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n-Hexane (CASRN 110-54-3)
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0486 n-Hexane; CASRN 110-54-3 Health assessment information on a chemical substance is included in IRIS only after a comprehensive review of chronic toxicity data by U.S. EPA health scientists from several Program Offices and the Office of Research and Development. The summaries presented in Sections I and II represent a consensus reached in the review process. Background information and explanations of the methods used to derive the values given in IRIS are provided in the Background Documents. STATUS OF DATA FOR n-Hexane File First On-Line 07/01/1990
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name -- n-Hexane Not available at this time. _I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)Substance Name -- n-Hexane The inhalation Reference Concentration (RfC) is analogous to the oral RfD and is likewise based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory system (extrarespiratory effects). It is expressed in units of mg/cu.m. In general, the RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs were derived according to the Interim Methods for Development of Inhalation Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be derived for the noncarcinogenic health effects of substances that are 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 carcinogenicity, a summary of that evaluation will be contained in Section II of this file. __I.B.1. Inhalation RfC Summary
*Conversion Factors: MW = 86.18. Sanagi et al., 1980: Assuming 25C and 760 mmHg, LOAEL (mg/cu.m.) = 58 ppm x 86.18/24.45 = 204. This is an extrarespiratory effect of a soluble vapor. The LOAEL is based on an 8-hour TWA occupational exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. LOAEL(ADJ) = 204 mg/cu.m x (MVho/MVh) x 5 days/7 days = 73 mg/cu.m. Dunnick et al., 1989: Assuming 25C and 760 mmHg, NOAEL (mg/cu.m) = 500 ppm x 86.18/24.45 = 1762. The NOAEL(HEC) was calculated for a gas:respiratory effect in the ET region. MVa = 0.04 cu.m/day, MVh = 20 cu.m/day, Sa(ET) = 2.9 sq. cm., Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa) / (MVh/Sh) = 0.122. NOAEL(HEC) - NOAEL(ADJ) x RGDR = 315 mg/cu.m x 0.122 - 38 mg/cu.m. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 629 mg/cu.m x 0.122 = 77 mg/cu.m. __I.B.2. Principal and Supporting Studies (Inhalation RfC)Sanagi, S., Y. Seki, K. Sugimoto and M. Hirata. 1980. Peripheral nervous system functions of workers exposed to n-hexane at a low level. Int. Arch. Occup. Environ. Health. 47: 69-79. Dunnick, J.K., D.G. Graham, R.S. Yang, S.B. Haber and H.R. Brown. 1989. Thirteen-week toxicity study of n-hexane in B6C3F1 mice after inhalation exposure. Toxicology. 57(2):163-172. Sanagi et al. (1980) and Dunnick et al. (1989) have been chosen as co- critical studies in establishing the RfC for n-hexane. A principal reason for this is that a NOAEL cannot be derived from the Sanagi study which identifies only a free standing LOAEL. The Dunnick study identifies a LOAEL very similar to that in the Sanagi study in addition to identifying a NOAEL both of which are based on mild inflammatory lesions of the nasal epithelium. The RfC for n- hexane was based on the Sanagi study as there is considerable and compelling evidence that hexane is neurotoxic to humans. Sanagi et al. (1980) conducted an epidemiology study on two age-matched groups consisting of 14 control workers and 14 exposed workers employed in a factory producing tungsten carbide alloys. The groups were matched with respect to age, stature, weight, alcohol consumption and smoking habits. Exposure was estimated with 22 personal samples taken from the breathing zones over a period of 2 years and reported on an 8-hour TWA exposure to solvent vapors consisting of n-hexane at 58 +/- 41 ppm (duration-adjusted = 73 mg/cu.m) and acetone at 39 +/- 30 ppm; no other solvent vapors were detected. Noticeably absent was methyl ethyl ketone as this chemical may apparently potentiate the neurotoxicity of n-hexane (Altenkirch et al., 1982; Veronesi et al., 1984). The exposure duration ranged from 1 to 12 years with an average of 6.2 years. Both groups underwent clinical neurological examinations (one examiner, blind design) with reference to cranial nerves, motor and sensory systems, reflexes, co-ordination, and gait. Neurophysiological studies performed included electromyography on muscles of the forearm and leg. Nerve stimulation studies (NSS) were performed with a surface electrode and included a number of parameters. Recordings were made in a temperature-controlled room allowing subjects 30 minutes to acclimate before the examinations. Skin temperatures were taken at several points along the nerve trunks with a thermocouple; there were no significant differences in average skin temperatures between these two groups. No neurological abnormalities were noted. However, neurophysiological tests showed that the mean motor nerve conduction velocities (MMCV) of the exposed group was significantly decreased over the values for the control group. Also, the residual latency (RL) of motor nerve conduction of the posterior tibial nerve in the exposed group was significantly slowed when compared with the nonexposed group. The alterations observed are consistent with n-hexane-induced peripheral neuropathy observed in other studies in humans (Chang, 1987; Chang and Yip, 1987) and in animals (Schaumburg and Spencer, 1976; Miyagaki, 1967; Huang et al., 1989). Thus, this study supports the designation of 58 ppm (73 mg/cu.m) as a LOAEL. Inhalation of n-hexane results in morphologic alterations in the respiratory tract in mice (Dunnick et al., 1989). A subchronic inhalation study with n-hexane (99%) was conducted in B6C3F1 mice (10/sex/dose) to evaluate and compare histopathologic nerve damage with neurologic damage determined by a series of behavioral tests. Exposure concentrations of 0, 500, 1000, 4000, or 10,000 ppm (0, 1762, 3525, 14,099, or 35,247 mg/cu.m, respectively) were administered 6 hours/day, 5 days/week (duration-adjusted = 0, 315, 629, 2518, or 6294 mg/cu.m). An additional group of animals was exposed to 1000 ppm (3525 mg/cu.m) for 22 hours/day, 5 days/week for 13 weeks (duration-adjusted = 2308 mg/cu.m) and was designated as the 1000 C group. Concentrations in each exposure chamber were monitored hourly by IR spectrophotometry; chamber concentrations were found to be within 15% of targeted concentrations. Clinical signs, body and organ weight, gross and histopathology, neuropathology and neurobehavioral tests were performed to assess toxicity. Organs examined included liver, spleen, kidneys, testis, uterus, trachea, lungs, bronchi, and the nasal cavity with nasal turbinates. Exposure had no effect on survival; 10 to 17% depression of final body weight relative to control weight was observed in males of the 1000 C group and in the high-dose males. Histopathologic changes included mild inflammatory, erosive, and regenerative lesions in the olfactory and respiratory epithelium of the nasal cavity in mice exposed to 1000 ppm (2308 mg/cu.m; group C), and higher concentrations; minimal lesions were observed in the 500-ppm (315 mg/cu.m) and 1000-ppm (629 mg/cu.m) exposure groups. An unequivocal relationship exists between the dose and the incidence and severity of these morphological alterations in female mice. Neurohistopathology showed modest paranodal axonal swellings in the tibial nerve in 6/8 mice of the 1000 C group (2308 mg/cu.m) and in 6/8 of the group exposed to 10,000 ppm (6294 mg/cu.m); the swellings were absent in the 8 control animals examined. The animals exposed to 500 ppm (315 mg/cu.m) and 1000 ppm for 6 hours/day (629 mg/cu.m) were not examined for neuropathological alterations. This study identifies a NOAEL of 500 ppm based on mild lesions of the nasal turbinates. The NOAEL(HEC) was calculated for a gas:respiratory effect in the ExtraThoracic (ET) ET region. MVa = 0.04 cu.m/day, MVh = 20 cu.m./day, Sa = (ET) 2.9 sq. cm., Sh = (ET) 177 sq. cm. RGDR = (MVa/Sa)/ (MVh/Sh) = 0.122. NOAEL(HEC) = NOAEL(ADJ) x RGDR = 315 mg/cu.m x 0.122 = 38 mg/cu.m. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 629 mg/cu.m x 0.122 = 77 mg/cu.m. The interpretation of results from this study is limited for a number of reasons. Neuropathological examinations were conducted only in the 1000 C group (2308 mg/cu.m), the 10,000-ppm group (6294 mg/cu.m) and the controls, not in the groups designated as representing the LOAEL or NOAEL. According to the severity grading of lesions provided in the paper, the average grade of the lesions seen at the LOAEL were "minimal to slight." The average grade of the lesions even at the highest exposure level ranged only from 1.2 to 3.0 (from "minimal to moderate"). Also, there was no dose-relationship in severity or incidence of pathologies in the nasal turbinates in the rats of the IRDC (1981) or Cavender et al. (1984) studies although the exposure levels in these studies were much higher than those used in Dunnick et al. (1989). __I.B.3. Uncertainty and Modifying Factors (Inhalation RfC)UF -- The uncertainty factor of 300 reflects a factor of 10 to protect unusually sensitive individuals and 10 for the use of a LOAEL rather than a NOAEL. An additional factor of 3 is proposed for both the lack of data on reproductive and chronic respiratory effects. MF -- None __I.B.4. Additional Studies/Comments (Inhalation RfC)In humans, sensorimotor polyneuropathy is the principal neurologic manifestation in long-term exposure to n-hexane, although cranial neuropathies, blurred vision, and abnormal color vision associated with macular changes have also been reported (Sobue et al., 1978; Yamamura, 1969; Paulson and Waylonis, 1976; Wang et al., 1986; Seppalainen et al., 1979). In the studies reporting solvent-related neuropathies in workers, the exposure is only generally characterized, often with 500 ppm (duration- adjusted = 630 mg/cu.m) the lowest concentration cited. The study by Yamada (1967) reported polyneuropathy (with subsequent development of muscular atrophy and paresthesia in the distal extremities) in 17 workers exposed to concentrations of n-hexane varying between 500 ppm (630 mg/cu.m) and 1000 ppm (1260 mg/cu.m) in a pharmaceutical plant. An outbreak of polyneuropathy among 93 of the 1662 (5.6%) workers of a Japanese sandal manufacturing plant was reported by several researchers (Yamamura, 1969; Inoue et al., 1970; Iida, 1982; Sobue et al., 1978). In 88% of these 93 workers, numbness of the distal portion of the extremities was the first symptom observed. The etiologic agent was presumed to be hexane, which was used as a glue solvent; air concentrations of the commercial hexane (60 to 70% n-hexane) in the poorly ventilated pasting rooms ranged from 500 to 2500 ppm (duration-adjusted to 8- hour work day = 630 to 3147 mg/cu.m). Some workers were in these work areas for up to 14 hours/day. Abnormal electromyography and decreased conduction velocity were observed in 31 of the 44 cases (70%) examined for these parameters. Neuropathology revealed the characteristic alterations of n- hexane-induced neuropathy - giant axonal degeneration, and paranodal and internodal swellings of axons. In severe cases, the clinical manifestations progressed for about 2 months even after removal from the noxious environment. Because of the limitations of these studies concerning accurate exposure estimates, possible exposure by other routes, co-exposure to other solvents (see Altenkirch et al., 1982), improper industrial hygiene practices, and lack of control populations, a LOAEL in humans of 500 ppm (630 mg/cu.m) cannot be adequately justified based on any of these studies. The following inhalation studies in animals provide effect levels of n- hexane toxicity with indicators of peripheral neuropathies as the critical effect. Thus, the NOAEL(HEC)s calculated for these studies were calculated for a gas:extrarespiratory effect assuming periodicity was attained. Since the b:a lambda values are unknown for the experimental animals (a) and humans (h), a default value of 1.0 is used for this ratio. NOAEL(HEC) mg/cu.m = NOAEL(ADJ) x [b:a lambda(a) / b:a lambda(h)]. Study consideration is by increasing NOAEL(HEC) values. Miyagaki (1967) continuously exposed groups (10/group) of male mice (SM-A strain) to 0, 100, 250, 500, 1000, or 2000 ppm commercial grade hexane (65 to 70% n-hexane; 0, 353, 881, 1762, 3525, or 7050 mg/cu.m) the remaining hydrocarbons were described as other hexane isomers), 6 days/week for 1 year (duration-adjusted = 0, 302, 755, 1510, 3020, or 6040 mg/cu.m). The following parameters were measured at the end of the study period: electromyography, strength-duration curves, electrical reaction time, and flexor/extensor chronaxy ratio. Also gait posture was noted and the grade of muscular atrophy estimated. Electromyographic analysis showed increased complexity of NMU (neuromuscular unit) voltages in 0/6 controls, 1/6 animals in the 100-ppm group, 3/6 animals examined in the 250-ppm group, 5/6 animals examined in the 500-ppm group, 3/3 animals examined in the 1000-ppm group, and 4/4 animals examined in the 2000-ppm group. Electromyography showed a similar dose- related increase both in incidence and severity of reduced interference voltages from muscles in animals exposed to 250 ppm and higher, but not in the controls (0/6 examined) nor in the 100-ppm group (0/6). A dose-related increase in abnormalities of strength-duration curves was also noted; slight fibrillation was detected in the electromyograms of 0/6 mice in the 100-ppm exposure group, 2/6 mice examined in the 250-ppm exposure group and in 0/6 in the 500-ppm group, whereas severe fibrillation was noted in 3/3 animals examined in the 1000- ppm group and in 4/4 examined in the 2000-ppm group. Presumably because of the hexane-induced neuropathies in evidence from the electromyographic analysis, abnormal posture and muscle atrophy were noted in a dose-related manner in animals exposed to concentrations of n-hexane at 250 ppm and higher (in the highest exposure group, where there was an unexplained assumption of normal posture in 3/4 animals examined). This study indicated that a neurotoxicity threshold between 100 and 250 ppm existed in mice, as neurotoxic effects were observed in mice exposed to 250 ppm and higher. Thus, this study identifies a NOAEL of 100 ppm (302 mg/cu.m) for neurotoxicity; when adjusted for 70% n-hexane the NOAEL becomes 0.7 x 302 mg/cu.m = 211 mg/cu.m. NOAEL(HEC) = 211 mg/cu.m. This study is limited as the data from only 3 to 6 of the 10 animals was presented and the exposure was to unpure n-hexane. However, it should be noted that the exposure regimen in this study was the most protracted (1 year), with the animals exposed almost continuously (6 of 7 days, 24 hours/day), and that toxicity was seen in a dose-related fashion. In regard to the purity of the n-hexane, it is fairly certain that the main neurotoxic component of hexanes mixtures is n-hexane. The other common isomers present in n-hexane are apparently not neurotoxic as they can not form the neurotoxic metabolite hexane-2,5-dione (Ono et al., 1981; Lapadula et al., 1986). Groups of Sprague-Dawley rats (12/sex/dose) were administered n-hexane vapor (purity not stated; obtained from J.T. Baker Chemicals) at concentrations of 0, 6, 26, or 129 ppm (0, 21, 92, or 455 mg/cu.m) for 6 hours/day, 5 days/week (duration-adjusted = 0, 3.8, 16.4, or 81 mg/cu.m) and at 0, 5, 27, or 126 ppm (0, 18, 95, or 444 mg/cu.m) for 21 hours/day, 7 days/week (duration-adjusted = 0, 15.4, 83, or 389 mg/cu.m). Both exposure regimens lasted 26 weeks (Bio/Dynamics, 1978). Neuropathology and neurological evaluations were performed, and hematology and clinical chemistry parameters were evaluated at 3 and 6 months. The study states that sections of the liver, lungs, kidneys, heart, and brain (apparently no tissue from the upper airways) were preserved, although no histopathology for these organs is discussed. The summary of the neuropathological study states that not a single animal exhibited the characteristic pathological signs of nervous system degeneration produced by n-hexane (paranodal thickening of peripheral nerves accompanied by giant axonal swellings in the CNS). This condition concurs with the observations of Altenkirch et al. (1982) for discrimination between age-related neuronal changes and alterations caused by n-hexane. While it can be deduced from the study that there were no animals with characteristic alterations at both peripheral and central sites, the association of any animal within a specific dose group was not possible due to lack of a proper key. From these results, the authors conclude that n-hexane does not elicit toxicity at the concentrations tested. Thus, the highest dose tested at the longest duration, 389 mg/cu.m, appears to be a no-effect level for neurotoxicity in this study. NOAEL(HEC) = 389 mg/cu.m. Groups of male Sprague-Dawley-derived Charles River rats (14/group) were exposed to n-hexane plus mixed hexanes 22 hours/day, 7 days/week for approximately 6 months (IRDC, 1981). The concentrations were as follows: 0, 126 ppm n-hexane (444 mg/cu.m, duration-adjusted = 407 mg/cu.m), 125 ppm n- hexane + 125 ppm mixed hexanes, 125 ppm n-hexane + 375 ppm mixed hexanes, 125 ppm n-hexane + 1375 ppm mixed hexanes, and 502 ppm n-hexane (1769 mg/cu.m, duration-adjusted = 1622 mg/cu.m). Microscopic examination of the lungs, liver, kidneys, brain, gonads, spleen, peripheral nerves, gastrocnemius, and nasal turbinateswas performed on all animals. Neurotoxicity was observed in rats exposed to 502 ppm (1622 mg/cu.m) n-hexane. The most significant observations were abnormal gait in 5 of the 14 animals (apparently a consequence of muscle atrophy), axonal degeneration, and myelin vacuolization in 9 of 10 animals examined. The authors concluded that neurotoxicity appeared to be a specific response of n-hexane exposure, as no other treatment groups developed neuropathic/myopathic alterations. Changes in the livers of some animals were considered necrotic although the incidence was not dose related (3/10 examined in the 126-ppm group and 3/10 examined in the 502-ppm group). There was no dose-related increase in severity or incidence of pathologies in the nasal turbinates. Alterations in average values for both absolute and relative organ weights were noted for the liver and kidney in the animals exposed to 125 ppm n-hexane + 1375 ppm mixed hexanes and in the liver for the animals exposed to 502 ppm n-hexane. This study identifies a NOAEL of 125 ppm (407 mg/cu.m). NOAEL(HEC) = 407 mg/cu.m for axonal degeneration. Huang et al. (1989) exposed Wistar male rats (8/dose) to n-hexane vapor (>99% pure) at 0, 500, 1200, or 3000 ppm (0, 1762, 4230, 10574 mg/cu.m) 12 hours/day, 7 days/week for 16 weeks (duration-adjusted = 0, 881, 2115, or 5287 mg/cu.m) and demonstrated a dose-dependent peripheral neurotoxicity induced by n-hexane exposure. The body weight gain and motor-nerve conduction velocity (MCV) in exposure groups show progressively concentration-dependent decreases compared to control values. The body weight was significantly depressed in the two highest exposure groups, but only slightly in the 500-ppm group. At of 1200 ppm and 3000 ppm n-hexane, MCV was significantly reduced. Histopathologic examination revealed degeneration of peripheral nerves characterized by paranodal swellings and demyelination and remyelination in the myelinated nerve fibers in the two highest exposure groups which was more advanced in the highest exposure group. This study identifies a NOAEL(HEC) = 881 mg/cu.m. Frontali et al. (1981) exposed Sprague-Dawley male rats (6-9/group) to 0, 500, 1500 or 5000 ppm (0, 1762, 5286, or 17,624 mg/cu.m; duration- adjusted = 0, 472, 1416, or 4721 mg/cu.m) of 99% n-hexane 9 hours/day, 5 days/week or to 2500 ppm (8812 mg/cu.m; duration-adjusted = 3147 mg/cu.m) 99% n-hexane 10 hours/day, 6 days/week for 14 to 30 weeks. A significant decrease in weight gain was observed in rats treated with 5000 ppm and 500 ppm of n-hexane. Pathological alterations characterized by giant axonal degeneration, and paranodal and internodal swellings of axons were observed in rats treated intermittently with 2500 ppm (after 30 weeks) and 5000 ppm n-hexane (after 14 weeks). This study identifies a NOAEL(HEC) of 1416 mg/cu.m for pathological alterations of the peripheral nerves. A 13-week inhalation study was conducted in Fischer rats (5/sex/dose) (Cavender et al., 1984) in which concentrations of 0, 3000, 6500, or 10,000 ppm of >99.5% pure n-hexane vapors (0, 10,575, 22,911, or 35,247 mg/cu.m) were administered 6 hours/day, 5 days/week (duration-adjusted = 0, 1888, 4091, or 6294 mg/cu.m). No significant differences were observed in female body weights or in clinical observations, food consumption, ophthalmologic examination, neurological function, or hematological or serum chemistry parameters for either sex. Other than axonopathies no histopathological results are discussed although the study states that representative specimens of all organs (including the nasal cavity with associated structures) were processed for examination. This study identifies a NOAEL(ADJ) of 1888 mg/cu.m. NOAEL(HEC) = 1888 mg/cu.m. Groups of male Wistar rats (Hannover strain; 5/group) were exposed under the following conditions: filtered air, 500 ppm n-hexane (1762 mg/cu.m; duration-adjusted = 1616 mg/cu.m), 700 ppm n-hexane (2467 mg/cu.m; duration- adjusted = 2262 mg/cu.m), 300 ppm n-hexane + 200 ppm methyl ethyl ketone (MEK), 400 ppm n-hexane + 100 ppm MEK, or 500 ppm n-hexane + 200 ppm MEK 22 hours/day, 7 days/week for a total of 9 weeks (Altenkirch et al., 1982). Two other groups were exposed to 700 ppm n-hexane (2467 mg/cu.m) or 500 ppm n- hexane + 200 ppm MEK for 8 hours/day, presumably 7 days/week for 40 weeks (duration-adjusted = 822 mg/cu.m). All animals survived the exposures. The results from this study show that, under continuous exposure, the neurotoxicity of n-hexane is potentiated by MEK. n-Hexane-induced hindlimb paralysis and related neuropathology was manifest in all five animals after 9 weeks of exposure to 500 ppm n-hexane, 22 hours/day, 7 days/week (1616 mg/cu.m); similar clinical signs and neuropathology were present 1 week earlier in animals (incidence not given) exposed to the n-hexane/MEK mixtures. Complete hindlimb paralysis was already visible (incidence not given) after 4 weeks in the group exposed to 500 ppm n-hexane + 200 ppm MEK. These observations were accompanied by the anticipated neuropathological alterations (that is, giant axonal swellings in both central and peripheral sites). Under the conditions of this study, clinical or neuropathological signs of n-hexane neuropathy developed in animals exposed to 700 ppm n-hexane under continuous conditions (2262 mg/cu.m), but not under intermittent conditions to the same concentration. Thus, n-hexane-induced neuropathies appear sooner under conditions of continuous exposure than under intermittent exposure. Respiratory tract lesions have been observed in rabbits (n=12) following both high-level acute (8 days) and longer-term (24 weeks) exposure to a single level of exposure to n-hexane vapors (Lungarella et al., 1984). The terminal bronchioles showed the most characteristic damage. In a subchronic study, rabbits (n=12) exposed to 3000 ppm (10,574 mg/cu.m), 8 hours/day, 5 days/week for 24 weeks (duration-adjusted = 2492 mg/cu.m) also developed exposure- related pulmonary lesions. Clinical signs of ocular and upper respiratory tract irritation and respiratory difficulties (such as gasping, lung rales, mouth breathing) were seen throughout the study in exposed rabbits. Neurologic effects were not investigated in this study, although mention is made in the discussion of this study that this species does not show any evidence of neuropathy after long-term exposure to n-hexane. n-Hexane can cause testicular damage. Adult male Sprague-Dawley rats (number of animals is unclear, but is at least 48 total) were exposed to either air, 1000 ppm n-hexane (3525 mg/cu.m; duration-adjusted = 2644 mg/cu.m), 1000 ppm xylene, or 1000 ppm n-hexane + 1000 ppm xylene 18 hours/day, 7 days/week for 61 days (Nylen et al., 1989). Groups of six rats each from these exposure were sacrificed for morphological examination at 2 weeks, 10 months, and 14 months after termination of the exposure. Androgen biosynthesis, serum testosterone, vas deferens morphology, epididymal sperm morphology, and fertility were studied. There was total loss of the germ cell line in a fraction (not designated) of the animals up to 14 months post- exposure. Examination for neuropathies was not done in this study. A freestanding FEL is identified by this study at 3525 mg/cu.m x 18/24 hour x 7/7 days = 2644 mg/cu.m. n-Hexane does not appear to be a teratogen. Pregnant albino rats exposed to 1000 ppm (3489 mg/cu.m, not duration adjusted) of 99% n-hexane vapor 6 hours/day during gestational days 8 to 16 had significantly depressed postnatal growth up to 3 weeks after birth, which returned to normal by 7 weeks; no difference in fetal resorption, birth weight or other abnormalities were noted (Bus et al., 1979). Marks et al. (1980) administered up to 9.9 g/kg/day by gavage to pregnant mice during gestational days 6 to 15 and observed no teratogenic effects, even at doses above the maximum tolerated dose for the dams. However, a reduction in fetal weight was dose-related at doses of 7.92 and 9.9 g/kg/day although no fetal malformations were observed. Five of 33 dams treated with 9.9 g/kg/day died. Thus, n-hexane was not teratogenic even at maternally toxic doses. Mast et al. (1987) conducted an inhalation developmental toxicity study in rats. Concentrations of 0, 200, 1000, or 5000 ppm 99.9% n-hexane vapor (0, 705, 3525, or 17,623 mg/cu.m, not duration-adjusted) were administered to pregnant rats (30 sperm-positive and 10 virgin females/dose) 20 hours/day for 14 consecutive days on gestational days 6 to 19. Maternal toxicity (reduction in weight gain) was noted in all exposure groups, but was statistically significant only at the high-dose group. n-Hexane had no effect on the number of implantations, the mean percent of live pups per litter, the mean percent of resorptions per litter, or on the fetal sex ratio compared to controls. There were no maternal deaths and no clinical signs of toxicity were noted. No significant differences were observed in intrauterine death rate, or in the incidence of fetal malformations. A statistically significant reduction in fetal body weight relative to controls was observed for males at the 1000-ppm (3525 mg/cu.m) and 5000-ppm (17,623 mg/cu.m) exposure levels (7 and 15% reduction, respectively). The lowest n-hexane concentration, 200 ppm (705 mg/cu.m) was a NOAEL for reduced fetal body weight. NOAEL(ADJ) = 705 mg/cu.m. Litton Bionetics (1979) reported negative teratologic results when pregnant female rats (n=20) were exposed to graded concentrations of 0, 100 or 400 ppm n-hexane 6 hours/day (0, 352, or 1410 mg/cu.m, not duration-adjusted) on gestational days 6 through 15. Two studies by Mast et al. showed no effect on reproductive tests in male mice after exposure to n-hexane at 0, 200, 1000, or 5000 ppm (0, 705, 3525, or 17,624 mg/cu.m) 20 hours/day for 5 consecutive days (duration-adjusted = 0, 420, 2096, or 10,484 mg/cu.m). Twenty mice per dose level were used in a sperm morphology study, 30/group in a male dominant lethal study. In the sperm morphology study (Mast et al., 1989a), the animals were examined during the fifth post-exposure week. In the male dominant lethal study (Mast et al., 1989b), 10 mice from each group were sacrificed 1 day after exposure for evaluation of the germinal epithelium. The remaining 20 mice were mated with unexposed virgin females for 8 weekly intervals (new females provided each week). The mated females were then sacrificed 12 days after the last day of cohabitation and their reproductive status and the number and viability of the implants noted. __I.B.5. Confidence in the Inhalation RfCStudy -- Medium Despite the small sample size, the epidemiological study of Sanagi et al. (1980) is given a medium confidence rating, since the LOAEL in this study was based on neurotoxicology and this endpoint is supported by numerous other subchronic inhalation studies in animals and by human occupational studies. The confidence rating in the database for n-hexane is rated only as medium because of the lack of long-term inhalation studies and appropriate reproductive studies. A medium confidence rating for the RfC follows. __I.B.6. EPA Documentation and Review of the Inhalation RfCSource Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 04/19/1990 Verification Date -- 04/19/1990 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for n-Hexane conducted in November 2001 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676. __I.B.7. EPA Contacts (Inhalation RfC)Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address). _II. Carcinogenicity Assessment for Lifetime ExposureSubstance Name -- n-Hexane Not available at this time. _III.
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Date
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Section | Description |
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07/01/1990 | I.B. | Inhalation RfC summary on-line |
07/01/1990 | VI. | Bibliography on-line |
02/01/1991 | I.B. | Text edited |
09/01/1991 | II. | Carcinogenicity assessment now under review |
07/01/1993 | I.B.1. | LOAEL(HEC) added |
08/01/1995 | II. | EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. |
04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
12/03/2002 | I.B.6. | Screening-Level Literature Review Findings message has been added. |
07/30/2003 | I., II. | This chemical is being reassessed under the IRIS Program. |
Substance Name -- n-Hexane
CASRN -- 110-54-3
Last Revised -- 07/01/1990
110-54-3
AI3-24253
ESANI [ITALIAN]
HEKSAN [POLISH]
HEXANE
N-HEXANE
HEXANEN [DUTCH]
HSDB 91
NCI-C60571
SKELLYSOLVE B
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