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p-CHLORO-o-TOLUIDINE CAS No: 95-69-2 p-CHLORO-o-TOLUIDINE HYDROCHLORIDE CAS No: 3165-93-3 I. PHYSICAL AND CHEMICAL PROPERTIES (From HSDB, 1994) p-Chloro-o-toluidine Molecular weight 141.61 Boiling point 241 °C Melting point 30 °C Vapor pressure not available Air concentration conversion 1 ppm = 5.79 mg/m 3 p-Chloro-o-toluidine hydrochloride Molecular weight 178.07 Boiling point not available Melting point not available Vapor pressure not available Air concentration conversion 1 ppm = 7.3 mg/m 3 II. HEALTH ASSESSMENT VALUES Unit Risk Factor: 7.7 E-5 (µg/m 3 ) -1 Slope Factor: 2.7 E-1 (mg/kg-day) -1 [Male and female mouse hemangioma and hemangiosarcoma tumor data (Weisburger et al., 1978; NCI, 1979), contained in Gold et al. database (1984), expedited Proposition 65 methodology (Cal/EPA, 1992), cross-route extrapolation.] III. CARCINOGENIC EFFECTS Human Studies IARC (1990) reviewed studies by Currie (1933) and Uebelin and Pletscher (1954) which investigated bladder tumor incidence in small groups of male workers exposed to p-chloro-o-toluidine; one case of bladder carcinoma was discovered (Currie, 1933). A cohort study by Ott and Langner (1983) investigated 342 male workers involved in the manufacture of organic dyes in the US between 1914 and 1958. One plant area involved 117 workers with potential exposure to p-chloro-o-toluidine and other raw materials and intermediates, including ortho- 205
toluidine. Followup of this subcohort from 1940 to 1975 indicated that a nonsignificant excess of total cancer deaths occurred (12 observed, 8 expected) and no bladder cancer was observed. Two studies were conducted on a cohort of 355 male workers in p-chloro-o-toluidine manufacturing plants in the Federal Republic of Germany (FRG) who had been followed up for mortality from 1929 to 1982. No deaths due to bladder cancer were found in the first study (Stasik et al., 1985). The second study examined a subcohort of 116 workers exposed prior to 1970 (the implementation date of improved exposure controls) with presumed high p-chloro-o-toluidine exposure levels. Excluding 2 cases of urinary bladder carcinomas in the current work force, 6 cases of bladder carcinoma were found between January 1983 and June 1986 in hospital and other institution records. No cancer registry data was available for the area of the FRG where the plant was located; cancer registration rates for a different area of the FRG was therefore used as a basis of comparison. The expected number of tumors was 0.11 based on sex- and age-specific cancer rates. Two patients had hemorrhagic cystitis thought to be due to massive exposure to p-chloro-o-toluidine. Cigarette smoking was discounted as a confounding variable after reviewing patient smoking histories (3 patients were nonsmokers). Quantitative exposure data was unavailable, but the predominant chemical exposure was to p-chloro-o-toluidine; however, exposure to other amines could have occurred. Animal Studies Male and female random-bred CD-1 albino mice (derived from HaM/ICR mice) and male Charles River CD Sprague-Dawley-derived rats (25/sex/group) were fed diets containing p-chloro-o-toluidine hydrochloride (97-99% pure) as part of a larger carcinogenicity study of several compounds (Weisburger et al., 1978). Mouse exposure levels were 0, 750 or 1500 mg/kg diet and 0, 2000 or 4000 mg/kg diet for males and females, respectively; the mice were fed treated diet for 18 months, followed by an additional 3 month observation period. Rats were fed diet containing 2000 or 4000 mg/kg diet p-chloro-o-toluidine for 3 months; the doses were then reduced to 500 and 1000 mg/kg diet for 15 months. An untreated control group (25 males) was included. All rats were killed after 24 months. Tumor incidence differences between control and exposed rat groups were not statistically significant. Hemangiomas and hemangiosarcomas were observed in male and female mice; tumor incidence data is listed in Table 1. These tumor types were found in 5/99 male and 9/102 female pooled controls from the larger carcinogenicity study, but were not present in the simultaneous controls. Diets containing p-chloro-o-toluidine hydrochloride (99% pure) were fed to groups of male and female B6C3F 1 mice and Fischer 344 (F344) rats (50 animals/sex/species/treatment group) (NCI, 1979). Exposure levels for mice were 3750 or 15000 and 1250 or 5000 mg/kg diet for males and females, respectively. Exposure levels for rats were 1250 or 5000 mg/kg diet. Untreated control groups (20 animals/sex/species) were included. Exposed animals were fed treated diet for the duration of the study. All surviving mice were killed at 99 weeks; however, all high-dose females had died by 92 weeks. All surviving rats were killed at 107 weeks. Exposure to p-chloro-o-toluidine did not affect mortality of either male or female rats; a dose-related increase in mortality was noted for both male and female mice (NCI, 1979). However, sufficient 206
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Air Toxics Hot Spots Program Risk A
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Prepared by: John D. Budroe, Ph.D.
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This document is one of five docume
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TABLE OF CONTENTS PREFACE i INTRODU
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N-Nitrosodimethylamine 401 N-Nitros
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Hot Spots Unit Risk and Cancer Pote
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Additional ATES and PETS documents
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data. If several data sets (dose an
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US EPA Calculation of Carcinogenic
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exposure to a concentration of 1 µ
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incidences for each of the dose lev
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computes the surface area of a sphe
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Comparison of Hot Spots Cancer Unit
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Gold, L., de Veciana, M., Backman,
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Animal Studies Rats Woutersen et al
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ased on sufficient evidence of carc
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ACETAMIDE CAS No: 60-35-5 I. PHYSIC
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Methodology Expedited Proposition 6
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cancer mortality. However, US EPA (
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Table 2. Lung adenoma incidence in
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Table 3 (continued). Acrylamide-ind
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Robinson M, Bull RJ, Knutsen GL, Sh
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Also, a trend was observed correlat
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eported. Cause-specific expected de
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Bio/Dynamics Inc. conducted a study
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examination. Interim sacrifices wer
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Table 8. Tumor incidence in male an
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Gaffey WR and Strauss ME. 1981. A m
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(technical grade; 98% pure) by gava
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International Agency for Research o
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still alive in the low-dose control
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ANILINE CAS No: 62-53-3 I. PHYSICAL
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fibrosarcomas, stromal sarcomas, ca
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ARSENIC (INORGANIC) CAS No: 7440-38
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elationship between arsenic exposur
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al. (1988) did not induce lung tumo
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A risk assessment was also conducte
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Chen C, Chuang Y, You S, Lin T and
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Schrauzer G, White D, McGinness J,
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Table 1: Summary of epidemiologic s
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had at least one animal demonstrati
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mesothelioma, recommended lifetime
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National Institute for Occupational
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BENZENE CAS No: 71-43-2 I. PHYSICAL
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Animal Studies Available experiment
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Table 3: Summary of NTP bioassay re
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Table 4: Summary of benzene low-dos
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Maltoni C, Conti B and Cotti G. 198
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a benign tumor of the kidney. No ba
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al. (1968) found no tumors in lifet
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following relationship, where C(t 1
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Miakawa M. and Yoshida O. 1975. Pro
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human population and that BPDE-DNA
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demonstrated the tumor initiating a
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Table 4: Bronchoalveolar tumors fro
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Table 5: IARC groupings of PAHs, mi
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Table 6 (continued): IARC Group 3 P
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Potency Equivalency Factors (PEF) f
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This was rounded to a PEF of 0.1. 1
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experiment (Takayama et al., 1985)
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Deutsch-Wenzel RP, Brune H, Grimmer
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Krewski D, Thorslund T and Withey J
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U.S. Environmental Protection Agenc
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Sorahan et al. (1983) studied cance
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Lijinsky W. 1986. Chronic bioassay
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the drinking water (Schroeder and M
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Table II. Effective dose, upper-bou
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BIS(2-CHLOROETHYL)ETHER CAS No: 111
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IV. DERIVATION OF CANCER POTENCY Ba
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BIS(CHLOROMETHYL)ETHER CAS No: 542-
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Table 1. Bis(chloromethyl)ether-ind
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Drew RT, Laskin S, Kuschner M and N
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ates for the 1968 U.S. male populat
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Table 1: Incidence of primary tumor
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National Institute of Occupational
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was less than 0.05 when controlling
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up period. The final cohort include
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If the cadmium-exposed workers incl
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Page 165 and 166: were exposed to a continuous (23.5
Page 167 and 168: procedure (NLIN), the parameters we
Page 169 and 170: International Agency for Research o
Page 171 and 172: Two reports were published on cance
Page 173 and 174: Mendel rats, respectively), and sub
Page 175 and 176: Eschenbrenner A and Miller E. 1946.
Page 177 and 178: III. CARCINOGENIC EFFECTS Human Stu
Page 179 and 180: cancers, were less than expected. T
Page 181 and 182: and no cases of cancer (although cl
Page 183 and 184: There was a statistically significa
Page 185 and 186: NTP (1982a) also conducted an carci
Page 187 and 188: Several pathologists have independe
Page 189 and 190: hepatocellular adenoma/carcinoma tu
Page 191 and 192: carcinogenic potency may decline in
Page 193 and 194: Cochrane W, Singh J and Miles W. 19
Page 195 and 196: North Atlantic Treaty Organization,
Page 197 and 198: CHLORINATED PARAFFINS (average chai
Page 199 and 200: ased on dose-response data for beni
Page 201 and 202: chloroform in drinking water with k
Page 203 and 204: Overall, the present epidemiologica
Page 205 and 206: female dogs received toothpaste bas
Page 207 and 208: Calculated q 1 * values from the ab
Page 209 and 210: Hogan MD, Chi Py, Hoel DG and Mitch
Page 211 and 212: Table 1. Study design summary for N
Page 213: V. REFERENCES California Environmen
Page 217 and 218: feeding studies on by NCI (1979) us
Page 219 and 220: CHROMIUM (HEXAVALENT) CAS No: 18540
Page 221 and 222: expected rate may be inflated becau
Page 223 and 224: Oral Borneff et al. (1968) exposed
Page 225 and 226: CREOSOTE (COAL TAR-DERIVED) CAS No:
Page 227 and 228: from an inhalation exposure study (
Page 229 and 230: U.S. Environmental Protection Agenc
Page 231 and 232: Table 1. Study design summary for N
Page 233 and 234: Methodology Expedited Proposition 6
Page 235 and 236: Table 1. Experimental design for ca
Page 237 and 238: Hazardous Substance Data Bank (HSDB
Page 239 and 240: Table 1: Tumor induction in Fischer
Page 241 and 242: Hazardous Substance Data Bank (HSDB
Page 243 and 244: Table 1. Experimental design of 2,4
Page 245 and 246: Methodology Expedited Proposition 6
Page 247 and 248: Additional analysis of these data b
Page 249 and 250: IV. DERIVATION OF CANCER POTENCY Ba
Page 251 and 252: Jackson RJ, Greene CJ, Thomas JT, M
Page 253 and 254: Table 1. Tumor incidence in rats ex
Page 255 and 256: Girard R, Tolot F, Martin P and Bou
Page 257 and 258: exposed more than 16 years before t
Page 259 and 260: interpretation of dose extrapolatio
Page 261 and 262: 1, 1-DICHLOROETHANE CAS No: 75-34-3
Page 263 and 264: Table 1b. Study design for carcinog
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National Cancer Institute (NCI) 197
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mice, hepatocellular carcinoma inci
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V. REFERENCES California Department
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DAB/day by gavage for the life of t
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2,4-DINITROTOLUENE CAS No: 121-14-2
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Ellis et al.(1979) (also reported b
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Final Statement of Reasons for OAL,
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to the small sample size and short
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In an inhalation study, Torkelson e
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V. REFERENCES American Conference o
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EPICHLOROHYDRIN CAS No: 106-89-8 I.
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espiratory tumors were noted in the
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Table 4. Epichlorohydrin-induced fo
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Konishi Y, Kawabata A, Denda A, Ike
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exposed to arsenicals for 20 months
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espectively (all statistically sign
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ETHYLENE DICHLORIDE CAS No: 107-06-
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Several factors have been suggested
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myelogenous leukemias (4 and 8 year
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statistically significant. CDHS not
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combined with the incidence in the
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incidence of primary brain tumors.
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Table 6 (continued): Organ/Sex Mali
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An Upper 95% Confidence Limit (UCL)
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ETHYLENE THIOUREA (ETU) CAS No: 96-
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male and female rats. Tumor inciden
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FORMALDEHYDE CAS No: 50-00-0 I. PHY
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presented an extension of a previou
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Methodology In developing a spectru
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Casanova M, Morgan KT, Steinhagen W
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Tobe M, Kaneko T, Uchida Y, Kamata
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Table 1. Hexachlorobenzene-induced
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50 pups (F 1 ) of each sex were ran
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Ertürk E, Lambrecht RW, Peters HA,
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Table 1. Liver hepatoma incidence i
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1988). An airborne unit risk factor
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HYDRAZINE CAS No: 302-01-2 I. PHYSI
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Methodology Inhalation A linearized
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LEAD AND LEAD COMPOUNDS (INORGANIC)
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and other occupational carcinogens
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y inhalation is similar for rats an
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Goyer RA. 1992. Nephrotoxicity and
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LINDANE (g-Hexachlorocyclohexane) C
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Using these relationships, a human
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METHYL TERT-BUTYL ETHER (MTBE) CAS
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Tumor incidences according to the r
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kidney changes indicative of chroni
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Interspecies scaling for oral doses
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Table 4 (continued): Dose Response
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Experimental Pathology Laboratories
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Animal Studies Male and female HaM/
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Gold L, Sawyer C, Magaw R, Backman
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Using the statistical tests (one-ta
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Table 1: Methylene chloride-induced
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Significant treatment-related incre
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National Toxicology Program (NTP) 1
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noted; however, the study duration
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Crump KS, Howe RB, Van Landingham C
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Table 1. Michler’s ketone-induced
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NICKEL AND NICKEL COMPOUNDS CAS No:
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the high exposure group was 14.0. A
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male and 121 female rats, was expos
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2.1 - 2.6 × 10 -4 (µg/m 3 ) -1 .
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The increased incidence of bladder
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A linearized multistage procedure w
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N-NITROSO-N-METHYLETHYLAMINE CAS No
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Hazardous Substance Data Bank (HSDB
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propylamine in drinking water at 0.
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N-NITROSODIETHYLAMINE CAS No: 55-18
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Table 2. Treatment groups, concentr
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California Department of Health Ser
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animals and the second generation t
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ationale for selection of the OEHHA
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A unit risk value based upon air co
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N-NITROSODIPHENYLAMINE CAS No: 86-3
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Methodology Dosage estimates of NDP
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Crump KS, Howe RB. 1984. The multis
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Table 1. P-Nitrosodiphenylamine-ind
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N-NITROSOMORPHOLINE CAS No: 59-89-2
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N-NITROSOPIPERIDINE CAS No: 100-75-
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Table 3. N-Nitrosopiperidine-induce
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Crump KS, Howe RB, Van Landingham C
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testicular tumors were noted in the
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PARTICULATE MATTER FROM DIESEL-FUEL
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etired railroad workers who had had
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employment (χ 2 test for trend: p
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elevated smoking-adjusted risk esti
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Table 1 (continued): Reference Miln
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Table 1 (continued): Reference Damb
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Table 1 (continued): Reference Burn
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Table 1 (continued): Reference Raff
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Table 1 (continued): Epidemiologica
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Table 1 (continued): Epidemiologica
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Table 1 (continued): Reference Wegm
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Animal Studies Section 6.1 (Animal
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The variability, or heterogeneity,
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estimate for those studies for whic
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Figure 1: Estimates of Relative Ris
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q 1 * = Excess relative risk × CA
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Table 3: Number of Workers in the E
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u nexposed workers at zero concentr
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for each µg/m 3 of diesel exhaust
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Table 4: Values from Unit Risk for
Page 477 and 478:
their findings that a reasonable es
Page 479 and 480:
Garshick E, Schenker M, Woskie S an
Page 481 and 482:
Lewis T, Green, FH MW, Burg J and L
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Rothman K. 1986. Modern epidemiolog
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PENTACHLOROPHENOL CAS No: 87-86-5 I
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The default lifespan for mice is 10
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documented. An excess risk from ski
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B6C3F 1 mice and F344/N rats were e
Page 493 and 494:
This model, rather than a time depe
Page 495 and 496:
POLYCHLORINATED BIPHENYLS (PCBs) CA
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several benign adenomatous lesions
Page 499 and 500:
Ito et al. (1973) exposed groups of
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could not be characterized by chlor
Page 503 and 504:
exposure (all pathways and mixtures
Page 505 and 506:
National Toxicology Program 1993. T
Page 507 and 508:
Table 1. Potassium bromate-induced
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1,3-PROPANE SULTONE CAS No: 1120-71
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PROPYLENE OXIDE CAS No: 75-56-9 I.
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oxide. In the NTP carcinogenicity s
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1,1,2,2-TETRACHLOROETHANE CAS No: 7
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assumed a body weight of 70 kg and
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total); an untreated control group
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TOLUENE DIISOCYANATE CAS No: 26471-
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Animal Studies The National Toxicol
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Mortillaro PT and Schiavon M. 1982.
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male or female rats. Increases in h
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TRICHLOROETHYLENE CAS No: 79-01-6 I
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A mortality analysis of a cohort of
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elative to that of the controls whi
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applied or metabolized. The range o
Page 539 and 540:
Katz RM and Jowett D. 1981. Female
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10,000 ppm 2,4,6-trichlorophenol in
Page 543 and 544:
Page 545 and 546:
Bionetics Research Laboratories. 19
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control; females: 6/10 exposed, 0/1
Page 549 and 550:
over controls (p < 0.04). Other tum
Page 551 and 552:
was increased (100/314 exposed vs.
Page 553 and 554:
Table 3. Cancer potency estimates f
Page 555 and 556:
Crouch E. 1983. Uncertainties in in
Page 557 and 558:
VINYL CHLORIDE CAS No: 75-01-4 I. P
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Table 1 (continued): A Summary of E
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al., 1983). Histopathology of all o
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Table 3: Tumor incidences in 100 pp
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experiment, animals were exposed to
Page 567 and 568:
Experiment BT1 Most previous risk a
Page 569 and 570:
No statistical analyses of mortalit
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Table 11 gives unit risk estimates
Page 573 and 574:
Bertazzi PA, Villa A, Foa V, Saia B
Page 575 and 576:
Nicholson WJ, Hammond EC, Seidman H
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immunotoxicity, reproductive toxici
Page 579 and 580:
scheme. TEFs for two major noncance
Page 581 and 582:
NATO/CCMS (1988a) Pilot Study on In
Page 583 and 584:
Table 2 Toxicity Equivalency Factor
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Table 4 A Comparison of CTEF- and I
Page 587 and 588:
Office of Environmental Health Haza
Page 589 and 590:
Group 4: The agent is probably not
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TECHNICAL SUPPORT DOCUMENT FOR DESC
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US EPA IRIS Inhalation Unit Risk an
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TECHNICAL SUPPORT DOCUMENT FOR DESC
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as appropriate, and revise IRIS fil
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Chemical Exposure Route Study Type
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Page 603 and 604:
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Methyl tert-butyl ether p. 5: Added
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