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

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Figure 3-2. Physiologically based toxicokinetic model of the distribution of n-hexane in the body and the urinary excretion of 2,5-hexanedione. Source: Perbellini et al., 1986. 22
Perbellini and coworkers obtained much of their data on tissue volumes and blood flows from the scientific literature (Perbellini et al., 1985; Mapleson, 1973). This information was combined with experimental data on the partition of n-hexane between air and various media and extracts of human tissue obtained at autopsy (Perbellini et al., 1985). At the core of the PBPK model was a series of differential equations that described: (1) the concentration of n-hexane reaching the lungs in venous blood; (2) the rate of change of n-hexane in the pulmonary compartment and the rate of change of the arterial blood n-hexane concentration; (3) the rate of change of n-hexane in the liver and the resulting amount of hepatic 2,5-hexanedione; (4) the amount of 2,5-hexanedione in the water compartment; and (5) the rate of change of 2,5-hexanedione in the urine. Solving the set of differential equations simultaneously for various hypothetical exposure scenarios allowed the model to be tested against experimental data on n-hexane and 2,5-hexanedione concentrations that had been reported for human volunteers by Veulemans et al. (1982). Key findings from this comparison were that when modeling hypothetical human exposures (approximately 100 ppm for 4 hours) the resulting n-hexane concentration in the venous blood (176 :g/L) was similar to the measured concentration in human volunteers (207 ± 32 :g/L) (Veulemans et al., 1982). The concentration of n-hexane declined rapidly at cessation of exposure, with the model showing close agreement to the charted experimental data (Perbellini et al., 1986). The latter was best described by the regression equation: C v (mg/L) = Ae !bt with values for the constants of 0.114 (mg/L) for A, and 0.0074 (min) !1 for b. The half-life for n-hexane in the blood was 94 minutes (Veulemans et al., 1982). The key utility of the model was to simulate occupational conditions that had been found in factories where n-hexane-containing products are used and where exposure is constant. When the hypothetical exposure duration was extended to 8 hours, the concentration of n-hexane in the fat compartment was shown to follow an upward trend, though with broad fluctuations, representing the interval between shifts. Similarly, the concentration of 2,5-hexanedione in urine displayed peaks and troughs without dropping to negligible levels until a time point after the last exposure representing the latter part of the weekend. Perbellini et al. (1990) drew attention to the persistence of n-hexane in the fat compartment and reported a half life of 64 hours in this tissue group. This half-life suggests that accumulated n-hexane in fat could not be completely excreted by the start of the following workweek, and that near to complete excretion of n-hexane 23
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 and 12: LIST OF ABBREVIATIONS AND ACRONYMS
Page 13 and 14: 1. INTRODUCTION This document prese
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: n-hexane, 200 mg/kg n-hexane plus 2
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
Page 67 and 68: Source: IRDC, 1992a, b. Exposure to
Page 69 and 70: Site/lesion Multifocal erosion Mult
Page 71 and 72: with overt maternal toxicity. Linde
Page 73 and 74: Mast et al. (1988a) also reported t
Page 75 and 76: 4.4. OTHER STUDIES 4.4.1. Acute Tox
Page 77 and 78: Glucose-6-phosphate dehydrogenase (
Page 79 and 80: Table 4-15. Changes in sciatic and
Page 81 and 82: neuropathy. No n-hexane-related eff
Page 83 and 84: (eight/group) were exposed to comme
Page 85 and 86:
There were no overt signs of clinic
Page 87 and 88:
After 40 weeks there was some evide
Page 89 and 90:
250 28 Not tested 21 27 Not tested
Page 91 and 92:
In addition to toluene, xylene, and
Page 93 and 94:
for rats treated with 2,5-hexanedio
Page 95 and 96:
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-
Page 103 and 104:
Chinese hamster fibroblasts CHL Bor
Page 105 and 106:
n-Hexane did not increase the incid
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exposed to n-hexane in the mixing a
Page 109 and 110:
Toxicology’s (CIIT) 13-week toxic
Page 111 and 112:
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
Page 117 and 118:
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
Page 125 and 126:
exposure to n-hexane support the ne
Page 127 and 128:
eduction in fetal body weight gain
Page 129 and 130:
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
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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
Page 203 and 204:
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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