency, Washington, DC. T1 (Research Triangle Institute) , 1997. Two-generation reproduction and fertilitV study of nickel chloride administered to CD rats in drinking water. * eport submjtted to Office of Solid Waste, U.S. Envirorrental Protec ti-on Aie'nJcEy, Washington, DC. 0chroed-r, H.. and M. Mi t-hner 1371. Toxic effects of trace el rments on the reproduction of mice and rats. Arch. Environ. Health. U PA. 19 . Hle3 I th As s&s sm-n-, -.,-.-.,.tDcmofo N i 1 Preared bv the Cf fce of Health and EnvioronmentaI Assessment, Environmental Crit-ria ano 5sssent Of-fice Resarch Trig I - irk, NC. External Review Draft U.S. EPA 1995. Drinking Water Criteria Documnnt for Nickel . Ountification of T oxicoloqical Eftect- chapter only. Fre pared by the Office of H'alth and 9 r1i ri r'Tn r r-, A. r 2 a E- f? . -:V. i r n rier-Itrri n fr i ,er-in r-nid A ,ent 0 ff ce CiT-cirr:ati OH or the -f i ce c) r in -:ir-j W cater I'OE.hi rviton i -L. U.S. EPA. 1986 A 73 day gavage study on Albinc rats using n icke. Lu"bmitted by Armeri carn Biogics Corp. Decatur rL. ------: Nickel , solubLie cal ts >. :D ------ 'VI.. 1NHALLATON RFD REFERENCES None ------Ni c I:e 1 , so l LuY l e s iLts >>L-Et. ------ V .C. CAPRCINOGENTCI ITY ASSESSMENT REFERENCES Nciri e ------Nickel ,OlLble sal ts VI .D. DRINKING WATER HA REFERENCES N 'n e 3YrN 0 NY r-I Substance Name Nickel, soluble saits CASRN -- 7440--2 Lasst Revised -- 09/30/87 440-02-0 NICHELI Nicl Ni c , l e l N i C 1e, SCDILLDbIe Slt s 10 ToiLEfne CASRN 100-3-3 (09/01/90 Health risk assessment informati on on a chemica l is incluCIO an-iRS on.v after a comprehensive review of chronic toxicity data by worI:k grOupS composed of U.S. EPA scientists from setveral Proor am Offices. The summaries pres5nted in Sections I and II represent a consensus reached in the revi.ew process. 1he' other sections contain U.S. EPA information which .a speciiic to a particujar EPA program and has been subject to review procedures prescribed by tht Program Office. The reQulatorv actions in Section P may not be based on the most current risk assessment, Or may be based on a current, but unreviewed, risk assessment, and may tak:e into account factors other than heal th effects (e.g. , treatment technology). When considering the use of r-egu IatorV. ac tionr data for a particular situation., note the date of the regulatory aicticn te date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background irifc:rmation and explan- ations of the methods used to derive the values given in IRIS are provided in the five Eackground Documents, in Service Code 5, which correspond to Sectioris I through V cf thne cihemical files STATUS OF DATA FOR Toluene File On-Line f1/31/S7 Category (section) - S tat us Last Revised Oral RfD Assessment (I.A.) on-line 08/01/ 90 Inhalation RfC Assessment (I.B.) pending 0-7/01 /9C Carcinogenicity Assessment (II.) on-li ne Drinking Water Heal th Advisories (III.A.) on-i ine 09 /01 / 90 U.S. EPA Regulatorv Actions (IV.) on-i ine f 3/0Z1/S - SuppIementa.ry Data (V.) no data I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS _I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name ---- Toluene CAHSRN --- i0S-E8-3 Last Revised -- OS/01/9 The Reference Dose (RfD) is based on the assumption that threshol ds exist for 1 certain tonic effects such as Eellular necrosis, but mav not exist for other tonic effects sLich as c arcinogeni c . I Ii lt gienera J , the RfD arn es t 3 1inte (wi th uncertainty spanning perhaps an order of m2gn i tude) of a dai] v cx posure to 'the htt.ilan popLitiori 'including sensitive -i OLbCroups')that. is ii. .y) to be without an appreciabl e rik of deleterious effec ts during a lifetime. Please refer to ackciround Doc-ument 1 in Service Code 5 for an elaboration of thee concepts. RfDs can il-]so be derived for the noncarcinogenic health effects of compounds which are a)so carcinogens. Therefore, it is essential to refer to other sources of information conc-erning the carcinge:3..ity of this substanrce. If the U.S. EPA has evaluated this subtance -ior potiential human carcinooen- icity, a summary of that evaluaticrn will be contained in Section II of this file when a review of that evQI atiAon is coip I eted. Toluere > I.A. 1. ORAL Rf D SUMMARY Critical Effect Experimental DosesW UF MF RfD ChanC es in liver an d NOAEL = 312 mg/kg 1000 1 2E-1 kidney weights converted to 223 mg/kg/day mg/kg/day 13-Week Rat savage Study LOAEL = 6.25 mg/kg converted to 4W6 NTP, 198? mg/kg/day *Conversion Factors: Dose adjusted for gavage schedule of 5 days/week. < I..A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1989. Toxicology and CarcinogeneEis Studies of toluene in F344/N rats and B6C3F1 mice. Technical Report Series No. 371. Research Triangle Park, NC. The oral toxicity of toluene was investigated in this subchronic cavace study in F344 rats. Groups of 10 rats/sex/group were administered toluene in corn oil at dosage levels of 0, 312, 625, 1250, 2500, or 5000 mg/kg for 5 days/week for 13 weeks. All animals receiving 5000 mg/kg died within the first week. One female and 8 males in the 2500 mg/kg group died, but 2 of these were due to gavage errors. No deaths occurred at lower doses. Several toxic effects were noted at doses greater than or equal to 2500 mg/kg, including prostration, hypoactivity, ataxia, piloerection, lacrimation, excessive salivation, ard body tremors. No signs of biologic significance were seen in groups receiving less than or equal to 1250 mg/kg. The only significant change in body weight was a decrease (p<0.05) for males in the 2500 mg/kg group. There were no toxicologically significant changes in hematology or urinalysis for any group of animai1s. Biochemical changes, including a significant increase (p 2 consisted of hepat!oellular hypertrophv. occurring at greater then or equal to 2500 mg/ kg. Naphrosis was observed in rats th-ia t diDd and damage to the tubul ar epithelia of the kidney occurred in terminally sacrificed rats. Ha stopat.ho logic c hanges were al. so roted in the brain and urinary blidd.er. In the brain, mineral .iz ed foci and necro.sis of ne..tronal ce -I Is were observed in mhalEs and females at 2500 mg/kcg and males at 1250 mg/kg. In the bladder, hemorrhage of the musc.laris was seen in males and females at 5000 mg/kg and ma) e-s at 2500 mgcj/kg4 . The NOAEL for this study is 312 mg/::g/dav based on 1iver and kidney weight changes in male rats at 625 mg/kg., The toxicolotgi c significance of these organ weight changes is strengthene-d by the occ.rrence of histopatholoQic changes in both the liver and kidney at higher doses. Because the expOsure was for 5 days/week, this dose is converted to 312 x 5/7 = 223 mg/kg/day. The LOAEL is 625 mo/kg, which is f446 mg/ kg/day w her converted. NTF (1989) also conducted a 13--week gavage studv in SSC3F1 mice, following the same regimen described above. All mice receiving 5000 mg/kg died and 8/20 receiving 2500 mi/kg also died. Signs of toxicity seen in animals receiving greater than or eqLal to 2500 mg/kg included subconvul sive jerking, prostration, impai red grasping reflex, bradypnea, hypothermie, etaxia, and hypoactivity. By week 13, the mean body weight of 2500 mg/kg males was significantly (p The subchronic study by Wolf et al. (1956) is supportive of the NTP studies. Groups of 10 female Wistar rats were administered gavage doses of 0, 118, 354, or 590 mg,/k-g toluene dissolved in olive oil. A total of 138 doses were administered over 193 days., resulting in average doses of approximately 2,24, 253, or 422 mg/kg/day. Hematologic, behavioral, gross and histopathologic examinations were conducted with no toxic effects being reported at any dose. Therefore, the highest dose of 422 mg/kg/day is considered to be the NOAEL for this study. However, this study is not used as the basis for the RfD because the LOAEL -of 446 mg/kg/day identified by NTP (1989) is too close to the NOAEL identified by Wolf et al. (1956). Also, the NTP study indicated that male rats are more sensitive to toluene and the Wolf Study utilized only female rats. < Toluene > 1 .A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 1000. An uncertainty factor of 1000 was appl ied to account for inter- and intraspecies extrapolations, for subchronic-to-chronic extrapolation and for limited reproductive arid developmental toxicity data. -F MF = 1. << Toluene > .A.4. ADDI T IONAL COMMENTS (ORAL RfD) Kostas and Hotchin (1981) exposed NYL4R mice ore- and post-rm atally to toluene provided in the drinking water et conLen trations of 0, 16, 8Q. or 4u por. Effects were noted in all dosed groups on rotorod performance, measured .t 45 to 55 days of age, but there was an inverse dose-response r-elationship. No effects of toluene exposure -cw-ere seen on maternal fluid consumption, offspring mortality rate, development of eye or ear openings,* or surface- righting response. This study is not suitable for use in risk assessment 3 becausL$ CIe y 6 to 9 Drerinnc i es/dose oruc-p were obtair, -d, %nd bECiuSe the dose-response rel ations hip was inverse. ri a aiibstrac t pr ovid in g 1 i.mi. ted informa ti on , Nawrot aind StaplesJ 979 reported an increase in embryonic lethality in mice ex posed to toluene from days 6 to 15 of nestation. Pregnant CD-1 dams were admriistered 0.3, 0.5, or 1.0 mrL/ko bw, 3 times/day (equivalent to approximately 780, 13.00, or 2600 m/kg/day) . Maternal toxicity was not observed at any dose level, but tol uene was shown to be teratogenic at t- 1 e high dose and embryolethal at the low dose. These levels are higher than the NOAE'9.L demonstrated by the NTP (199) study. Several subchronic and chronic inhalaLion studies have been performed on toluene but are not considered to be SUitable for dervincj an oraI RfD . These studies are immaarized nicely in the introduction to the 2-year inhalation bioassay by NIP, 1999. The Etudies identify the following potential target organs: kidney (male rat); hematologic effects (mice) central nervous system (rats, fire, primate); developmental toxicity (rats, rahbits). It is' beyond the scope of this oral RfD sumaiiary sheet to describe each of theae studies, but the two chronic (2. year) inhalation stLdiCeS are summarized briefly below. In a 2-year inhalation study by NTF (1929), F344 rats (60/sex/group) were exposed to 0, 600, or 1200 ppm toluene and B6C3F1 mice (60/sex/group) to 0., 2, 600 or 1200 ppm toluene for 6.5 hours/day, 5 days/week. Ter aninmals/group .(except male mice) were removed at 15 months for toxicologic evaluition. At 15 months, there was an increased incidence and severity Of nonneoplastic lesions of the nasal cavity of exposed rats. Minimal hyperplasia of the bronchial epithelium was seen in 4/10 female mice at 1200 ppm. There were no significant differences in survivai among any group of animals during the 2-year study. Mean body weights were generally similar for all gcroups throughout the study, Nephropathy was seen in almost all rats with the severity somewhat increased in exposed rat=. There were also effects on the olfactory and respiratory epithelia of exposed rats. No biologically important lesions were seen in any groups Of mice. There was no evidence of carcJnogenicitv for any group of animals in this study. A chronic inhalation study in rats performed by CIIT (19-0) failed to produce an adverse effect. Groups of 40 F344 rats/sex were exposed to 30., 100, or 300 ppm toluene for 6 hours/day, 5 days/week for 24 months. An unexposed group of 120 rats/sex served as a control. Clinical chemistry, hematology, and urinalysis testing were conducted at 18 and 24 months. A11 parameters measured at the termination of the study were normal except for a dose-related reduction in nematocrit values in females exposed to 100 and 3.00 pp m toluene. The highest dose of 300 ppm was considered to be a N4AEL. Toluene ) > 1.A.5. CONFIDENCE IN THE ORAL RfD Study: High Data Base: Med iuM Rf D: Medium Confidence in the principal study is high becausE a Sufficiont numbr Of anji mals/Sex were tested in Each of six dose groups (including vehicle controls) and many parameters were studied. The same protocol was tested in both mice and ratsq with rats being identified as the more sensitive species The data base is rated medium because it is supported by a 6-month oral study. T is not higher than medium because there is no reproductive stu.dy. AIso, the oral studies are all subchronic, with th critical studly being only 4 weeks in duration. Medium confidence in the RfD follows. Toltene - - I . A . 6. EPA DDCUMENTATION AND REV I EW OF THE ORAL. RID Source Document -- This assessment is not presented in any existing U.S. EPA document. Agency RfD Work Group Review: 05/20/85 .8/05/85, Ce/05/86, 05/17/0, 06/20/90 Verification Date: 06/20/90 I.A.7. EPA CONTACTS (ORAL RfD) Sue Velazquez / ORD -- (513)569-7571 / FTS 584-7571 Krishan Khanna / ODW -- (202)382-7588 / FTS 382-7588 _1.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Toluene CASRN -- 108-28-3 A risk assessment for this substance/agent is under review by an EPA work group. II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Toluene CASRN -- 108-88-3 Last Revised -- 00/01/90 Section II provides information on three aspects of t he carcinogenic risk assessment for the agent in question; the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen. 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 I in i,000,000. Background Document 2 (Service Code 5) provides details on the rationale and methods used to derive the carcinogenicity values found in IRIS. Users are referred to Section 1 for information on long-term toxic effects other than carcinogenicity. 5 _ To] uee II . EV,!' I DENCE FDR CL ASS IF ICA TION AS TD HL.'MAI CARCINOGEN] CITY II.A.1. WEIGHT-OF-EUIDENCE CLASSIFICATION Classificati on --- D; not classified Ba -- NO hUmari data aind i nadeUUatE( ari mal data - To luene did rt produce positive resLlts in the majority of genotoxic assayvs Toluene III.A.2. HUMAN CARCINOGENICITY DATA None. 7< Toluene II .A. ANIAL CARCINOGENICITY DATA - chronic 1.fc-weekl bioassay of toluene in F344 rats of both sexes reported no carcianoqenic responses (,IIT, 1930). A total of c;'(0 rats wer-e exposed by inhalation for 6 hours/day, 5 days/week to toluene at C, 30, i., or 300 ppm. Groups of 20/sex/dose' were sacrificed at 1 months. Gross and icroscopic examinetion of tissues and organs identified no increase in neoplastic tissue or tumor masses among treated rats when compared with controls. The study is considered inadequate because the highest dos administered was well below the MTD for toluene and becauTse Of the high incidence of lesions and pathological changes in the control animals. Several studies have examined the carcinogenicity of toluene following repeated dermal applications. Toluene (dose not reported) applied to snaved interscapular skin of 54 male mice (strains A/He, C3HeB, SJR) throughout their lifetime (3 times weekly) produced no carcinogenic response (Poel, 1953). One drop of toluene (about 6 mL) applied to the dorsal skin of 20 random-bred albino mice twice weekly for 50 weeks caused no skin papillomas or carcinomas after a i-year latency period was allowed (Coombs et al., 1973). No increase in the incidence of skin or systemic tumors was demonstrated in male or female mice of three strains (CF, C3H, or CBaH) when toluene was applied to the back of 25 mice of each sex of each strain at 0.05-0.1 mL/mouse, twice weekly for 56 weeks (DEoak et al., 1776). One skin papilloma and a single skin carcinoma were reported among a grouo of 30 mice treated dermallv with one droo of 0.2% iw/v) solution tcluene twice weekly, administered from droppers del ivering 16- 20 uL per drop for 72 weeks (Liiinsky and Garcia, 1972) It is not reported whether evaporation of toluene from the skin was prevented durino these studies. <<< Toluene> II . A .4. SUPFORT ING DATA FOR CARC I NOGEN IC I TY Toluene was found to be nonmiutagenic in reverse mutation assays with S. typ himuriuam (Mortelfmans and Riccio, 1980 Nestmann et al., 1980; 1os et al.. 1921; Litton Bionetics, Inc., 1991; Snow et al., 191) and E. coli (Mortelmans and Riccio, 1930) with and without metabolic activation. Toluene did not induce mitotic gene conversion (Litton BioneticS, Inc. 1981; Mortelmans and Riccio. 1980) or mitctic crossing over (Mortelmans and Riccio, 19w) j in . 6 cereviaa. Athuah Litton Bionetic, inc.. (1981) reported that toluen did * ot. catse .i ntc r pasE-d c hr cmc:soma] aber rat j on s in bone mar ro w cL- I I s. s e9ve ral Russian studies (Dobrokhotcv, 1972: LvapJaio. 1973) report t.luen a. E f flrt.i t ve in c &LS rc cliruciosa I d arlE in bonre marr ow cells of rats. T ere was no evidence of chrom2sorma aberrations in blood ] ymphocytes of i-orkers exposed to touene or 1y Maki-Paa. kanen ft a1., I98f; For ni et Al. 1971), I though a slight increase was noted in workers exposed to to luene arid benzene (Forn i et al. , 1971; Funes-Craviota et al. 1977). This f ildi no is supported by studies of cultured human lymphocytes exposed to toluene in vitro: ri c. eLvation of chromosomal aberrations or sister chromatiC exchangjes w observed (Gerner- Smidt and Friedrich, 1978). ------Tolnc e ------ j I .B. OUANTTITfATIVE ESTIM ATE OF C ARRCINOGENIC RISK FROM ORAL EXFOSURE 3 Not available. ------<<." TolIuene >>------ TI.C. DUANTIT ATIVE ESTIMATE OF CARCINfGEN1C RISK FROM INHALATION EXPOSURE Not available. --- < TolIuene ------ II.D. EPA DOCUMENTATION. REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) II .D.. EPA DOCUMENTATION U.S. EPA. 1987. Drinking Water Criteria Document for Toluene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washinqton., DC. ECAO-CIN-408. Toluene!< >> II .D.2. REVIEW (CARCINOGENICITY A2SERSMENT) The values in the 1787 Drinking Water Criteria Document for Toluene have received peer-and administrative review. A gency Work Group Rc-view: 09/15/87 Verification Date: 0'9/15/87? ID3. U . S. EPA CONTACTS (CARCI NOGENICITY ASS-ESSENT Dh:rme V. Sinch / ORD -- (202)382-5958 / FTS 382-5952 7 Robert C. McGaughy / URD -(202)32-5598 / FTS 2.-2-5893 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III.A DRINKING WATER HEALTH ADVISDRIES Substance Name - To 1uene Last Revised -- 09/01/90 The Office of Drinking Water prrovides Driniking WAter Hea] th Advisories (HAs) as technical guidance for tie protection of public health. HAs are not enforceable Federal standards. HAs are concentrations of a substance in drinking water estimated to have neliqible deleterious effects in umans, when ingested, for a specified period of time. Ex:;.poLsure to the substance from other media is considered only in the derivation of the lifetime HA. Riven the absence of. chemical-specific data , the assumed fraction of. total intake f rom drinking "ater is 2'/. . The I i fetim HAr is calculated from the Drinking Water Equivalent Level (DWEL) which, in turn, is based on the Oral Chronic Reference Dose. Lifetime HAs are not derived for compounds which are potentially carcinogenic for humans because of the difference in assumptions concerning toxic threshold for carcinogenic ano noncarcinogenic effects. A more detailed description of the assumptions and methods Lsed in the derivation of HAs is provioeo in Background Document 3: in Service Code 5. Toluene > _IiI.A.1. ONE-DAY HEALTH ADVISORY FOR A CHILD One-day HA -- 2E+1 mg/L NOAEL -- 21.5 mg/kg/day UF -- 10 (allows for intrahuman variability with the use of a NDAEL from a human study) Assumptions -- 1 L/day water consumption for a lO-kg child Principal Study -- Gamberale and Hul tengren, 1972 This study reported that a 20-minute exposure to 100 ppm tolLuene was a no- effect level when determined by perceptual speed and reaction time tests in human volunteers. At 200 Opm, tol uene was noted as clearily causing toxic effects such as incoordination, exhilaration, and prolonged "reaction~ time. These and other data SUcpport the selection of 100 ppm (377 mg/cu.m) toluene as the NOAEL in humans exposed for up to 2 hours. Rased on the conditions of ex.posure and an assumed absorption rate of 60Y, this level is equivamlent to- 271.5 mg/kcg/day. <<< Toluene > IIl .A.2. TEN-DAY HEALTH ADVISORY FOR A CHILD No information was found in the available literature that wa= _uitable for 8 determination of a Ten-day HA Value. It is, therefore, recommuaended that the DWEL, adjusted for a 10-kg child (3 ng/L) be used as the Ten--day HA value. To IUene.2 SII A.-3'-. LONGER-TERM HEALTH ADVI SORY FOR A CHILD No information was found in the avail able literature that was suitible for determination of a Loncer-term HA vAlIu-e. It is, therefore , reonchd that the DWEL, Adjusted for a 1.0-g child (3 mg/L) be uaed as I.t.he Longer-term H 9 value for a child. Toluene > III.A.4. LONGER-TERM HEALTH ADVISORY FOR AN ADULT No information was found in the available literature that was suitabIe for determinatiion of a Longer-term HA value. It is, therefore- recommended that the DWEL , adjusted for a 70-kg adult (10 mg/L) be used as the Longer-term HA value for an adul. t << Toluene >> III.A.5. DRINKING WATER EDUIVALENT L.EVEL / LIFETIME HEALTH ADVISORY DWEL -- 7E-0 mm/L BAsumptions -- 2 L/dav water consumotion for a 70-kg adult rfD Verification Date -- 06/20/90 ILifetime HA -- iE-0-mg/L A ssumptions -- 20%. exposure by drinking water Rrincipal Study -- NTP, 1989 (This study was used in the derivation of the chronic oral RfD; see Section I.A,2.) << Tol1uene >> _ II ,I.A.6. ORGANOLEPTIC PROPERTIES Taste threshold in water is reported as 0.04 and 1 ng/L. Odor threshold xn water is reported as 0.04 and 1 mg/L. < Toluene >>> __III.A.7. ANALYTICAL METHODS FOR DETECTION IN DRINKING WATER Analysis of toluene is by a purge-and-trap gas chromatographic procedure used for the determination of volatile aromatic and unsaturated organic cOmpOLLnds in water. <<< ToILUene >> 3 III.A.S. WATER TREATMENT Treatment options for removing toluene form drinking water sources incl air. stripping and adsorption onto granular activated carbon. 9 T 'Ilu re III.A.9. DOCUMENTATION AND REVIEW OF HAT U.S. EPA. 1990. Final Draft of the Drinking Water Criteria Document for Toluene. Office of Drinking Water, Washington, DC. EPA review of HAs in 1986. Public review of HAs in 1937. Science Advisory Board review to be determined. Preparation date of this IRIS summary -- 08/20/90 II I . A . 10. EPA CONTACTS Krishan Khanna / ODW -- (202)475-9568 / FTS 475-9568 Edward V. Ohanian / ODW -- (202)382-7571 / FTS 382-7571 1 I I . B. OTHER ASSESSMENTS Substance Name -- Toluene CASRN -- 108-82-3 Content to be determined. IV. U.S. EPA REGULATORY ACTIONS Substance Name -- Toluene CASRN -- 108-36-3 Last Revised -- 03/01/88 EPA risk aosessments may be updated as new data are published and as assessment methodologies evolve. Regulatory actions are frequently not u odated at the same time. Compare the dates for the regulatorv actions in this section with the verification dates for the risk assessments in sections I and II, as this may explain inconsistencies. Also note that some regulatory actions consider factors not related to Hkalth risk, such as technical or economic feasibility. Such considerations are indicated for each action. in addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning theme regulatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the back.round inform- ation on each regulatory action in Background Document 4 in Service Code 5. Toluene 10 I V . A. CL EAIN A J R ACT ; CAA) IV. A. . CAA REGULATDRY DEC 1 IRJON Action -- Decision not to regulate Considers techno]ogical or economic feasibility? -- NO Discussion -- The U.S. EFA concluded that current information does not indicate that toluene endangerS public health at ambient concentrations (excluding emergency releases), and thus no regulation directed 5 pecifica3ly at to)uene is necessary at this tismE under the CAA. Reference -- 45 FR 22195 (05/25/84) EPA Contact -- Emissions Standards Division, OAQPF' ( 9 1 ?) 5 4 1- 5 5 7 1 / FTS 62.9-5571 ----- < Ti uitene > ----- __IV.B. SAFE DRINKING WATER ACT (EDWA) IV.B.3, MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water VaLue (status) -- 2.0 mg/L (Proposed, 1985) Considers technological or economic feasibility? -- N0 Discussion -- An MCLG of 2.0 mg/L for toluene is proposed based on a DWEL of 10.1 mg/L and an assumed contribution of 20% from drinking water. A DWEL of 10.1 mg/L was calculated from a NOAEL of 1130 mg/cu.m (highest dose tested) for lung effects in rats (2-year inhalation study), with an uncertainty factor of 100 applied and an assumed 50% pulmonary absorption rate. Reference -- 50 FR 46936 Fart IV (11/13/95) EPA Contact -- Krishan Khanna / Criteria and Standards Division, ODW / (202)3S2-7571 / FTS 3E2-75715 or Drinking Water Hotline / (500)426-4791 - -- Toluene >------ __IV.C. CLEAN WATER ACT (CWA) IV .C. 1. AMBIENT WATER QUALITY CRITERIA, Human Health Water and Fish Consumption: 14.3 mg/L Fish Consumption Only: 424 mg/L Sonsiders technological or economic feasibility? -- NO Discussion -- The WOC of 14.3 mg/L is based on consumption of contaminated 11 6qLatic orgnni sis and water. A WC of 424 pn/L has al1 so ecn estabI jhed based o n cOnumfrpti on of con t. mrina ted acuatic organ i Sms &i (Dane. Reference -- A9 FR 79313 (11/2/80) EPA Contact -- Criteria and Standards Division / OWRS / (22) 475-7715 / FTS 475-731l5 < Toluene V.IV..2. AMBI ENT WATER UI;AL. I TY CR I TERI .i. AiqL(iutic Orga ni.sfs Freshwater: Acute -- 17 500 LI/L (LEL) Chronic -- None M arinie: Acute -- 6300d ugi/L (LEL) Ch ronic --- 3:'00 L (LEL.) Considers technol ogical or economic feasibi i tV? -- NO DiscuEsion -- Water oualit' criteria for the protection of Laquatic life are derived from a minimum data base of aCLutE? and chronic ests on a variety of aquatic orqanismns. The "(LEL)" after the value indicates that the minimum data were not available and the concentration civen is not a criteria value bLt the lowest effect level found in the literature. Reference -- 45 FR 79318 (11/26/80) FPA Contact -- Criteria and Standards Division / OWES / (202) 4 7 5-7315 / FTS 475-7315 --- < Tol uene > -:------ IV.D. FEDERAL iNSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) ND data available ------Toluene ------ IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available - --- Tuene . ------ IV. F. RESOURCE CONSERVATION AND RECOVERY ACT (FCRA) IV.F.1. RCRA A'PENDIX IX, for Ground Water Monitc:ring 12 Status -- Listed Reference -- 52 FR 25?42 (07/09/57) EPA Contact -- RCRA/Superfund Hotline (BOO ) 4 24--9346 / ( 202 ) 382-3000 / FT 3 382-3000 ------< < Toluene .>------ IV.G. SUF'ERFUND (CERCLA) IV.G.1. REPORTABLE QUANTITY (RD) for Release into the Environment Value (status) -- 1000 pounds (Final, 1985) Considers technological or economic feasibility? -- ND Discussion -- The final R is based on aquatic toxicity, as established under Section 311(b)(4) of the Clean Water Act, ignitability, and chronic toxicity. Available data indicate that the aquatic 96-Hour Median Threshold Limit for Toluene is between 10 and 100 ppm.. its closed-cup flash point is 3ess than 100F and its boiling point is >100F. RD assignments bas*d on chronic toxicity reflect two primary attributes of the hazardous substance, the minimui effective dose (MED) levels for chronic exposure (mg/day for a 70-kg person) and the type of effect (liver necrosis, teratogeniciy, et) . A composite score is determined from an evaluation of these two attributes. Toluene was determined to have a composite score between 6 and 20, corresponding to a chronic toxicity RD of 1000 pounds. Reference -- 50 FR 1456 (04/04/25) EPA Contact -- RCRA/Superfund Hotline SOO)424--946 / (202)382-3000 / FTS 332-3000 V. SUPPLEMENTZRY DATA Substance Name -- Toluene CASRN -- 108-88-3 Not available at this time. VI. BIBLIORAPHY Substance Name -- Toluene CASRN -- 108-e3-3 Last Revised -- 09/C.1/90 13 VI .A. ORAL RfD F,E~ERENCES C7 IT (Chemical I ndustry I nsti tu te cf Tec hnc: I ccy) - 10. A 24moni th i.nhalation toxicolog y study in Fischer-344 rats exposed to atmospheri c tolLueri. CIIT, Research Triagrile Park, NC. Kostas, j. and J. Hotchin. 1981. Behavioral effec ts of l ow-level perinatal expo=Sure to to]uene in mice. Neuroehav. Taxic. . Teratol. 3: 47-, Nasrot, P.S. and P.E. Staples. 1979. Embryo-fetal toxicity and teratogenicity of berzene and toIOIne in the mouse. Teratol ogy 19: 1 A (abstr.) NTP (National Toxicology Program). 1989. Tcxi cology andU catrcrinogenesis studies of tcluene (CAS No. 108-88-3) in F344/N rats and B5C3F1 mice (inhalation studies). Technical Report Series No. 371- Research Triancgle Park, NC. Wolf M.A., V. Rowe, D.D. McCollister, R.L. Ho]linrsworth and P. Dyen. 1956. Toxicoloqical studies of certain alkylated benzes and benzene. Arch. Ind. Hea Ith. 14: 387-39. ------ VI.B. INHALATIDN Rf D REFERENCES None T oluene VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bos, R.P. , R.M.E. Brouns, R. van Doorn. J.L.G. Theuws and P T ' Henderson. 1981. Non-mutagenicity of toILene, o-, m- and p-xylene, o-methylbenzylaicohol and o-methyibenzylsulfate in the Ames assay. Mutat. Res. 8(3): 273-279. CIIT (Chemical Industry Institute of Toxicology). 1980. A twentv-four-month inhalation toxicology study in Fischer-Z44 rats exposed to atmospheric toLene. ExecutiveSummary and Data Tables., October 15. CIIT, Research Triangle Park, NC. Coombs, J.M., T.9. Bhatt and C.J. Croft. 1973. Correlation between carcinogenicity and chemical structure in cyclopenta(a)phenanthrenes. Cancer Res. 33( 4): 832-837. Doak, S.M.A., B.J.E. Simpson. P.F. Hunt arid D.;E. Stevenson. 1976. The carcinogenic response in mice to the topical application of propane sultone to te skin. Tox~icoloqv. 6: 13.9-154. Dobrokhotov, V.E. 1972. The m utoagenic influenco of benzene and LIoluene under experimental conditions. Gig. Sanit. 37: 36-39. (Rue.) (Evaluation based on an English translatior, provided by the U.S. EPA.) 14 Forni , A . E. P-ac if ico and A. Limonta. 1971. nChmooIme studiaes in workers exposed tco benrene or toluitene or both. Arch. Environ . Heal t. 22(3): 373-372. Furies--Cr&Vaita, F., B. o lmoin-hedman, J. Lindste-n, et al. 1977. Chromct.o.ome aberrations and sister-chromatid exchancje in workersi in chemical 1 laboratories And a rotoprinting factory and in children of women l aboratory workers. Lancet. 2: 22-3525. Gerner-Smidt , P. ard U. F riedrich. 1978. The mLtageni c eff ct of berizene toluene and xvlene studied by the SCE technique. Mutat. Re'. 5(2- 3.13-316. Lijinsky, W. and H. Barcia . 1972. Skin carc inoclenesis tests of hydroc.enated derivatives of anthanthrene and other pol.ynuclear hydrocarbons.- Krebstorsch. Klin. Onkol. 77: 226-230. Litton Bionetics, Inc. 1981. Mutaqenicity Evaluation of Toluene. Final Report. Submitted to the Aimerican Petroleum Institute. Washington, DC in January, 1981. LBFI Proj ect Nc. 2114.1-C5. Litton Bionetics,* Inc ., Kansington rD. p. 58. Lyapkalo, A.A. 1973. Genetic activity of benzene ard to)june. Sig. Tr. Frof. Zabol . 17(3): 24--28. (Rue..) (Evaluation based on an Eng ish translation provided by the U.S. EPA.) Maki-Paakkanen, J ., K. Husgafvel-Pursiainen, P.L. Kliomaki, j. Tuominen and M. Sorsa. 1980. Toluene-ex posed workers and chromosome aberrations. J. Toxicol. Environ. Health. 6: 775-781. Mortelmans, K.E. and E.S. Riccio. 1930. In vitro microbiological genotcoxicity assays of toluene. Prepared by SRI International Menlo Fark, CA, under Contract No. 6--02-2947 for the U.S. EPA, Research -irianole Park, NC. p. 25. Nestmann. E.R., E.G.H. Lee,-T.I. Matula, G.R. Douqlas and j.C. Mueller. 1980. Mutagenicity of constituents identified in pulp and paper mil effluents using the Salmonella/mammalian-microsome assay. Mutat. RES. 79: 203-212. Poel. W.E. 1963. Skin as a test site for the bioassay of carciriocgenLs and carcinogen precursors. Natl . Cancer Inst. Monogr. 1i: ,11-625. Snow, L., F. MacNair and B.C. Casto. 1981. Mutagenesis testing of to uene in Salmonella strains TAI0O and TAqS. Report prepared -for the U.S. EPA by Northrup Services, inc., Research Triangle park, NC. U.S. EPA. 1987. Drinking Water Criteria Document for To'uene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria ano Assessment Office, Cincinnati, OH for the Office of Drinking Water., Washing ton , DC. - - Touene ------ VI.D. DR INNG WATER HA REFERENCES Gamberale, F. and M. Hultenoren. 1972. Toluene exposure. II. 15 EiFyn Iop'hys c rgi O cal -r Tullnctonsr .iWork Environ. HIe t.h 9(3 131-13.. (CA .. EPA. I99C. Fi naIP Drid -L of thI ue Dtrirdki rig Wiater Cri ter i a Doc:Lunerntt Ior Tol uene. Office of Drinking Water LWashington, DC. I SYNNYMS z O bstnce Nanme -- ToluLerIe CA GSRN -- 108-3S Last Revised -- 01/31/87 1 103-2-3 M ArNTI'SAL la B'ENZ ENE, METHYL METHZCIDE METHYL-BhEN'JZEN'JE IETHYL.BEN ZOL C 72I-C7T22 HENY'L-MTHANE RCR WASTE NUMIBER U220 TOLUEN Toluene TO L U 0L TOLUOLO U OLU-SOL UN 129?4 16 i.irl-Trichloroethane; CASRN 71-55-6 (09/01/90) Health risk assessment information on a chemical is included in iRIS only after a comprehensive review of chronic toxicity data by work groips composed of U.S. EPA scientists from several Program Offices. The summaries presented in Sections I and II represent a consensus reached in the review process. The other sections contain U.S. EPA information which is specific to a particular EPA program and has been subject to review procedures prescribed by that Program Office. The regulatory actions in Section IV may not -be based on the most current risk assessment, or may be based on a current, but unreviewed, risk assessment, and may take into account factors other than health effects (e.g., treatment technology). When considering the use of regulatory action data for a particular situation, note the date of the regulatory action, the date of the most recent risk assessment relating to that action, and whether technological factors were considered. Background information and emplan- ations of the methods used to derive the values given in IRIS are provided in the five Background Documents in Service Code 5, which correspond to Sections I through V of the chemical files'. STATUS OF DATA FOR 1.1,1-Trichloroethane File On-Line 03/31/37 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on-line 09/01/90 Inhalation RfC Assessment (I.B.) pending Carcinogenicity Assessment (II.) on-line 09/01/90 Drinking Water Health Advisories (III.A.) on-line 09/ 01 /90 U.S. EPA Regulatory Actions (IV.) on-line 09/01 /90: Supplementary Data (V.) no data _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS -- I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance NAmc -- 1,i,1-Trichloroethane CASRN -- 71-55-6 Last Revised -- 09/01/90 The Reference Dose (RfD) is based on the assumption that thresholds exist for 1 certain toxic effects such as cellular necrosis, but may not exist for other toxic effects such as carcinogenic ity. In general, the RfD is an estimate iwith 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. Flease refer to BFackoaround Document 1 in Service Code 5 for an elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of compounds which 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 carcinogen- icity, a summary of that evaluation will be contained in Section II of this file when a review of that evaluation is completed. <<< 1,1,1-Trichloroethane >> NOTE: The Oral RfD for 1.1,1-trichlorcethane may change in the naar future pending the outcome of a further review now being conducted by the Oral RfD Work Group. I. A. 1. ORAL RfD SUMMARV Critical Effect Experimental Doses* UF MF RfD No adverse effects NOAEL: 500 ppm (air) 1000 1 9E-2 (2730 mg/cu.m) mg/kg/day Guinea Pig 6-Month converted to Inhalation Study 90/mg/kg/day Torkelson et al., 1958 Slight growth LOAEL: 650 ppm (air) retardation (3550 mg/cu.m) (converted to Guinea Pig 120 mg/kg/day) 2-3 Month Inhalation Study Adams et al., 1950 *Conversion Factors: dose (mg/cu.m) x 7 hours/24 hours x 5 days/7days x (0.3) x (0.23 cu.mn/day/.43 kg) where: 0.3 is the assumed inhalation retention factor, and 0.23 cu.m/day /0.43 kg are the assumed ventilation rate and body weight of the guinea pig, respectively. 1.1.1-Trichloroethane I.Z.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Torkelson, T.R., F. Qyen, D.D. McCollister and V.K. Rowe. 1958. Toxicity of 1,1,1-trichloroethane as determined on laboratory animals and human sub- jects. Am. Ind. Hyg. Assoc. J. 19: 353-362. Adams, E.M., H.C. Spencer, V.K. Rowe and D.D. Irish. 1950. Vapor toxicity of 1,1,1-trichloroethane (methyl chloroform) determined by experiments on laboratory animals. Arch. Ind. Hyg. Occup. Med. 1: 225-236. Torkelson et al. (1956) exposed groups of rats, rabbits. guinea pigs, and monkeys to 1,1,1-trichloroethane vapor at concentrations of 500. 1000, 2000. 2 or 10,000 ppm. rrom these Studies, it was determined that the female guinea pig was the most sensitive species of those tested. At 500 ppm, groups of guinea pigs (8/sex) showed no evidence of adverse effects compared with unexposed and air-exposed controls after exposure for 7 hours/day, 5 days/week for 6 months. Groups of five female guinea pigs exposed to 1000 ppm 1,1.1- trichloroethane vapor 3 hours/day, 5 days/week for 3 months had fatty changes in the liver and statistically significant increased liver weights. Thus. this study defined a NOAEL of 500 ppm (2730 nig/cLL.m) in guinea pigs. Adams et al. (1950) subjected groups of 6-10 male And female guinea pigs to 650 ppm 1,1,1-trichloroethane vapor 7 hours/day, 5 days week for 2 to 3 months. These animals exhibited a slight depression in weight gain compared with both air-exposed and unexriosed controls, thereby establishing a LOAEL of 650 ppm (3550 mg/cu.m) in guinea pigs. < 1.1.1-Trichloroethane I .A.3. UNCERTAINTY ANr MODIFYING FACTORS (ORAL RfD) UF = 1000. Factors of 10 each were employed for use of a subchronic assay, for ex.trapolation from animal data, and for protection of sensitive human sub- populations. NF = 1. <<< 1,1,1-Trichloroethane >> I.A.4. ADDITIONAL COMMENTS (ORAL RfD) The 1,1,1-trichloroethane samples used by Torkelson et al. (1958) were found to be 94-97% pure while the samples used in the Adams et al. (1950) study had a purity of greater than or equal to 99%. The effects of 1,1,1-trichloroethane vapor have been investigated in mice (Quast et al., 1924; McNutt et al., 1975), rats (Quast et al., 1978),. and rabbits and dogs (Pendergast et al., 1967). The only chronic oral exposure study was conducted by NCI (1977) in rats. The observations from these studies and from Torkelson et al. (1958) and Adams et al. (1950) are somewhat inconsistent, thLs making conclusions difficult as to the dose levels of 1,1,1-trichloroethane that result in adverse effects. For example, exposure to 650 ppm in the Adams et al. (1950) inhalation study was associated with slight growth retardation in guinea pigs. Further review of this study indicates that 1500 ppm exposure also caused slight growth retardation without causing any organ-specific adverse effects following 1 to 3 months exposure. These observations are in contrast with those of Torkelson et al. (1956), who observed adverse effects in the liver and lungs of guinea pigs exposed to 1000 ppm for 90 days. Technical re-evaluation of inhalation studies in mice conducted by Quast et al. (1984) and data from recent inhalation stuides in rats conducted by Dow Chemical, when published, may be of greater value for the overall RfD consideratin for 1,1,1-trichloroethane. << 1,1,1-Trichloroethane II.A.5. CONFIDENCE IN THE ORAL RfD Study: Low Data Sase: Medium RfD: Medium 3 Although both the Adams et al. (1950) and Torkelson et al. (1958) studies used both sexes of several species, the number of animals at each dose level was limited, the length of exposure varied with diiterent dose levels, and few toxic endpoints were examined. Confidence in these studies is thus considered low. The data base is fairly comprehensive; however, results from these studies are somewhat inconsistent and some of the more recent studies have yet to be critically evaluated. Confidence in the data base is, therefore, rated medium. Confidence in the RfD can be considered medium to low. <<< 1,1,1-Trichloroethane >> I .A.6. EPA DOCUMENTATION AND REVIEW OF THE DRAL RfD The only U.S. EPA documentation at present is on IRIS. Agency RfD Work Group Review: 05/31/S5, 07/08/85, 07/22/85, 05/15/S6 Verification Date: 05/15/86 i.A.7. EPA CONTACTS (ORAL RfD) Yogendra Patel / ODW -- (202)362-7585 / FTS 382-7585 Michael L. Dourson / ORD -- (513)569-7544 / FTS 64-7544 I .B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,1,1-Trichloroethane CASRN -- 71-55-6 A risk assessment for this substance/agent is under review by an EPA work group. II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,1,1-Trichloroethane CASRN -- 71-55-6 Last Revised -- 09/01/90 Section II provides information on three aspects of the carcinogenic risk assessment for the agent in question; the U.S. EPA classification, and quant- itative estimates of risk from oral exposure and from inhalation exposure. The classification reflects a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen. 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 4 drinl:inq water or risk per ukg/cL.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 10,000 or . in 1.,00,Q0, Background Docume'nt 2 (Service Code 5) provides details on the rationale and methods used to derive ther carcinogenicity values found in IRIS. Users are referred to Section I for information on long-term toxic effects other than carcinogenicity. < 1,11-TrichIoroethane > II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity. Basis -- There are no reported human data and animal Studies (one lifetime gavage. one intermediate-term inhalation) have not demonstrated carcinogenicity. Technical grade 1,1,1-trichloroethane has been shown to be weaklv mutagenic, although the contaminant, 1,4-dioxane, a known animal carcinogen, may be responsible for this response. 1 1.1-Trichloroethane >> II.A.2. HUMAN CARCINOGENICITY DATA None. < ,1,1-Trichloroethane II.A.3. ANIMIAL CARCINOGENICITY DATA Inadequate. The NCI (1977) treated Osborne-Mendel rats (50/sex/dose) with 750 or 1500 mg/kg technical-grade 1,1,1-trichloroetnane 5 times/week for 75 weeks by gavage. The rats were observed for an additional 32 weeks. Twenty rats of each sex served as untreated controls. Low survival of both male and female treated rats (37) may have precluded detection of a significant number of tumors late in life. Although a variety of neoplasms was observed in both treated and matched control rats, they were common to aged rats and were not dose-related. Similar results were obtained when the NCI (1977) treated 6C.F1 hybrid mice with the time-weighted average doses of 2807 or 5615 mg,/kg 1.1,1-trichloroethane by gavage 5 days/week for 78 weeks. The mice were observed for an additional 12 weeks. The control and treated groups had 20 and 50 animals of each sex, respectively. Only 25 to 45% of those treated survived until the time of terminal sacrifice. A variety of neoplasms were observed in treated groups, but the incidence not statistically different from- matched controls. - - Duast et al. (1572) exposed 96 Sprague-Dawley rats of both sexes to 575 or 1750 ppm 1,1,1-trichioroethane vapor for 6 hours/day. 5 days/week for 12 months, followed by an additional 19-month observation period. The only significant sign of toxicity was an increased incidence of focal hepatocellular alterations in female rats at the highest dosage. It was not evident that a maximum tolerated dose (MTD) was used nor was a range-finding Study conducted. No significant dose-related neoplasms were reported, but these dose levels were below those used in the NCI study. << 1,1,1-TrJchlorethanP > II.A.4. SUPPORTING DATA FOR CARCINOGENICITY 5 Mutagenicity testing of 1,1,1-trichloroethane has produced positive results in S. typhimurium strain TA100 (Simmon et zl., 1977; Fishbein. 1979; Snow et al., 1979) as well as some negative results (Henschler et a)., 1977; Taylor, 1978). It was mutagenic for S. typhimurium strain TA1575 both with e:xogenous metabolic activation (Farber, 1977) and without activation (Nestmann et al.. 1980). 1,1,1-Trichloroethane did not result in gene conversion or mitotic recombination in Saccharomyces cereviaiae (Farber, 1977; Simmon et al., 1977) nor was it positive in a host-mediated forward mutation assay using Schizosaccharomyces pombe in mice. The chemical also failed to produce chromosomal aberrations in the bone marrow of cats (Rampy et al., 1977), but responded positively in a cell transformation test with rat embryo cells (Price et al., 1972). An isomer, 1,1,2-trichloroethane, is carcinogenic in mice, inducing liver cancer and pheochromocytomas in both se:es. Dichloroethanes, tetrachloroethanes and hexachloroethanes also produced liver cancer in mice and other types of neoplasms in rats. It should be noted that 1,4-dioxane, a known animal carcinogen that causes liver and nasal tumors in more than one strain of rats and hepatocellular carcinomas in mice, is a contaminant of technical-grade 1,1,1-trichlorethane. ------<< I,1,1-Trichloroethane >>>------ 11.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPuSURE Not available. ------<< 1.1,1-Trichloroethane ------ II .C. OUANTITATIVE ESTIMATE -OF. CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ------1-,-Trichloroethane >>>------ II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) 11,D.1. EPA DOCUMENTATION U,S. EPA. 194a. Health Effects Assessment for 1,1,1-Trichloroethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, UH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1984b. Health Assessment Document for 1,1,1-Trichloroethane. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-60'/8-82-OOF. 6 <<< 1,1,1-Trichloroethane II D.2. REVIEW (CARCINOGENICITY ASSESSMENT) The 1984 Health Effects Assessment for 1,1,1-Trichloroethane has received limited Agency review. The values in the 1984 Health Assessment Document for 1,1,1-Trichloroethane have received both Agency and public review. Agency Work Group Review: 08/05/87 Verification Date: 08/05/87 I.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Charlingayya Hiremath / ORD -- (202)382-5898 / FTS 382-5898 III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS III.A. DRINKING WATER HEALTH ADVISORIES Substance Name -- 1,1,1-Trichloroethane CASRN -- 71-55-6 Last Revised -- 09/01/90 The Office of Drinking Water provides Drinking Water Health Advisories (HAs) as technical guidance for the protection of public health. HAs are not enforceable Federal standards. HAs are concentrations of a substance in drinking water estimated to have negligible deleterious effects in humans, when ingested, for a specified period of time. Exposure to the substance from other media is considered only in the derivation of the lifetime HA. Given the absence of chemical-specific data, the assumed fraction of total intake from drinking water is 20%. The lifetime HA is calculated from the Drinking Water Equivalent Level (DWEL) which, in turn, is based on the Oral Chronic Reference Dose. Lifetime HAs are not derived for compounds which are potentially carcinogenic for humans because of the difference in assumptions concerning toxic threshold for carcinogenic and noncarcinogenic effects. A more detailed description of the assumptions and methods used in the derivation of HAs is provided in Background Document 3 in Service Code 5. <<< 1,1,i-Trichoroethane > III.A.i. ONE-DAY HEALTH ADVISORY FOR A CHILD One-day HA -- !E+2 mg/L NOAEL -- 1400 mg/kg/day UF -- 100 (allows for interspecies and intrahuman variability with the use of a NOAEL from an animal study) Assumptions -- 1 L/day water consumption for a 10-kg child 7 Principal Study -- Vainio et al. , 1976 A single oral dose of approximately 1400 mg/kg of 1,1,1-trichloroethane depressed some hepatic microsomal metabolic indices (including cytochrome P- 450 and epoxide hydrase) in rats but resulted in no other adverse effects. This level can be viewed as a NOAEL in this study. 1,1,1-Trichloroethane II .A. 2. TEN-DAY HEALTH ADVISORY FOR A CHILD Appropriate data for calculating a Ten-day HA are not available. Jt is recommended that the Longer-term HA for the 10-Kg child of 40 mg/L be usced as the Ten-day HA. <<< 141,*1-Trichloroethane III .A.3. LONGER-TERM HEALTH ADVISORY FOR A CHILD Longer-term (Child) HA -- 4E+1 mg/L NOAEL -- 350 mg/ko/day UF -- 100 (allows for interspecies arid intrahuman va riabi 1 ity with the use of a NOAEL from an anima-l study) Assumptions -- I L/day water consumption for a 10-kg child Principal Study -- Bruckner et al., 1985 Rats were administered 1,1,1-trichoroethane by gavage 5 times/week for 12 weeks at levels of 0, 0.5 2.5, or 5.0 g/kg/day. At levels above 0.5 g/kg reduced body weight gain and CNS effects were observed. Approximately 35 of these rats died during the first 50 days of the study. Also, the 5.0 g/kg/day dose group showed an increase in serum enzyme levels. The 0.5 g/kg/day level is identified as the NOAEL for this study. Based on a 7-day per week dosing regimen, this level would be equivalent to 350 mg/kg/day. < 1,1,1-Trichloroethane III.A.4. LONGER-TERM HEALTH ADVISORY FOR AN ADULT Longer-term (Adult) HA -- 1E+2 mg/L NOAEL -- 350 mg/kg/day U; -- 100 (allows for interspecies and intrahuman variability with the use of a NOAEL from an animal study) Assumptions -- 2 L/day water consumption for a 70-kg adult Principal -Study -- Bruckner et al. 1985 (study described in III.A.3.) < III.A.5. DRINKING WATER EQUIVALENT LEVEL / LIFETIME HEALTH ADVISORY DWEL -- IE+0 mg/L Assumptions -- 20% exposure by driniking water RfD Verification Date -- 05/15/85 8 Lifetime HA -- 2E-1 m/L Principal Study -- McNutt et al., 1975 Male mice were continuously exposed to 1.,1,-trichlorethane via inhalation at 0, 1365 mg/cu.m, or 5460 mg/cu.m 6 hours/day for 14 weeks. Animals exposed to 5460 mg/cu.m displayed significant changes in the centrilobular hepatocytes. Based on the conditions of exposure and an assumed absorption rate of 30%. the LOAEL of 1365 mg/cu.m is equivalent to 35 mg/kg/day. << 1, 1,1-Trichloroethane III.A.6. ORGANOLEPTIC PROPERTIES No information is available on the organoleptic properties of 1,1,1- trichloroethane. << 1.1,1-Trichloroethane > III.A.7. ANALYTICAL METHODS FOR DETECTION IN DRINKING WATER Analysis of 1,1,1-trichloroethane is by a purge-and-trap gas chromatographic procedure used for the determination of volatile organohalides in drinking water. Confirmatory analysis.is by mass spectrometry. 1,1,1-Trichloroethane iII.A.B. WATER TREATMENT Treatment technologies which will remove 1,1,1-trichloroethane from water include granular activated carbon adsorption and boiling. Air stripping is also an effective method; however, this process transfers the contaminant directly to the air stream. << 1,1,1-Trichloroethane III.A.9. DOCUMENTATION AND REVIEW OF HAs U.S. EPA. 1985. Final Drinking Water Criteria Document on 1,1,1- Trichloroethane. Office of Drinking Water, Washington, DC. EPA review of HAs in 1985. Public reviews of HAs foiling notification of availability in October, 1985. Science Advisory Board review of HAs in January, 1986. Preparation date of this IRIS summary -- 08/20/90 _IIIA. 10. EPA CONTACTS Charles Abernathy / ODW -- (202)32-5374 / FTS 392-5374 Edward V. Ohanian / ODW -- (202)362-7571 / FTS 382-7571 9 III.2. OTHER ASSESSMENTS Substance Name -- 1,1.,1-Trichloroethane CASRN -- 71-55-6 Content to be determined. IV. U.S. EPA REGULATORY ACTIONS Substance Name -- 1,1,1-Trichloroethane CASRN -- 71-55-6 Last Revised -- 09/01/90 EPA risk assessments may be updated as new data are published and as assessment methodologies evolve. Regulatory actions are frequently not updated at the sctame time. Compare the dates for the regulatory actions in this section with the verification dates for the risk assessments in sections I and II, as this may explain inconsistencies. Also note that some regulatory actions consider factors not related to health risk, such as technical or economic feasibility. Such considerations are indicated for each action. In addition, not all of the regulatory actions listed in this section involve enforceable federal standards. Please direct any questions you may have concerning these regulatory actions to the U.S. EPA contact listed for that particular action. Users are strongly urged to read the background inform- ation on each regulatory action in Background Document 4 in Service Code 5. <<< 1,1,1-Trichloroethane >>> _IV.A. CLEAN AIR ACT (CAA) No data available - --- << 1I1,-Trichloroethane >>>------ _IV.B. SAFE DRINKING WATER ACT (EDWA) _!V.B.1. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinkinq Water Value (status) -- 200 ug/L (Final, 1985) Considers technological or economic feasibility? -- NO DiSCUSsiOn -- An ICLG of 200 uQ/L for 1,1,1-trichloroethane is proposed based upon a DWEL and an assumed drinking water contribution of 20%. A DWEL of 1.0 mg/L was calculatd based on liver toxicity in mice (inhalation study) Reference -- 50 FR A6990 EPA Contact -- Yoqendra Patel, Criteria and Standards Division, ODW / 10 (202)392-7571 / rTS 332-7571; or Drinking Water Hotline / (900)426-4791 1,1,1-Trichloroethane >>> IV.B.2. MAXIMUM CONTAMINANT LEVEL (ICL) for Drinking Water Value (status) -- 200 ugiL (Final, 1997) Considers technological or economic feasibility? -- NO Discussion -- Reference -- 52 FR 25690 EPA Contact -- Yogendra Patel / Criteria and Standards Division, ODW / (202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791 ------<<< 1.1.1-Trichloroethane >>>------ _IY.C. CLEAN WATER ACT (CWA) IV.C.1. AMBIENT WATER QUALITY CRITERIA, Human Health Water and Fish Consumption -- 1.34E+4 ug/L Fish Consumption Only -- 1.03,E+6 ug/L Considers technological or economic feasibility? -- NO Discussion Reference -- 45 FR 79319 (11/28/80) EPA Contact -- Criteria and Standards Division, OWRS (202)475-7315 / FTS 475-7315 <<< 1,1,1-Trichloroethane >> _IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms Freshwater: Acute LEC -- None Chronic LEC -- None arine: - Acute LEC -- 3.12E+4 ug/L Chronic LEC -- None Considers technological or economic feasibility? -- NO Discussion -- The values that are indicated as "LEC" are not criteria, but are the lowest effect levels found in the literature. LECs are given when the minimum data required to derive water quality criteria are not available. Reference -- 45 FR 79318 (11/28/80) 11 EPA Contact -- Criteria and Standards Division, OWR (202)475-7315 / FTS 475-7315 ------<<< 1,1,1--Trichloroethane >------ IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) No data available ------<< 1,1,1-Trich)oroethane >------ _IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA) No data available ------< 1,11-Trichloroethae ------ IV .F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA) IV.F.1. 'RCRA APPENDIX IX, for Ground Water Monitoring Status -- Listed Reference -- 52 FR 25942 (07/09/87) EPA Contact -- RCRA/Superfund Hotline (800) 424-9346 / (202) 382-3000 / FTS 382-7000 ------<<< 1,1,-Trichloroethane >>>------ __IV.G. SUPERFUND (CERCLA) _IV.G.1. REPORTABLE DUANTITY (RO) for Release into the Environment Value (status) -- 1000 pounds (Final, 1985) Considers technological or economic feasibility? -- NO Discussion -- The final RD is based on aquatic and chronic toxicity. Availabl data indicate a 96-hour Median Threshold Limit between 10 and 100 ppm, which corresponds to an RD of 1000 pounds. RD assignments based on chronic toxicity reflect two primary attributes, the minimum effect dose (NED) levels for chronic exposure (mg/day for 70-kg man) and the type of effect (teratogenicity, etc.). The composite score of these attributes for this substance is 6.0, corresponding to an RQ of 1000 pounds. Reference -- 50 FR I3456 (04/04/85) EPA Contact -- RCRA/Superfund Hotline 12 (B0O)424-9-46 / ( 202 )382-000 / FTS 3.2-300O _V. SUPPLEMENTARY DATA Substance Name -- 1.1,1-Trichloroethane CASRN -- 71-55-6 Not available at This time. _VI. BIBLIOGRFHY SLbstance Name -- 1,1,1-Trichloroethane CASRN -- 71-55-6 Last Revised -- 09/01/90 VI.A. ORAL RfD REFERENCES Adams, E.M., H.C. Spencer, Y.K. Rowe and D.D. Irish. 1950. Yarpor toxicity of 1,1,1,-trichloroethane (methyl chloroform) determined by experiements on laboratory animals. Arch. Ind. Hyg. Occup. Med. 1: 225-236. McNutt, N.S., R.L. Amster, E.E. MicConnell and F. Morris. 1i75. Hepatic lesions in mice after continLoLus inhalation exposure to 1,1,1-trichloroethane. Lab. Invest. 32: 642-654. NCI (National Cancer Institute). 1977. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity. Carcinog. Tech. Rep. Ser. No. 3., NCI-CG-TR-3. p. 70. Pendergast, J.A., R.A. Jones, L.J. Jenkins, and J. Seigel. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodiflourcomethane and 1,1- dichloroethylene. Toxicol. Appl. Pharmacol. IC': 270-229. Quast, J.F., B.K.L. Leong, L.W. Rampy and P.J. Gehring. 1978. Toxicologic and carcinogenic evaluation of a methylchloroform 1,1.,1-trichloroethane formulation by chronic inhalation in rats-- interim report after 24 months. Dow Chemical Co., Midland, MI. p. 14 Duast, 3.F., L.L. Calhoun and M.J. McKerna. 1984. Chlorothene YE: A Chronic Inhalation Toxicity and Oncogenicity Study in Rats and Mice. Part I. Results of Findings in Mice. Toxicology Research Laboratory Health and Environmental Sciences, U.S.A. Dow Chemical U.S.A. Midland, Michigan. Torkelson, T.R. , F. Oyen, D.D. McCollister and V.K. Rowe. 1958. Toxicity of 1.1-trichloroethane as determined on laboratory animals and human subjects. Am. Ind. Hvg. Assoc. j. 19! 353-362. 13 1.1,1-Trichloroethane - VI .B. INHALATION RID REFERENCES None ------1,,-Tihoo tae > ------111-Trichioroethane *-- VI .C. CiRCINOGENICITY ASSESSMENT REFERENCES Farber, H. 1977. Manager of Environmental Affairs, Dow Chemical letter to James Price, Chief of Air Quality Data Analysis, Texas Air Control Board. Austin. TX. (Cited in: NCI, 1977) Fishbein, L. 1979. Potential halogenated industrial carcinogenic and ITutagenic chemicals. II. Halogenated saturated hydrocarbons. Sci. Total Environ. 11: 163. Henschler, D., E. Eder, T. Neudcker and M. Metzler. 1977. Carcinogenicity of trichloroethylene: Fact or artifact? Arch. Toxicol. 37: 233-235. NCI (National Cancer institute). 1977. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity. Carcinog. Tech. Rep. Ser. No. 3., NCI-CG-TR-.. Nestmann, E.R.. E.G.H. Lee, T.I. Matula, G.R. Douglas and J.C. Mueller. 1990. Mutagenicity of constituents identified in pulp and paper mill effluents using the Salmonella/mammalian-microsome assay. Mutat. Res. - 79: 203-212. Price, P.j., C.M. Hassett and J.I. Mansfield. 197a. Transforming activities of trichloroethylene and proposed industrial alternatives. In vitro. 14: 290-293. Qluast, 3.F., B.K.J. Leong, L.W. Rampy and P.J. Gehring. 1978. Toxicologic and carcinogenic evaluation of a methylchloroform (1,1,1-trichloroethane) formulation by chronic inhalation in rats -- interim report after 24 months. Dow Chemical Co., Midland; MI. Rampy, L.W., J.F. Quast, B.K.J. Leong and P.j. Gehring. 1977. Results of long-term inhalation toxicity studies on rats of 1,1,1-trichloroethane and perchioroethylene formulations. In: Proc. Int. Cong. Toxicol. Toronto. Simmon, V.F., K. Kauhanen and R'.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. In: Progress in Genetic Toxicology, D. Scott et al., Ed. Elsevier/rlorth Holland Biomedical Press, Amsterdam. Snow, L.P., B.C. Nair and B.C. Castro. 1979. Mutagenesis testing of methylene chloride and 1,1,1-trichloroethane in Salmonella strains TA1i0 arnd TA9. Northrop Services, Inc., Research Triangle Park, NC. Taylor. 6. 197. Personal cormLnication. NIOSH, Norgantown. NV. (Cited in: U.S. EPA, 1934a) U.S. EPA. 1984a. Health Effects Assessment for 1.1,1-Trichloroethane. Prepared by the Office of Health and Environmental Assessment., Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and 14 Remedial Response, Washington, DC. U.S. EFA. 1984b. Health Assessment Document for 1,1,1-Trichloroethane. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle F'ark, NC. EF'A-600/8-82-OO3F. ------<<<-X 1,1,1-Trichloroethane > ------ VI .D. DRINKING WATER HA REFERENCES Bruckner, J.B., S. Muralidhara, W.F.Mackenzie, G.M. Kyle and R. Luthra. 1985. Acute and subacute oral toxicity studies of 1,1,1-trichloroethane (TRI) in rats. The Toxicologist. 5(1): 100. McNutt, N., R. Amster, E. McConnell and F. Morris. 1975. Hepatic lesions in mice after continuous exposure to 1,1,1-trichloroethane. Lab. Invest. 32: 642-654. U.S. EPA. 1985. Final Drinking Water Criteria Document on 1,11- Trichloroethane. Office of Drinking Water, Washington, DC. Vainio, H., M.A. Parkki and J.A. Marniemi. 1976. Effects of aliphatic chlorohydrocarbons on drug-metabolizing enzymes in rat liver in vivo. Xenobiotica. 6: 599. SYNONYMS Substance Name -- 1,1,1-Trichloroethane CASRN -- 71-55-6 Last Revised -- 03/31/87 71-55-6 AEROTHENE TT CHLOROETENE CHLOROETHENE CHLORQETHENE NU CHLOROFORM, METHYL- CHLOROTHANE NU CHLOROTHENE CHLOROTHENE NU CHLOROTHENE VS CHLOPTEN ETHANE, 1,1,1-TRICHLORO- INHIBISOL METHYLCHLOROFORM METHYLTRICHLOROMETHANE NCI-C04626 RCRA WASTE NUMER U226 STROBANE alpha-T 1,1,1-TCE 1,1,1-TRICHLOORETHAAN 15 1,1 . 1-TR I CHLORAE THAJ Trichloroethane. 1,1,1-- al pha- TR I CHLOROET HANE 1 , 1, 1-TR ICLORET ANO TRI-E T HANE UN _283. 16 APPENDIX I AVERAGE DAILY DOSE CALCULATIONS a Chronic ADD (ADDC) a Lifetime ADD (LADD) ch 0 < 0 c 0 0 40 0 c2 4 < 4 - < -C C~~~~ C aOOOQ=x x z 0"O 00000000 WhW W Mhi 0 C, 0 5C2 (9 0. 0 -9~ O(On O -ih Oi n ( 4% -h4c Z ------0 -- 42 n r- - --n n--- - C6 44 "in n in in in in in n in in in n n n in in in in in in in in n in in| E2 0004(00 0 0044045D 2%4cc 'I .4. A U in in in in in in in in in in in in in in in in in in in in in in i 0 V 4. 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Z Z -I Z --- Z I 000 - Z 0 Z Z - O10 EL3 W W 2 E.3 Cd E4 Sc .0ec C1 eq .ic 0 i w -- 0 C - . 0 S CA Kn W 0 0 0 0 0 0 0 00 0 0 0 0 00 0 0 0 0 0 O 0 0 0 0 in in Sn IA S IA IAi A In n sne A en Sn sAn in n Sna i In in n 9 Sn Sn Sn IA n in n in in inn n Sn Sn Sn Sn in i ina n n Sn In Sn 4 C e in S IA S IA in i n in in in n Sn n Sn n in in in in In In In 030 000.00000000000 O W E 0 - 0 C 0 11 N E 9 9 9 9 9 9 9 it 0i9 9 0 0 0 1t 0 0 0 I OC' Sm CO 0 02 02 m p C - 0 02 1404uN >. -C K- -e -i - -1 I , I - I -.- -.- .- .- -.- - - I - I - I .-- I - , I , I .- ..-,S -.- HP.i - .0d, 0. P4 HO C 0 -Ku 64 4o1.. 400iwo 2 11210. C 0EA 0 000 Cc X 0 00 C 0 0 oo C .0C - ..N i 0000000000000000000000000ezeE CO ..------O------O .. 0 0 'OW M it 0 CN a PC 'C -, @0 C C O n . - g C-0 C C C e- C a,------.------a,0 0 Lu a,0 -. >.-4 Lii CC4C6. O r ZZ 1 c.a 0N 1 4 ' 0 Z . 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La 1 Ov "Ot.- us 0 O e- w occcc mow c -i c 0 - -- n F.... e ... - . 0hM E" i in i in i in in n "i ini in in in in in in in in i'n in in in in in ini n i in in in in in in in in i in in "i in in in in i"n i'n in in i so. ~ in i n i i"n i' in in in in in ini in in in in in in in 'i in in in i in in in in in in in in in in in in in in in in in in in in i in in in ------E- U V. -- - - -,------>-- .- l .- -- - 0C C- Fa CA z Q 0 0 ------'------H La I C-a -n U EN1 '. M n 11 H2 - 0 -- 0 uO o 00000000 0 0 0 0 0 0) 0 0 00 0 - -- U-- e C ao U...... --...e.... -.....- - - 0 C C - ldO 4 0 . 0 cVO-- -. 0 -- ' r. - 0 0 .l"" 0 O 15.0 -iEC D-Ia - -- O eA e 0-a' 0. IC -- MW0-i - O e C a U -I - - CiaCluC M @ O @DO @ U - .CE E4" , W @ @ @-e O , @,-I C -" -'------U ---- U D--- -- aI& - -- 3 4 - C 0 p 0E a ~ ~~~~ I o 0 0 00 00 o o o o o o 1^o o - - - 00000Zo0 Zz000 OZPOOZZC0Zo 0o a g N ------ C 0 W -"V x S.. CA 0 SC C C 0 m C C C t Cu u C t C- C x CC 0 000 0 0 00e 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 W C - r- O O O O O- r O- O- r r O O- O- O- O- r r O O r- O O- - 3 0 i i i i i i i I i i e i .0 eb In. N3 U - z E- 10 E-(0 .0 e13 2 C CC CC C C to C C C C C C CeC C C C C C 0 E- S 0: 14 C-M 0. PC. E- '0 4 D 'C '0w- A. (0 Oeeae 4 E. (0 D~ Ce. S0 xCa14 0 N. H tox 13a lC O0 H U :1 m 0ni n An ni rn 14 a 0- Ca A0 E e e a n i C . 2 Ca. 00El 0 0 0 0 0 0 0 0 . 0 0 0 'x Ca 0 2 PQ C e 13 .------O---- 0r--r r 2r-r- r--r- r-r0 - N ,C C- C C CC.C C CC-C C CC.C C . c a 1-4 ::: 3 6 U - 400A0O .O ac OU'O a ,. -- 'a 1- o --- -4 4---4 ------C 0 en 0 - (0 C e Sa 2 - ae CCD' E C 0 0000 0000 0 0 0 0 e o0 CCe U' 'U U' 'U U'3U U' 'U U U' 'U U' 'U U' 'U @ U U 13.0 0. Coo eeo a o o e 131 0 - 440,'041( 0g -fl0+ U' . O C-C'' O - C - 0 I -- *a u 0 0 a (44EAA 0 E- a ' 013 s3 m 0 0 o eo o[. Sa 1313 UN O C C2 i2-- EEoOO eaem- C 0Cy 13. - u J C - aaa -eo Cua C - 1213- - .se13 e C NC - .. ee, c.cr 130 - 0 ea ' C -' .- <0< OO C > -00 -u . 2&,<> C - 13-' IC-a C < 4 4 4 i . 4 4 4 C..0 4 . W n @C i C C 4 w < 4 w I z z o II o o o o co i zo I n r I I ID - cN M r .g. U, IN = OS .C NflPr- OSC 4 4' 7 MM M 9 9 M i 1: 9 tM M 0! M -SC -n-- O ------J 0 -1 C r 0 0 0, C - Q U 0 0 0 Q 0 . 0~~~ 99 9.2.2 , ...... 0. 2. 2.0 01.2.0M... 9 0 -o .- .--IC . -N - ,- to W O C C 00 00 0 00 C C 000 0 0 C C 0 0 C C F. 2Ca H 0 z CA4r 1 H A. w x CA H4 oi, Al m 03 H 0 114 2. W 0 0 - EI I~~~~I6 rIr r r r l 0 N ,r is r , r iri , -:p, r ' L.-. . r6 S0., aa 0 0 o C0 00 00.CC C 00 C- C C 0 0 , C C .- S Cd 0000 ID0000 -0 |> 0 000 0 0 C C -- I ,-- - E- - -.- '- - -- a -- I-@ - 0 0 a E -- |-. a -- 2 O O E .C Ei - a IDa 0 0E: C M 0 u. N 41DD Oy @@ @[.5L o " - -- OO -EC MCD .- a -- W WE E@ O e .. 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Q0 -'CC C C -- o C C C Ce - 0 e 0 0 0 ee.7ea r f eeem 0 -1 U.- C C C C C C C C-CC C C C C C ,- 0 00 0 0 0C 0 H 000 0 00 0 .- 0 0 'CC 4"n MO M M CM Mnn MnM M MM M MM M .1"| --, 44' 4--' 44 C 4 -1 U, fl C 01Cf -u -1 00 0 C* ,I0 '-''. CC 0 ,- 02 -I- 120 'l 2 0 2 0 E E . C C E 0 -ao '. .2 -1 0. C@ C a C C O -. 1 E M 2 O O -e i-1|- - -- V a-I.iC1 M O @C 4 1E C D M a-- - In C -O 0 O I C C G 41 - -.- D Cs f iCa -- dCC 2. C - C C & . NL O U @ -| 0 xC " -"' fa 4 4 < C 04.- DU - -I 00a3" Z[ - . y PARAMETER KEY: INHALATION OF GASEOUS OEM (VAPORS) [OHM]air - representative concentration of gaseous OEM (vapor phase) in air at the exposure point [ug/m] VR - daily respiratory volume [m'/day] BAF - bioavailability adjustment factor [unitless] (F x Dl) - frequency of exposure [days/year) D2 - duration of exposure [years] C - conversion factor {mg/ug] BWavg - average body weight [kg] AP * averaging period [years) DERMAL CONTACT WITH SOILS [OHM]soil - representative concentration of OHN in soil at the exposure point [mg/kg] SA - skin surface area in contact with soil [cm2/day] MS - mass of soil in contact with the unit surface area [mg/cm'] BAF - bioavailability adjustment factor [unitless] DAF - dermal absorption factor [unitless] (F x Dl) - frequency of exposure [days/year] D2 - duration of exposure (years] C - conversion factor [kg/mg] BWavg - average body weight [kg] AP - averaging period [years] INCIDENTAL INGESTION OF SOILS [OHMsoil - representative concentration of OHM in soils [mg/kg] I - daily soil ingestion rate [mg/day] RAF - bioavailability adjustment factor [unitless) (F x DI) - frequency of exposure [days/year] D2 - duration of exposure [years] C - conversion factor (kg/mg] BWavg - average body weight [kg] AP - averaging period [years] DERMAL CONTACT WITH GROUNDWATER [0HM]gw - representative concentration of OHM in groundwater [mg/l] SA - skin surface area in contact with groundwater [cm 3 ] PC - permeability constant [cm/hr] BAF - bioavailability adjustment factor [unitless] (F x DI) - frequency of exposure [days/year] D2 - duration of exposure [years] Cl - conversion factor [1/cm3] C2 - conversion factor [hours/day] BWavg - average body weight [kg] AP - averaging period [years] 7 APPENDIX J INDIVIDUAL RISK CALCULATIONS I JI i V C iO E in EOC C'. MOW WC C CC4 O C C O C U O 1 I i I I i I I I 4 I 1 O. MM MMM M.MM CC C M M M 0 4000 0490=40 -0 0 in in S.-- U- En Ci Ed td L3 t. Ed E E 0 - C Ni u 0 N O .C z M C E U ZI - 44 z Z444 Z z44 z44z - U 40 -049 4 0 U -4 0 i of M 00 o Qo C I... 6, C "-' C CltC 0) J- vC A mZ - - x z z z w Z x m m zZ Z E z E- 0 Z 7 0 C 0 7-Z 0 C Cmm0 M C 0 1 1 r i i ZD E- 43 a: wi 0 O E 43 0Cl 43 94 0 Cli 04 oc £0 m-4 14 0 0 m w o0 0 u O o 0 o O 0 o 1 o- o E3 40 0D3 4 E 0 4 < W < 1- 1 00 C -x 0 k c u E C .C 06 Ci C m r n O A C Ci- C C x 0) 0 - Li M U Ci .0 .C C Ci C V 0 i Li - v 0 a, o-~ o- C o *S C CC-- --c .-.ii Ux-i .l C U S o -a-sC -C E2 - a C -I C ci C Ca CA .4 - Li L 0 0 --a 0101 U O U C iC 2 e U EC :i i i I -i w wSC 2 -CeU -4 U a -s a-.* .- 4 "4 C zi 0 --I C-- D.1 D1. 0. oUU C - | -C ic -Ci...E ""4. => CC-- C C 03 04 U U U - I . 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C C 44: @C v UU .4 C C e U '.44 UU8 m a 0 0 CSG O',--D . -- C i H 0 a 12 Ci Ha X QUQ .& 3 0O ~ -0 00 z 12 APPENDIX K ENVIRONMENTAL CHARACTERIZATION INFORMATION CORRESPONDENCE WITH THE MASSACHUSETTS DIVISION OF FISHERIES AND WILDLIFE NATURAL HERITAGE AND ENDANGERED SPECIES PROGRAM C0)1)0)Ve1! t M , iS"'1ChfL)t C Divisionof Fisheries &Wildlife Wayne F MacCallum, Director NHESP File: 93j-31j 6 June 191? Sara B. Float Eckenielder. Inc. 227 French Landing [yr. Nashville, IN 37226 Re: Pemediation site. Necford. 'A. Dear Hs. Floit: Thank you for contacting the Natural Heritage and Endangered Species Program regarding rare species and ecolocically significant natural communities in the vicinity of the Medford site as described in your fax of 4 June 1991. At this time, we are not aware of any rare and endangered species within tne vicinity of the proposed project. Please note that this determination is based on the most recent information available in tne Natural Heritace database, whicn is constantly being expanded and updated through ongoing research and inventory. Should new rare species information become avaalable, this determination may be reconsidered. ihis evaluation coes not consider the Dotential impacts to inland fisheries. To receive sucn an evaluation contact rMark Tisa, Assistant Director for Fisheries, DivIsion of Fisheries end Wildlife. Field HeaOquarters, Route 135, Westborough. NA 01581. Please contact Jay Copeland, Environmental Reviewer, if you have any questions. Sin cerely, Diane Lauber Environmental Review Assistant Natural Heritage & Endangered Species Program 100 Caimbridge Street, Boston, MA 02202 (617) 727-9194, (617) 727-3151 An Agency of the Lparlrnent of Fisheri., .kil e Envjrrerena I \x forcement June 4, 1991 6255.05 Natural Heritage and Endangered Species Program Division of Fisheries and Wildlife 100 Cambridge Street Boston, MA 02202 Attn: Environmental Review I am an environmer.tal scientist employed by ECKENFELDER INC. We are currently working on an environmental assessment for a client located in the Medford area of Boston, Massachusetts. We are interested in knowing the types and locations of state and federal threatened or endangered species and of critical or special habitats (both for plant and animal). We are also interested in information regarding wetland areas, scenic rivers and state natural areas, and general types of biota in this region. We will use this information in the development of a remediation plan for our client. I have enclosed a portion of the USGS topographic quadrangle containing our area of interest. Please send any information you can provide on the listed topics through Federal Express delivery. Our delivery number is 0370-0344-1. As our schedule is tight, your rapid response would be greatly appreciated. Thank you for your assistance. Sincerely, ECKENFELDER INC. Sara B. Floit Environmental Scientist Risk Assessment Services USGS j90s sk oS-o\ '7orth MA o-, 000O -sudfre i-T')o VV\ P U I I I CORRESPONDENCE WITH THE U CITY OF MALDEN PLANNING BOARD I U U I I I U I I U U U I I Maidlen Government Center City of Malden Two Hundred Pleasant Street Maiden, Massachusetts 02148 Massachusetts July 2, 1991 Sara B. Floit Echenfelder, Inc. 227 French Landing Drive Nashville, Tennessee 37228 Dear Ms. Floit: As I stated in our telephone conversation, the Conservation Commission (Chairman Maccario), and not the Planning Board are the local experts regarding wetlands in Malden. In addition, this city does not have an official "wetlands map". The only obvious wetlands within the area you have designated in Malden are the Malden River, the creek at the Medford line between the river and the railroad tracks, and Fellsmere Pond off Fellsway East at the northern extreme of your circle. With regard to scenic rivers, natural areas, or critical or special habitats for plants and animals, I cannot offer you any information other than the fact that this is a highly urbanized area. Specific information regarding these subjects may be available through the Commonwealth of Massachusetts (try (617) 292-5500). Sorry this was not faxed, but we must receive payment of $1.00/sheet in advance to fax material. Sincerely, Alfred L. Thurlow Principal Planner ALT/ec Encl-map US GS 196s retr asfo n 1\orC)Y-& M A S0C)0 -s Jmr +-Zpo vA0 &Trp June 25, 1991 6255.05 Fred Thurlow Planning Department City of Malden Malden Government Center 200 Pleasant Street Malden, MA 02148 Dear Mr. Thurlow: Per our telephone conversation, I am interested in knowing the locations of any wetland areas that are in the area delineated in the enclosed USGS topographic quadrangle. I would also be interested in any information regarding scenic rivers, state naturals areas, or critical or special habitats for both plants and animals. This information will be used in the development of a remediation plan for our client. Please send any information you can provide on the listed topics either through fax (615-256-8332), if brief, or through Federal Express delivery (0370-0344-1). Thank you for your assistance. Sincerely, ECKENFELDER INC. Sara B. Floit Environmental Scientist Risk Assessment Services Enclosure CORRESPONDENCE WITH THE MASSACHUSETTS DEPARTMENT OF ENVIRONMENTAL MANAGEMENT INLAND ACEC PROGRAM Commonwealth of Massachusetts Executive Office of Environmental Affairs Department of Environmental Management June 24, 1991 100 Cambridge Strcei Sara B. Floit Boson Eckenfelder Inc. Massachusells 227 French Landing Drive 02202 Nashville, TN 37228 Dear Ms. Floit: I am writing in response to your June 21, 1991 letter requesting information regarding the Inland ACEC Program. I have spoken with Brad Barr of the Massachusetts Coastal Zone Management Office who told me that he spoke with you last week and is sending you information regarding Coastal ACECs and the ACEC Program. To avoid sending you duplicative information, enclosed is a list of Inland ACECs and "an Inland ACEC Program Guide. If you need additional information, please let me know. In regard to the project area that is circled on the map that you sent me, there are no inland ACECs located in this area. Sincerely, leslie Ldchonok Director, Inland ACEC Program Enclosures Prime--d onl recceld mtper Commonweathh of Massachusetts Executive Office of Environmental Affairs Department of Environmental Management June, 1991 100 Cambridge Street Boston INLAND AREAS OF CRITICAL ENVIRONMENTAL CONCERN (ACECs) Massachusetts 02202 , (617) 727-3160 1) Westboro Cedar Swamp Fay: 727-2630 o Designated 1975, located in Westboro and Hopkinton o Approximately 1,500 acres Division of Resource Conservation 2) Cranberry Brook Watershed o Designated 1983, located in Braintree and Holbrook o Approximately 1,000 acres 3) Golden Hills o Designated 1987, located in Saugus, Wakefield and Melrose o Approximately 450 acres 4) Hockomock Swamo o Designated February, 1990, located in Easton, West Bridgewater, Bridgewater, Raynham, Taunton and Norton o Approximately 17,000 acres 5) Schenob Brook Drainaae Basin o Designated August, 1990, located in Sheffield and Mount Washington o Approximately 14,000 acres 6) Canoe River Aguifer o Designated May, 1991, located in Easton, Foxborough, Mansfield, Norton, Sharon and Taunton o Approximately 17,000 acres Primed on rle.\C. Cd I)1per - - - --. - t 5- '. - s -R-- S 7 . y -- - .4"" .. 4 - . - n - - - ' - - 7-2- --. R 0 . y HB ow( E3 -32 Ono ir ------=-- O .,- ,, +--- L. -- .-- O "E E $""c. 2 -I 2 C em oI 2., .- si '- 2 u U- an . . -. n --- e en So - 2 - . ....g. . - - e - --- ye - ---* r= .2 C -C.2 - x .- C c z :z 3- M- "!i '"-- z e r * . c g ' 2 nC - =E 0 o 3= = A' C e C. o i:-9 --=3< T - E -- ee. <.:a = =-- -g 2,,-.a ao :o -C .2 tt , e g -;;:y e -. = - .. ..- .. C a - -:-- "IN t' i .3.2 -- 2 2es ...C =3 = --2 '.:' .. 2 ..,, -- ' - - C -~ 2 - - u y--U - 'a 3f - - .-. r - 0 . C 5' C- u y- o2- - oZ F v -k- ZE . -L U- -N June 21, 1991 6255.05 Mr. Leslie Luchonok Department of Environmental Management 136 Damon Road Northampton, MA 01060 Dear Mr. Luchonok: Please consider this letter a request for "Area of Critical Environmental Concern" (ACEC) information. The site of specific interest is located on the USGS 7.5 x 15 minute quadrangle map of Boston North, Massachusetts in the Medford/Malden region (see enclosed map). As part of.our investigation of this area it is necessary for us to obtatin all relevant information regarding critical sites or areas of environmental concern, As it is not clearly understood what form the ACEC information is presented (i.e., maps, descriptive text, etc.), please include any explanatory information needed to interpret the ACECs. it would also be helpful to have a description of what exactly an ACEC is, and how it is used in the regulatory process within the State of Massachusetts. As our project schedule is quite short, your prompt attention to this request would be greatly appreciated. If the information is easily transmitted by fax, please send it via our fax number 615/256-8332. If it is necessary to transmit the information by mail, please send it via Federal Express. Our delivery number is 0370-0344-1. Thank you for your assistance. Sincerely, ECKENFELDER INC. Sara B. Floit Environmental Scientist Risk Assessment Services Enclosure USGiS (9 S [V\+ s iP rr 'Mcden 6 vL bos4on - dor, t O 00 -su, me-tr i,e i&b D ap