Toxicological Review of n-Hexane (CAS No. 110-54-3) (PDF)

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LC50 Median lethal concentration LD50 Median lethal dose LDH Lactate dehydrogenase LOAEL Lowest-observed-adverse-effect level MAP Motor nerve action potential MCV Motor nerve conduction velocity MDL Minimum detection limit MN Micronucleus NADPH Reduced nicotinamide adenine dinucleotide phosphate NCE Nonchromatic erythrocytes NSC National Safety Council NCTR National Center for Toxicological Research NF Neurofilament NL Nested logistic NOAEL No-observed-adverse-effect level NTP National Toxicology Program OR Odds ratio PBTK Physiologically based toxicokinetic PCE Polychromatic erythrocyte PND Postnatal day PNS Peripheral nervous system ppm Parts per million PROD Pentoxyresorufin O-depentylase RfC Reference concentration RfD Reference dose RvR Rai and van Ryzin SCE Sister chromatid exchange SCV Sensory nerve conduction velocity SD Standard deviation SDS-PAGE Sodium dodecyl sulfate polyacrylamide gel electrophoresis SEM Standard error of the mean SEP Somatosensory evoked potential SNAP Sensory nerve action potential TLV Threshold limit value TWA Time weighted average UF Uncertainty factor UPDRS Unified Parkinson Disease Rating Scale VEP Visual evoked potential WBC White blood cell xii
1. INTRODUCTION This document presents background information and justification for the Integrated Risk Information System (IRIS) Summary of the hazard and dose-response assessment of n-hexane. IRIS Summaries may include an oral reference dose (RfD), inhalation reference concentration (RfC), and a carcinogenicity assessment. The RfD and RfC provide quantitative information for noncancer dose-response assessments. The toxicity values are based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis but may not exist for other toxic effects such as some carcinogenic responses. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious noncancer effects during a lifetime. It is expressed in units of mg/kg-day. The inhalation RfC is analogous to the oral RfD, but provides a continuous inhalation exposure estimate. The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory system (extrarespiratory or systemic effects). It is generally expressed in units of mg/m 3 . The carcinogenicity assessment provides information on the carcinogenic hazard potential of the substance in question and quantitative estimates of risk from oral and inhalation exposure. The information includes a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen and the conditions under which the carcinogenic effects may be expressed. Quantitative risk estimates are presented in three ways to better facilitate their use: (1) generally, the slope factor is the result of application of a low-dose extrapolation procedure and is presented as the risk per mg/kg-day of oral exposure; (2) the unit risk is the quantitative estimate in terms of either risk per g/L drinking water or risk per g/m 3 continuous airborne exposure; and (3) the 95% lower bound and central estimate on the estimated concentration of the chemical substance in drinking water or air presents cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000. Development of these hazard identification and dose-response assessments for n-hexane has followed the general guidelines for risk assessment as set forth by the National Research Council (1983). The United States Environmental Protection Agency (EPA) guidelines that were used in the development of this assessment includes the following: Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998a), Guidelines for carcinogen risk assessment (U.S. EPA, 2005a), Supplementary Guidance 1
Page 1 and 2: TOXICOLOGICAL REVIEW OF n-HEXANE (C
Page 3 and 4: CONTENTS—TOXICOLOGICAL REVIEW OF
Page 5 and 6: LIST OF TABLES AND FIGURES Table 3-
Page 7 and 8: Table B-2. Parameters and modeling
Page 9 and 10: AUTHORS, CONTRIBUTORS, AND REVIEWER
Page 11: LIST OF ABBREVIATIONS AND ACRONYMS
Page 15 and 16: 2. CHEMICAL AND PHYSICAL INFORMATIO
Page 17 and 18: Veulemans et al. (1982) studied the
Page 19 and 20: Tissue Exposure (ppm) 500 1000 3000
Page 21 and 22: Bioactivation Pathway (predominates
Page 23 and 24: primary metabolite formed in rats f
Page 25 and 26: than the enzyme represented by K m2
Page 27 and 28: for CYP2A1. CYP2B1/2 primarily prod
Page 29 and 30: free 2,5-hexanedione in the urine o
Page 31 and 32: correlation between workplace n-hex
Page 33 and 34: n-hexane, 200 mg/kg n-hexane plus 2
Page 35 and 36: Perbellini and coworkers obtained m
Page 37 and 38: 4. HAZARD IDENTIFICATION 4.1. STUDI
Page 39 and 40: questionnaire was comprised of 23 q
Page 41 and 42: Floor tapping (times/15s) 39.9 ± 7
Page 43 and 44: Governa et al. (1987) investigated
Page 45 and 46: exposure, concentration of urinary
Page 47 and 48: screened. These workers were divide
Page 49 and 50: normal values even when the patient
Page 51 and 52: Amplitude of MAP (mV) Median 7 (2)
Page 53 and 54: Huang and Chu (1989) used evoked po
Page 55 and 56: to Group II because of their involv
Page 57 and 58: 0.79 mg/L 2,5-hexanedione. Neurolog
Page 59 and 60: 4.2. SUBCHRONIC AND CHRONIC STUDIES
Page 61 and 62: in the proximal (approximately 6-8%
Page 63 and 64:
and weanlings within 2 weeks of the
Page 65 and 66:
Accordingly, the study authors cons
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Source: IRDC, 1992a, b. Exposure to
Page 69 and 70:
Site/lesion Multifocal erosion Mult
Page 71 and 72:
with overt maternal toxicity. Linde
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Mast et al. (1988a) also reported t
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4.4. OTHER STUDIES 4.4.1. Acute Tox
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Glucose-6-phosphate dehydrogenase (
Page 79 and 80:
Table 4-15. Changes in sciatic and
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neuropathy. No n-hexane-related eff
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(eight/group) were exposed to comme
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There were no overt signs of clinic
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After 40 weeks there was some evide
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250 28 Not tested 21 27 Not tested
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In addition to toluene, xylene, and
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for rats treated with 2,5-hexanedio
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Schaumburg and Spencer (1978) showe
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the ,-amino group to some extent, i
Page 99 and 100:
formation represents an increase in
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2,5-hexanedione concentration. SDS-
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Chinese hamster fibroblasts CHL Bor
Page 105 and 106:
n-Hexane did not increase the incid
Page 107 and 108:
exposed to n-hexane in the mixing a
Page 109 and 110:
Toxicology’s (CIIT) 13-week toxic
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1999; Biodynamics, 1993a, b). The s
Page 113 and 114:
Table 4-23. Toxicity findings in in
Page 115 and 116:
Reference Strain/species Doses (ppm
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methyl-2,5-hexanedione, 3,4-dimethy
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espect to self-reported exposure to
Page 121 and 122:
may be accounted for by either sex
Page 123 and 124:
5.2. INHALATION REFERENCE CONCENTRA
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exposure to n-hexane support the ne
Page 127 and 128:
eduction in fetal body weight gain
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the various studies are presented f
Page 131 and 132:
5.2.2.1. Adjustment to a Human Equi
Page 133 and 134:
directly observing susceptibility d
Page 135 and 136:
The chosen NOAEL (500 ppm) in the c
Page 137 and 138:
6. MAJOR CONCLUSIONS IN THE CHARACT
Page 139 and 140:
neuropathological effects within a
Page 141 and 142:
Baelum, J; Molhave, L; Hansen, SH;
Page 143 and 144:
Daughtrey, WC; Putman, DL; Duffy, J
Page 145 and 146:
decline after long-term occupationa
Page 147 and 148:
Lam, HR, Larsen, JJ, Ladefoged, O;
Page 149 and 150:
ats. Toxicol Lett 23:141-145. Nakaj
Page 151 and 152:
adducts production by (-diketone-fo
Page 153 and 154:
U.S. EPA. (2005b) Supplementary gui
Page 155 and 156:
a) Have the rationale and justifica
Page 157 and 158:
justified based on the coexposure o
Page 159 and 160:
in modeling of the results from the
Page 161 and 162:
these studies do not report data fo
Page 163 and 164:
eported in the human study by Sanag
Page 165 and 166:
APPENDIX B: BENCHMARK DOSE (BMD) AN
Page 167 and 168:
which the random errors appear to h
Page 169 and 170:
0.75 fixed 2.5 fixed 3 95.57 2 0.09
Page 171 and 172:
one or two parameters of the model
Page 173 and 174:
0 Specified 4 67.48 0 NE 80 51.3 1.
Page 175 and 176:
B-9) is reasonably robust to model
Page 177 and 178:
constant-variance model in which ex
Page 179 and 180:
Output B-1: Nested, logistic model
Page 181 and 182:
0.0000 13.0000 0.206 13 2.684 0 -0.
Page 183 and 184:
0.0000 11.5000 5.299 1 -1.0809 0.00
Page 185 and 186:
Total number of dose groups = 4 Tot
Page 187 and 188:
BMD = 1540.16 BMDL = 848.016 B-23
Page 189 and 190:
User Inputs Initial Parameter Value
Page 191 and 192:
Output B-4: Continuous, Hill model
Page 193 and 194:
Model R: Yi = Mu + e(i) Var{e(i)} =
Page 195 and 196:
alpha = 0.1 rho = 1 Specified inter
Page 197 and 198:
Output B-6: Power model results for
Page 199 and 200:
control 50.2999 1.91213 slope -0.13
Page 201 and 202:
B-37
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ho is set to 2 power is set to 0.5
Page 205 and 206:
Explanation of Tests Test 1: Does r
Page 207 and 208:
Output B-8: Power model results for
Page 209 and 210:
control 52.2904 0.838647 slope -0.3
Page 211 and 212:
BMDL = 28.8322 B-47
Page 213 and 214:
The form of the response function i
Page 215 and 216:
Test 1 52.1579 6
Page 217 and 218:
Default Initial Parameter Values al
Page 219 and 220:
The p-value for Test 4 is less than
Page 221 and 222:
alpha = 0.903938 rho = 0 Specified
Page 223:
Specified effect = 1 Risk Type = Es
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