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

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Table 3-6. Metabolites excreted in urine during a 72-hour period following inhalation exposure to n-hexane in male F344 rats Exposure concentration (ppm) Metabolite No treatment Total metabolites formed (µg) a Hydrolysis with $-glucuronidase Hydrolysis with 3N HCl 500 2-Hexanone 0.4 ± 0.1 0.8 ± 0.0 1.5 ± 0.2 Dimethylfuran 7.0 ± 4.0 14.3 ± 0.5 162.0 ± 2.0 2,5-Hexanedione 4.0 ± 1.0 3.8 ± 0.2 9.9 ± 0.2 5-Hydroxy-2-hexanone 3.3 ± 0.7 0.5 ± 0.1 2.3 ± 0.0 2-Hexanol ND 1.5 ± 0.3 ND 1000 2-Hexanone 1.3 ± 0.2 1.3 ± 0.1 4.0 ± 0.1 Dimethylfuran 1.2 ± 0.2 86.2 ± 5.1 194.3 ± 60.2 2,5-Hexanedione 3.3 ± 0.2 4.8 ± 0.6 72.4 ± 6.1 5-Hydroxy-2-hexanone 2.9 ± 0.01 33.0 ± 2.2 5.8 ± 0.9 2-Hexanol ND 0.6 ± 0.1 ND 3000 2-Hexanone 8.6 ± 0.3 15.1 ± 1.0 10.1 ± 2.4 Dimethylfuran 17.0 ± 2.0 357.4 ± 49.2 879.3 ± 231.1 2,5-Hexanedione 44.4 ± 0.5 50.3 ± 4.3 222.4 ± 21.0 5-Hydroxy-2-hexanone 41.5 ± 0.8 38.1 ± 2.4 45.4 ± 2.3 2-Hexanol 1.3 ± 0.2 9.0 ± 3.1 3.5 ± 0.2 a Values are means for three animals ± SEM. ND = Not detected. Source: Baker and Rickert, 1981. Frontali et al. (1981) exposed Sprague-Dawley rats (six to nine/group) to 500, 1000, 2500, or 5000 ppm n-hexane, 9–10 hours/day, 5 days/week for up to 30 weeks. Some animals were transferred to metabolic cages after exposure to permit the collection of overnight urine samples. Metabolites of n-hexane identified in $-glucuronidase and acid hydrolyzed urine samples included 2,5-dimethylfuran, (-valerolactone, 3-hexanol, 2-hexanol, and 2,5-hexanedione. Perbellini et al. (1982) studied the metabolic interaction between n-hexane and toluene in vivo in six male Wistar rats/group following intraperitoneal administration of either 200 mg/kg 20
n-hexane, 200 mg/kg n-hexane plus 200 mg/kg toluene, or 200 mg/kg toluene alone. Amounts of n-hexane metabolites obtained in 24-hour urine samples were lower in animals receiving n-hexane mixed with toluene (Table 3-7). Table 3-7. n-Hexane metabolite levels in urine of Wistar rats coexposed to n-hexane and toluene Metabolite Treatment n-hexane (200 mg/kg) a n-hexane (200 mg/kg) and toluene (200 mg/kg) a 2-Hexanol 230.42 ± 145.83 88.74 ± 54.16 b 2,5-Hexanedione 138.97 ± 58.91 72.93 ± 41.06 b 2,5-Dimethylfuran 91.57 ± 35.83 32.50 ± 11.94 c (-Valerolactone 47.67 ± 20.71 16.70 ± 11.56 c a Data are means ± SD. Significantly different from n-hexane: b p
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: correlation between workplace n-hex
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
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
Page 101 and 102:
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
Page 107 and 108:
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
Page 119 and 120:
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
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
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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