3
Furan1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs have been defined as follows:


AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

1

This document was prepared by the AEGL Development Team composed of Claudia Troxel (Oak Ridge National Laboratory) and Chemical Manager George Rodgers (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 136
3 Furan1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs have been defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Claudia Troxel (Oak Ridge National Laboratory) and Chemical Manager George Rodgers (Na- tional Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 136

OCR for page 136
137 Furan effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progres- sive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGLs represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Furan is a colorless, highly flammable liquid with a strong, ethereal odor. It is used primarily as an industrial intermediate. Occupational exposure to furan is limited because it is handled in closed containers and is used in a closed sys- tem in industrial processes. The general public is typically exposed to furan on a daily basis. The chemical has been detected in cooked foods, the gas-phase component of cigarette smoke, wood smoke, exhaust gas from diesel and gaso- line engines, and oils obtained by distilling rosin-containing pine wood. If furan is released, it is predicted to exist almost entirely in the vapor phase in the at- mosphere because of its relatively high vapor pressure. Quantitative toxicology data on effects after inhalation exposure to furan were limited to one study in rats. Oral administration of furan resulted in hepa- tocarcinogenicity and toxicity, and a number of studies determined that a reac- tive metabolite was responsible for most of the hepatic effects furan induced. In particular, metabolism studies indicate that furan is bioactivated in the liver to a reactive metabolite, cis-2-butene-1,4-dial, by cytochrome P-450 2E1. On the basis of a chronic oral carcinogenicity study in which clear evidence of carcino- genicity was noted in male and female rats and mice, the National Toxicology Program (NTP) classifies furan as “reasonably anticipated to be a human car- cinogen” and the International Agency for Research on Cancer (IARC) lists fu- ran as a Group 2B carcinogen (possibly carcinogenic to humans). The U.S. En-

OCR for page 136
138 Acute Exposure Guideline Levels vironmental Protection Agency (EPA) has not classified furan according to its carcinogenicity. AEGL-1 values were not derived for furan. No human or animal data rele- vant to the derivation of any AEGL-1 for furan were located. The Terrill et al. (1989) study was used as the basis for the AEGL-2 and -3 derivations. Groups of five male and five female Sprague-Dawley rats were ex- posed to furan for 1 h at analytic concentrations of 1,014, 2,851, or 4,049 ppm in a dynamic inhalation chamber. The rats were observed for 14 days, at which time a gross necropsy was conducted on the surviving animals. Signs of furan intoxication during exposure included respiratory distress, increased secretory response, and death. The degrees of respiratory distress and increased secretory response at each concentration (or chemical) were not provided. Body weight (b.w.) declined in the mid- and high-concentration groups (actual b.w. not pro- vided). No treatment-related lesions were observed in surviving animals. Mor- tality was not observed at the low or middle concentrations, but all males and four of five females died at the high concentration. A general statement was made that “in many instances, deaths were delayed until the end of the first week and the beginning of the second week.” The AEGL-2 derivation is based on the threshold for adverse effects in male and female rats at a concentration of 1,014 ppm for 1 h (Terrill et al. 1989). Although the severity of the clinical signs (respiratory distress, increased secre- tory response) was not reported, this lowest exposure group did not exhibit a decrease in b.w. as did the rats exposed to 2,851 or 4,049 ppm. The AEGL-3 derivation is based on the highest nonlethal concentration in male and female rats of 2,851 ppm for 1 h (Terrill et al. 1989). Rats exposed to 1,014, 2,851, or 4049 ppm exhibited clinical signs, including respiratory distress and increased secretory response: however, the degree of the symptoms at each concentration was not provided. Death occurred in the highest exposure group. For the AEGL-2 and -3 derivations, an uncertainty factor of 10 was ap- plied for species-to-species extrapolation because there are inadequate data to properly assess interspecies variability. Terrill et al. (1989) was the only pub- lished furan toxicity study that investigated the toxicity of inhaled furan, and it evaluated only one species (rat). Therefore, insufficient empirical data were available to examine species differences in response to inhaled furan. A physio- logically based pharmacokinetic (PBPK) simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5-fold higher, respectively, than that in humans, whereas the integrated liver exposure to furan metabolites would be ~6- and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that rats are more sen- sitive than mice despite PBPK modeling predictions that mice would have a 3- fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than rats. Therefore, there are too many uncertainties about the re- sponse to furan of the rat, mouse, and human liver to base an uncertainty factor on PBPK modeling predictions.

OCR for page 136
139 Furan An intraspecies uncertainty factor of 3 was applied for the following rea- sons: 1. Assuming death was the result of a progression of the toxicity present at the lower concentrations, the steep dose-response curve for lethality indicates there is not much variability in the response (0/10 rats died at 1,014 and 2,851 ppm, whereas 9/10 rats died at 4,049 ppm). The delayed deaths in the high- concentration group suggest that hepatotoxicity was the cause of death. 2. If no hepatotoxicity is present, the clinical signs are likely due to a di- rect contact effect, which is not expected to vary much among individuals. 3. If hepatotoxicity is present, it is due to the reactive metabolite produced in the liver. PBPK modeling data indicate that production of the metabolite is blood flow limited. Therefore, variations in cytochrome P-450 2E1 levels are not likely to be a significant factor (Kedderis and Held 1996). Using hepatocytes as the basis, PBPK modeling indicates that when adults and children (ages 6, 10, and 14 years) are exposed to the same furan concentrations, the blood concentra- tion of furan is likely to be greater in children than in adults by a factor of only 1.5 (at steady state), and the maximum factor of adult-child differences in liver concentration of furan metabolite is about 1.25 (Price et al. 2003). A modifying factor of 5 was applied to account for a limited data set (only one data set addressing furan toxicity after inhalation exposure was available; this study was not repeated, and there was no information on furan toxicity in other species). Therefore, a total uncertainty factor and modifying factor of 150 was applied to the AEGL-2 and -3 values. The experimentally derived exposure values were scaled to AEGL time- frames using the concentration-time relationship given by the equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 0.8 to 3.5 (ten Berge et al. 1986). The value of n was not empirically derived because of insufficient data; therefore, the default value of n = 1 was used for extrapolating from shorter to longer exposure periods and a value of n = 3 was used to extrapolate from longer to shorter exposure periods. The derived AEGL values are listed in Table 3-1. 1. INTRODUCTION Furan is a colorless, highly flammable liquid with a strong, ethereal odor. An odor threshold value for furan could not be located in the available literature. Furan is miscible with most organic solvents but is only slightly soluble in wa- ter. It has low boiling and flash points and is often stabilized with butylated hy- droxytoluene to inhibit the formation of explosion-prone peroxides upon expo- sure to air (EPA 1987). Furan is produced by decarbonylation of furfural (Kottke 1991). The industrial uses of furan are predominantly as an intermediate

OCR for page 136
140 Acute Exposure Guideline Levels TABLE 3-1 Summary of AEGL Values for Furan Classification 10 min 30 min 1h 4h 8h End Point (Reference) NRa AEGL-1 NR NR NR NR Not applicable (Nondisabling) AEGL-2 12 ppm 8.5 ppm 6.8 ppm 1.7 ppm 0.85 ppm 1,014 ppm for 1 h: (Disabling) (33 (24 (19 (4.7 (2.4 threshold for adverse mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) effects in rats; clinical signs: although the severity of respiratory distress and increased secretory response not reported, no decrease in body weight occurred (Terrill et al. 1989) AEGL-3 35 ppm 24 ppm 19 ppm 4.8 ppm 2.4 ppm 2,851 ppm for 1 h: (Lethality) (97 (67 (53 (13 (6.7 threshold for lethality in mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) rats (Terrill et al. 1989) a NR: not recommended. Numeric values for AEGL-1 are not recommended because of the lack of available data. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. in the production of tetrahydrofuran, pyrrole, and thiophene; in the formation of lacquers and solvents for resins; in the production of pharmaceuticals; in agri- cultural chemicals; and in stabilizers (IARC 1995). Furan is an EPA high- production-volume chemical (revised Sept. 6, 2001), with production exceeding 1 million pounds annually. Occupational exposure to furan is predicted to be minimal as it is handled in closed containers because of its volatility, and indus- trial processes that use furan are conducted in closed systems (NTP 1993). The general public is typically exposed to furan on a daily basis. The chemical has been detected in the gas-phase component of cigarette smoke, wood smoke, exhaust gas from diesel and gasoline engines, and oils obtained by distilling rosin-containing pine wood (Budavari et al. 1989; IARC 1995). Furan is also present in cooked foods: analysis of approximately 300 food samples found furan levels ranging from nondetectable (below the limits of detection of the method) to 175 parts per billion (FDA 2009). Food and Drug Administration (FDA) calculations found that mean daily furan exposure ranged from 0.26 µg/kg of b.w. per day for adults to 0.41 µg/kg/day for infants consuming baby food and 0.9 µg/kg/day for those consuming infant formula (FDA 2007). Com- mon sources of exposure in adults include coffee, juices, snack foods, nutritional drinks, and gravies; common sources in infants (up to 1 year old) are jarred baby foods and canned infant formulas (Becalski et al. 2005; FDA 2007; Zoller et al. 2007). FDA has posted these furan data on the agency’s Web site at http://www.cfsan.fda.gov/~lrd/pestadd.html#furan. It is postulated that the pri- mary source of furans in food is from thermal degradation and rearrangement of organic compounds, especially carbohydrates (69 CFR 25911[2004]).

OCR for page 136
141 Furan If it is released, furan is predicted to exist almost entirely in the vapor phase in the atmosphere because of its relatively high vapor pressure. The pri- mary removal mechanism during daylight is predicted to be the reaction with photochemically generated hydroxyl radicals, with an estimated half-life of 2 to 6 h (EPA 1987) or 9.5 h (Atkinson 1989). Reaction with nitrate radicals is pre- dicted to be the primary removal mechanism during night hours (approximate half-life of 2 h) (EPA 1987). Although furan is present in cigarette smoke (Newsome et al. 1965), no human data were available regarding acute nonlethal toxicity of this compound. The NTP report (1993) summarized possible human exposure data. While it was reported that approximately 35 employees were potentially exposed to furan at 14 plants, no further details, such as health effects, were provided. The physicochemical data on furan are presented in Table 3-2. TABLE 3-2 Chemical and Physical Data for Furan Parameter Value Reference Synonyms Furfuran, oxole, tetrole, divinylene Budavari et al. 1989 oxide, 1,4-epoxy-1,3-butadiene, oxacyclopentadiene CAS registry number 110-00-9 Chemical formula C4H4O Budavari et al. 1989 Molecular weight 68.07 Budavari et al. 1989 Physical state Liquid Budavari et al. 1989 Color Colorless, turns brown upon standing Garcia and James 2000 Melting point −86ºC Garcia and James 2000 Boiling point 31.36ºC at 760 mmHg Budavari et al. 1989 32ºC at 758 mmHg Liquid density 0.9371 at 19.4/4ºC Budavari et al. 1989 (water = 1) Vapor density (air = 1) 2.36 Kottke 1991 Solubility Freely soluble in alcohol and ether; Budavari et al. 1989 solubility in water: 1% at 25ºC Kottke 1991 Vapor pressure 658 mmHg at 20ºC Kottke 1991 600 mmHg at 20ºC HSDB 2003 1 ppm = 2.78 mg/m3 Garcia and James 2000 Conversion factors 1 mg/m3 = 0.359 ppm Calculated: ppm  molecular weight = mg/m3 at 24.45 ºC

OCR for page 136
142 Acute Exposure Guideline Levels 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data were available regarding the acute lethality of furan in humans. 2.2. Nonlethal Toxicity No human inhalation toxicity data for furan were available. 2.3. Developmental and Reproductive Effects No human developmental and reproductive toxicity data concerning furan were found in the available literature. 2.4. Genotoxicity No human genotoxicity data on furan were found in the available litera- ture. 2.5. Carcinogenicity No human data were found in the available literature regarding the car- cinogenic potential of inhaled furan. 2.6. Summary No data were found in the available literature regarding lethal and nonlethal toxicity, developmental and reproductive toxicity, genotoxicity, and carcinogenicity of inhaled furan in humans. Although it was reported that ap- proximately 35 employees were potentially exposed to furan at 14 plants, no further details, such as health effects, were provided. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Dogs A 10-kg dog (sex, age, and strain unspecified) was anesthetized with ether and then injected with 0.2 cubic centimeters (cm3) of furan (Koch and Cahan 1925). Blood pressure immediately decreased, followed by an increase in the amplitude of the heartbeat and a rapid recovery of blood pressure to slightly higher than the initial reading. Three more injections gave similar results. It was

OCR for page 136
143 Furan concluded that furan stimulated the vagus mechanism because intravenous ad- ministration of furan after injection of 3 cm3 of 1% atropine resulted in a de- crease in blood pressure but no increase in the amplitude of the heartbeat. Furan was then substituted for ether (concentration of furan and protocol for furan in- halation were not provided). Blood pressure rapidly decreased, followed by an increased amplitude of the heartbeat. Respiration then ceased, followed by car- diac arrest. Necropsy revealed marked dilation of the blood vessels in the vis- cera; blood that was a bright, cherry red; and hyperemic lungs. The authors con- cluded that the immediate cause of death was asphyxia resulting from paralysis of the medulla. 3.1.2. Rats Groups of five male and five female Sprague-Dawley rats were exposed for 1 h to furan vapor at analytic concentrations of 1,014, 2,851, and 4,049 ppm (Terrill et al. 1989). The vapor was generated with a bubbler, and exposures were conducted in a modified, 1-m3 Hinner’s-type, glass and stainless steel chamber (a Hinner’s-type chamber is a vertical-flow chamber with cubic expo- sure sections, tangential inlets, and pyramid-shaped upper and lower sections) (McClellan and Henderson 1995). An infrared analyzer was used to monitor the exposure concentrations beginning at 15 min of exposure and continuing every 5 to 15 min thereafter. Animals were observed for 14 days, at which time a gross necropsy was conducted on the surviving animals. Signs of furan intoxication during exposure included respiratory distress, increased secretory response, and death. The degrees of respiratory distress and secretory response at each concen- tration were not provided. Body weight decreased in the middle- and high- concentration groups (actual b.w. not provided). No exposure-related lesions were observed in surviving animals. The mortality at each concentration was recorded and is presented in Table 3-3. Mortalities were not observed at the low and middle concentrations, but all males and four of five females died at the high concentration. The 1-h LC50 (concentration with 50% lethality) values and 95% confidence intervals were 3,398 ppm (2,683 to 4,303 ppm) for males, 3,550 ppm (2,726 to 4,623 ppm) for females, and 3,464 ppm (2,905 to 4,131 ppm) for both sexes combined. TABLE 3-3 Mortality in Sprague-Dawley Rats Exposed to Furan Mortalitya Concentration (ppm) Male Female 1,014 ± 36.6 0/5 0/5 2,851 ± 246.7 0/5 0/5 4,049 ± 227.8 5/5 4/5 a Number dead/number exposed. Source: Terrill et al. 1989. Reprinted with permission; copyright 1989, American Industrial Hygiene Association.

OCR for page 136
144 Acute Exposure Guideline Levels A rat was exposed to furan by inhalation via saturated cotton held over the nose (Koch and Cahan 1925). After a short struggle, the rat collapsed. There was an increase in the rate of respiration and the rat exhibited complete analgesia and relaxation lasting 2 to 3 min. The authors then stated that this experiment was repeated, but it is unclear if they meant both the exposure and the clinical signs or just the exposure. Although the rat appeared normal when replaced in its cage after treatment, it was dead the next morning. 3.1.3. Mice Groups of three or four Swiss mice weighing 18 to 21 grams (g) were ex- posed to furan vapor ranging in concentration from 10.5 to 350 ppm for 1 h (Egle and Gochberg 1979). Information about the sex of the animals, individual vapor concentrations, method of vapor analysis, and period of observation after exposure was not provided. The vapor was generated by passing air through pure furan at room temperature and then transferring it with a 100-cm3 syringe into a 5.2-liter (L) sealed glass desiccator. The 1-h LC50 was calculated to be 42 ppm. Gross necropsy revealed pulmonary inflammation and fluid accumulation, although it was not stated if these findings were limited to decedents or were also seen in survivors. Clinical signs of toxicity in mice that died during the 1-h exposure included hyperactivity for 5 to 15 min, followed by labored breathing and death soon after. As addressed by Garcia and James (2000), it is likely that hypoxia contributed to the toxicity observed in this study. According to their calculations, four mice placed in a closed system for 1 h would breathe 9.6 L of air (4 mice × 40 milliters [mL]/min × 60 min). The desiccator in which the ex- posure occurred was only a 5.2-L desiccator. The closed system in which the mice were exposed did not provide enough oxygen for the number of mice tested. Therefore, the mortality observed in the mice was most likely con- founded by the hypoxic conditions, and the study is considered unacceptable. 3.1.4. Rabbits A rabbit was exposed to furan through saturated cotton held over the nose (Koch and Cahan 1925). The rabbit struggled and collapsed. As the animal be- came sedated, respiration ceased but the heart continued to beat. After artificial respiration, breathing returned. Furan was administered a second time, but this time, respiration could not be restored after cessation. Necropsy revealed marked dilation of the blood vessels in the viscera; blood that was a bright, cherry red; and hyperemic lungs. The authors concluded that the immediate cause of death was asphyxia resulting from paralysis of the medulla. 3.2. Nonlethal Toxicity Limited acute nonlethal exposure data were available on rats from furan

OCR for page 136
145 Furan kinetic studies (Kedderis et al. 1993). Using a closed recirculating chamber, gas uptake studies were conducted with three male Fischer 344 (F344) rats per group, with initial furan concentrations of 100, 500, 1,050, and 3,850 ppm. From the graph provided, it appears that rats were kept in the chamber up to 6 h. In a later study, 12 male rats per group were exposed for 4 h to furan at 52, 107, or 208 ppm. The liver and blood were sampled after exposure to determine furan concentrations. These studies were designed to develop and validate a PBPK model. Therefore, no data on possible toxicity resulting from the furan expo- sures were provided. It appears that all rats survived the exposures as there was no mention of mortality. The authors stated that 4-h exposures to concentrations higher than 300 ppm were not simulated by the PBPK model because the expo- sures would probably be lethal (Kedderis and Held 1996). 3.3. Developmental and Reproductive Effects Data addressing the developmental and reproductive effects of furan in animals were not available. 3.4. Genotoxicity Furan (up to 10,000 µg per plate) tested negative for genotoxicity in Sal- monella typhimurium strains TA100, TA1535, TA1537, and TA98 in the pres- ence and absence of exogenous metabolic activation (Mortelmans et al. 1986; NTP 1993) and in the induction of sex-linked recessive lethal mutations in germ cells from male Drosophila melanogaster when administered by feeding (10,000 ppm) or injection (25,000 ppm) (NTP 1993). Furan tested positive for genotox- icity in a number of in vitro and in vivo mammalian systems: furan induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of metabolic activation (concentrations of 1,139 to 3,800 µg per plate, equiva- lent to ~16.5 to 45 micromolars [µM]) (McGregor et al. 1988; NTP 1993); in- duced chromosome aberrations in Chinese hamster ovary (CHO) cells with metabolic activation at concentrations of 100 to 200 millimolars (mM) (Stich et al. 1981), while another study reported induction of chromosome aberrations and sister chromatid exchanges in CHO cells with and without metabolic activa- tion (NTP 1993); and induced chromosomal aberrations (intraperitoneal [i.p.] concentration of 250 mg/kg) but not sister chromatid exchange (i.p. concentra- tion up to 350 mg/kg) in bone marrow cells after i.p. injections to male B6C3F1 mice (NTP 1993). Kong et al. (1988) reported positive findings in the micronu- cleus test (species and route of administration not provided) but negative find- ings in the SOS chromotest and the umu test at furan concentrations of 400 mg/kg. Furan tested negative for genotoxicity when evaluated in the in vivo hepa- tocyte DNA repair assay (Wilson et al. 1992). For this assay, unscheduled DNA repair was measured in hepatocytes that were isolated from male F344 rats after

OCR for page 136
146 Acute Exposure Guideline Levels a single gavage administration of furan at 5, 30 or 100 mg/kg or from male B6C3F1 mice after administration of 10, 50, 100, or 200 mg/kg. 3.5. Chronic Toxicity and Carcinogenicity No data were available assessing the potential carcinogenicity of inhaled furan. Therefore, the data addressing carcinogenicity after oral exposure are in- cluded below. Furan was administered at doses of 0, 2, 4, or 8 mg/kg in corn oil by ga- vage to groups of 50 male or 50 female F344/N rats for 5 days/week for 2 years (NTP 1993). All groups of dosed rats exhibited an increased incidence of cholangiocarcinomas (males: 0/50, 43/50, 48/50, and 49/50; females: 0/50, 49/50, 50/50, and 48/50 for the 0, 2, 4, and 8-mg/kg groups, respectively). Cholangiocarcinomas were also present in animals examined at the 9- and 15- month interim evaluation. Male rats had an increased combined incidence of hepatocellular adenomas or carcinomas (1/50, 5/50, 22/50, and 35/50), while female rats had an increased incidence of hepatocellular adenomas (0/50, 2/50, 4/50, and 7/50). Nonneoplastic liver lesions that occurred in both male and fe- male treated rats included biliary tract fibrosis, hyperplasia, chronic inflamma- tion, proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, de- generation, nodular hyperplasia, and necrosis. An increased incidence of mononuclear cell leukemia was observed in rats treated with furan at 4 or 8 mg/kg (males: 8/50, 11/50, 17/50, and 25/50; females: 8/50, 9/50, 17/50, and 21/50). Nephropathy was observed in all dosed animals; severity increased with the dose. The nephropathy was accompanied by an associated increased inci- dence of parathyroid hyperplasia (renal secondary hyperparathyroidism). Treated male and female rats exhibited forestomach hyperplasia (males: 1/50, 4/49, 7/50, and 6/50; females: 0/50, 2/50, 5/50, and 5/50), and female rats had an increased incidence of subacute inflammation of the forestomach (0/50, 1/50, 5/50, and 6/50). The NTP concluded that there was clear evidence of carcino- genic activity of furan in male and female F344/N rats based on increased inci- dences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. Fifty male F344/N rats were administered furan at 30 mg/kg of b.w. in corn oil by gavage for 13 weeks and then maintained for 2 years without addi- tional furan dosing (NTP 1993). Cholangiocarcinoma was present in all dosed animals, and hepatocellular carcinoma occurred with an overall incidence of 15%. Groups of 50 male and 50 female B6C3F1 mice were administered furan at 0, 8, or 15 mg/kg in corn oil by gavage for 5 days/week for 2 years (NTP 1993). Treated mice had an increased incidence of hepatocellular adenomas (males: 20/50, 33/50, and 42/50; females: 5/50, 31/50, and 48/50) and carcinomas (males: 7/50, 32/50, and 34/50; females: 2/50, 7/50, and 27/50). A significant number of nonneoplastic hepatocellular lesions were also observed, including

OCR for page 136
162 Acute Exposure Guideline Levels 8.3. Data Adequacy and Research Needs Quantitative inhalation toxicology data in animals were limited to one study in rats. Much of the literature on furan focused on metabolism and disposi- tion. Research needs are many and include acute inhalation toxicity studies in- cluding gross and microscopic examination of exposed animals, inhalation data on multiple species, inhalation developmental and reproductive toxicity studies, and carcinogenicity evaluations after inhalation of furan. Detailed inhalation studies would elucidate whether the target organ is primarily the liver (as it is after oral or i.p. administration) or if other organs are also affected. The studies would also determine whether inhalation exposure to furan produces a direct contact effect, such as irritation. 9. REFERENCES AIHA (American Industrial Hygiene Association). 1993. Workplace Environmental Ex- posure Level Guide: Furan. Fairfax, VA: AIHA Press. Atkinson, R. 1989. Kinetics and Mechanisms of the Gas-Phase Reactions of the Hy- droxyl Radical with Organic Compounds. Journal of Physical and Chemical Ref- erence Data Monograph No. 1 [online]. Available: http://www.nist.gov/srd/PDF files/jpcrdM1.pdf [accessed Mar. 25, 2010]. Becalski, A., D. Forsyth, V. Casey, B.P. Lau, K. Pepper, and S. Seaman. 2005. Develop- ment and validation of a headspace method for determination of furan in food. Food Addit. Contam. 22(6):535-540. Budavari, S., M.J. O'Neil, A. Smith, and P.E. Heckelman, eds. 1989. Furan. P. 672 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. Rahway, NJ: Merck. Burka, L.T., K.D. Washburn, and R.D. Irwin. 1991. Disposition of [14C]furan in the male F344 rat. J. Toxicol. Environ. Health 34(2):245-257. Carfagna, M.A., S.D. Held, and G.L. Kedderis. 1993. Furan-induced cytolethality in iso- lated rat hepatocytes: Correspondence with in vivo dosimetry. Toxicol. Appl. Pharmacol. 123(2): 265-273. Chen, L.J., S.S. Hecht, and L.A. Peterson. 1995. Identification of cis-2-butene-1,4-dial as a microsomal metabolite of furan. Chem. Res. Toxicol. 8(7):903-906. Egle, J.L., and B.J. Gochberg. 1979. Respiratory retention and acute toxicity of furan. Am. Ind. Hyg. Assoc. J. 40(4):310-314. Elmore, L.W., and A.E. Sirica. 1993. “Intestinal-type” of adenocarcinoma preferentially induced in right/caudate liver lobes of rats treated with furan. Cancer Res. 53(2):254-259. EPA (U.S. Environmental Protection Agency). 1987. Health and Environmental Effects Document for Furan. ECAO-CIN-G020. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, U.S. Environmental Pro- tection Agency, Cincinnati, OH. EPA (U.S. Environmental Protection Agency). 2003. Furan (CASRN 110-00-9). Inte- grated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/IRIS/subst/0056.htm [accessed Mar. 30, 2010].

OCR for page 136
163 Furan FDA (U.S. Food and Drug Administration). 2007. An Updated Exposure Assessment for Furan from the Consumption of Adult and Baby Foods, April 18, 2007. U.S. De- partment of Health and Human Services, Food and Drug Administration [online]. Available: http://www.fda.gov/Food/FoodSafety/FoodContaminantsAdulteration/ChemicalCo ntaminants/Furan/ucm110770.htm [accessed Mar. 25, 2010]. FDA (U.S. Food and Drug Administration). 2009. Exploratory Data on Furan in Food: Individual Food Products. U.S. Department of Health and Human Services, Food and Drug Administration [online]. Available: http://www.fda.gov/Food/FoodSafe ty/FoodContaminantsAdulteration/ChemicalContaminants/Furan/UCM078439 [accessed mar. 25, 2010]. Garcia, H.D., and J.T. James. 2000. Furan. Pp. 307-329 in Spacecraft Maximum Allow- able Concentrations for Selected Airborne Contaminants, Vol. 4. Washington, DC: National Academy Press. HSDB (Hazardous Substances Data Bank). 2003. Furan (CAS No 110-00-9). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [ac- cessed Mar. 25, 2010]. IARC (International Agency for Research on Cancer). 1995. Pp. 393-407 in Dry Clean- ing, Some Chlorinated Solvents, and Other Industrial Chemicals, IARC Mono- graphs on the Evaluation of Carcinogenic Risks to Humans Vol. 63. Lyon, France: International Agency for Research on Cancer. Kedderis, G.L., and S.D. Held. 1996. Prediction of furan pharmacokinetics from hepato- cyte studies: Comparison of bioactivation and hepatic dosimetry in rats, mice, and humans. Toxicol. Appl. Pharmacol. 140(1):124-130. Kedderis, G.L., M.A. Carfagna, S.D. Held, R. Batra, J.E. Murphy, and M.L. Gargas. 1993. Kinetic analysis of furan biotransformation by F-344 rats in vivo and in vi- tro. Toxicol. Appl. Pharmacol. 123(2):274-282. Koch, E.M., and M.H. Cahan. 1925. Physiologic action of furane. J. Pharmacol. Exp. Ther. 26(4):281-285. Kong, Z.L., M. Mitsuiki, M. Nonaka, and H. Omura. 1988. Mutagenic activities of fur- furals and the effects of Cu2+ [abstract]. Mutat. Res. 203:376. Kottke, R.H. 1991. Furan derivatives. Pp. 155-183 in Kirk-Othmer Encyclopedia of Chemical Technology, 4th Ed., Vol. 23. New York: John Wiley and Sons. McClellan, R.O., and R.F. Henderson, eds. 1995. Pp. 33-36 in Concepts in Inhalation Toxicology, 2nd Ed. Washington, DC: Taylor and Francis. McGregor, D.B., A. Brown, P. Cattanach, I. Edwards, D. McBride, C. Riach, and W.J. Caspary. 1988. Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ. Mol. Mutagen. 12(1):85-154. Mortelmans, K., S. Haworth, T. Lawlor, W. Speck, B. Tainer, and E. Zeiger. 1986. Sal- monella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ. Mutagen. 8(Suppl. 7):1-119. Moser, G.J., J. Foley, M. Burnett, T.L. Goldsworthy, and R. Maronpot. 2009. Furan- induced dose-response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Exp. Toxicol. Pathol. 61(2): 101-111. Newsome, J.R., V. Norman, and C.H. Keith. 1965. Vapor phase analysis of tobacco smoke. Tobacco Sci. 9:102-110.

OCR for page 136
164 Acute Exposure Guideline Levels NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NTP (National Toxicology Program). 1993. Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies). NTP TR 402. NIH 93-2857. U.S. Department of Health and Human Services, Pub- lic Health Service, National Institute of Health, National Toxicology Program, Re- search Triangle Park, NC. NTP (National Toxicology Program). 2005. Furan in Report on Carcinogens, 11th Ed. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program [online]. Available: http://ntp.niehs.nih.gov/ntp/roc/eleventh/ profiles/s090fura.pdf [accessed Mar. 25, 2010]. Parmar, D., and L.T. Burka. 1993. Studies on the interaction of furan with hepatic cyto- chrome P-450. J. Biochem. Toxicol. 8(1):1-9. Peterson, L.A., M.E. Cummings, C.C. Vu, and B.A. Matter. 2005. Glutathione trapping to measure microsomal oxidation of furan to cis-2-butene-1, 4-dial. Drug Metab. Dispos. 33(10):1453-1458. Price, K., S. Haddad, and K. Krishnan. 2003. Physiological modeling of age-specific changes in the pharmacokinetics of organic chemicals in children. J. Toxicol. En- viron. Health A 66(5):417-433. Stich, H.F., M.P. Rosin, C.H. Wu, and W.D. Powrie. 1981. Clastogenicity of furans found in food. Cancer Lett. 13(2):89-95. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3): 301-309. Terrill, J.B., W.E. Van Horn, D. Robinson, and D.L. Thomas. 1989. Acute inhalation toxicity of furan, 2-methylfuran, furfuryl alcohol, and furfural in the rat. Am. Ind. Hyg. Assoc. J. 50(5):A359-A361. Wilson, D.M., T.L. Goldsworthy, J.A. Popp, and B.E. Butterworth. 1992. Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan. Environ. Mol. Mutagen. 19(3):209-222. Zoller, O., F. Sager, and H. Reinhard. 2007. Furan in food: Headspace method and prod- uct survey. Food Addit. Contam. 24(Suppl. 1):91-107.

OCR for page 136
165 Furan APPENDIX A DERIVATION OF AEGL VALUES FOR FURAN Derivation of AEGL-1 10-min AEGL-1: Not recommended based on insufficient data 30-min AEGL-1: Not recommended based on insufficient data 1-h AEGL-1: Not recommended based on insufficient data 4-h AEGL-1: Not recommended based on insufficient data 8-h AEGL-1: Not recommended based on insufficient data Derivation of AEGL-2 Key study: Terrill et al. 1989 Toxicity end point: Exposure concentration of 1,014 ppm for 1 h in rats (Terrill et al. 1989). Although the severity of the reported clinical signs (respiratory distress, increased secretory response) was not reported, this lowest exposure concentration group did not exhibit a decrease in b.w. like the rats exposed to 2,851 or 4,049 ppm. Cn × t = k (this document; default of n = 1 for shorter Time-scaling: to longer exposure periods and n = 3 for longer to shorter exposure periods) Uncertainty factors: 10 for interspecies variability 3 for intraspecies variability Modifying factor: 5 for limited data set Total uncertainty factors and modifying factor: 150 C/uncertainty factors)n × t = k Calculations: (1,014 ppm/150)1 × 1 h = 6.76 ppm-h (1,014 ppm/150)3 × 1 h = 308.9 ppm-h

OCR for page 136
166 Acute Exposure Guideline Levels C3 × 0.167 h = 308.9 ppm-h 10-min AEGL-2: C3 = 1,849.7 ppm C = 12.3 ppm = 12 ppm C3 × 0.5 h = 308.9 ppm-h 30-min AEGL-2: C3 = 617.8 ppm C = 8.5 ppm 1-h AEGL-2: C × 1 h = 6.76 ppm-h C = 6.76 ppm C = 6.8 ppm C1 × 4 h = 6.76 ppm-h 4-h AEGL-2: C1 = 1.69 ppm C = 1.7 ppm C1 × 8 h = 6.76 ppm-h 8-h AEGL-2: C1 = 0.845 ppm C = 0.85 ppm Derivation of AEGL-3 Key study: Terrill et al. 1989 Toxicity end point: Highest nonlethal exposure concentration in rats of 2,851 ppm for 1 h Cn × t = k (this document; default of n = 1 for shorter Time-scaling: to longer exposure periods and n = 3 for longer to shorter exposure periods) Uncertainty factors: 10 for interspecies variability 3 for intraspecies variability Modifying factor: 5 for limited data set Combined uncertainty factors and modifying factor: 150 (C/uncertainty factors)n × t = k Calculations: [(2,851 ppm)/150]1 × 1 h = 19.01 ppm-h [(2,851 ppm)/150]3 × 1 h = 6866.2 ppm-h

OCR for page 136
167 Furan C3 × 0.167 h = 6866.2 ppm-h 10-min AEGL-3: C3 = 41,114.97 ppm C = 34.5 ppm = 35 ppm C3 × 0.5 h = 6866.2 ppm-h 30-min AEGL-3: C3 = 13,732.4 ppm C = 23.9 ppm = 24 ppm 1-h AEGL-3: C × 1 h = 19.01 ppm-h C = 19.01 ppm C = 19 ppm C1 × 4 h = 19.01 ppm-h 4-h AEGL-3: C1 = 4.75 ppm C = 4.8 ppm C1 × 8 h = 19.01 ppm-h C1 = 2.376 ppm C = 2.4 ppm

OCR for page 136
168 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR FURAN Derivation Summary for Furan AEGL-1 VALUES 10 min 30 min 1h 4h 8h Not Not Not Not Not recommended recommended recommended recommended recommended Reference: Not applicable Test Species/Strain/Number: Not applicable Exposure Route/Concentrations/Durations: Not applicable Effects: Not applicable End Point/Concentration/Rationale: Not applicable Uncertainty Factors/Rationale: Not applicable Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: Not applicable Time-scaling: Not applicable Data Adequacy: Insufficient data to propose AEGL values AEGL-2 VALUES 10 min 30 min 1h 4h 8h 12 ppm 8.5 ppm 6.8 ppm 1.7 ppm 0.85 ppm Reference: Terrill, J.B., W.E. Van Horn, D. Robinson, and D.L. Thomas. 1989. Acute inhalation toxicity of furan, 2 methylfuran, furfuryl alcohol, and furfural in the rat. Am. Ind. Hyg. Assoc. J. 50(5):A359-A361. Test Species/Strain/Number: Sprague-Dawley rats, 5/sex/exposure group Exposure Route/Concentrations/Durations: 1,014, 2,851, and 4,049 ppm for 1 h Effects: Signs of toxicity during exposure included respiratory distress, increased secretory response (severity at each concentration not provided). 1,014 ppm: 0/10 died, no changes in b.w. 2,851 ppm: 0/10 died, decreased b.w. 4,049 ppm: 9/10 died, decreased b.w. End Point/Concentration/Rationale: Exposure concentration of 1,014 ppm for 1 h in rats. Although the severity of the reported clinical signs (respiratory distress, increased secretory response) was not reported, this lowest exposure concentration group did not exhibit a decrease in b.w. like the rats exposed to 2,851 and 4,049 ppm. Total Uncertainty Factor and Modifying Factor = 150 (Continued)

OCR for page 136
169 Furan AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 12 ppm 8.5 ppm 6.8 ppm 1.7 ppm 0.85 ppm Uncertainty Factors and Rationale: Interspecies: 10; applied because there are inadequate data to properly assess interspecies variability. Terrill et al. (1989) was the only published furan toxicity study that investigated the toxicity of inhaled furan, and it evaluated only one species (rat). Therefore, insufficient empirical data were available to examine species differences in response to inhaled furan. A PBPK simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5-fold higher, respectively, than that in humans, while the integrated liver exposure to furan metabolites would be ~6- and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that the rat is more sensitive than the mouse despite PBPK modeling predictions that the mouse would have a 3-fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than the rat. Therefore, there are too many uncertainties about the response of the rat, mouse, and human liver to furan to base an uncertainty factor on the PBPK modeling predictions. Intraspecies: 3; applied for the following reasons: 1. Assuming death was the result of a progression of the toxicity present at the lower concentrations, the steep dose-response curve for lethality indicates there is not much variability in the response (0 of 10 rats died at 1,014 or 2,851 ppm, while 9 of 10 rats died at 4,049 ppm). The delayed deaths in the high-concentration group suggest that hepatotoxicity was the cause of death. 2. If no hepatotoxicity is present, the clinical signs are likely due to a direct contact effect, which is not expected to vary much among individuals. 3. Higher, respectively, than that in humans. If the effect is hepatotoxicity, it is due to the reactive metabolite produced in the liver. PBPK modeling data indicate that production of the metabolite is blood flow limited. Therefore, variations in cytochrome P-450 2E1 levels are not likely to be a significant factor (Kedderis and Held 1996). Additionally, when using hepatocytes as the basis, PBPK modeling indicates that when adults and children (ages 6, 10, and 14 years) are exposed to the same furan concentrations, the blood concentration of furan is likely to be greater in children than in adults by a factor of only 1.5 (at steady state), and the maximum factor of adult-child differences in liver concentration of furan metabolite is about 1.25 (Price et al. 2003). Modifying Factor: 5; applied to account for a limited data set (only one data set addressing furan toxicity after inhalation exposure was available). This study was not repeated, and there was no information on furan toxicity in other species. Animal to Human Dosimetric Adjustment: Not applicable Time-scaling: Cn × t = k, where the default value of n = 1 was used for extrapolating from shorter to longer exposure periods and a value of n = 3 was used to extrapolate from longer to shorter exposure periods. Data Adequacy: Only limited data were available to assess the inhalation toxicity of furan.

OCR for page 136
170 Acute Exposure Guideline Levels AEGL-3 VALUES 10 min 30 min 1h 4h 8h 35 ppm 24 ppm 19 ppm 4.8 ppm 2.4 ppm Reference: Terrill, J.B., W.E. Van Horn, D. Robinson, and D.L. Thomas. 1989. Acute inhalation toxicity of furan, 2 methylfuran, furfuryl alcohol, and furfural in the rat. Am. Ind. Hyg. Assoc. J. 50(5):A359-A361. Test Species/Strain/Number: Sprague-Dawley rats, 5/sex/exposure group Exposure Route/Concentrations/Durations: 1,014, 2,851, and 4,049 ppm for 1 h Effects: Signs of toxicity during exposure included respiratory distress, increased secretory response (severity at each concentration not provided). 1,014 ppm: 0/10 died 2,851 ppm: 0/10 died 4,049 ppm: 9/10 died End Point/Concentration/Rationale: Highest nonlethal concentration in rats Total Uncertainty Factor and Modifying Factor = 150 Uncertainty Factors and Rationale: Interspecies: 10; applied because there are inadequate data to properly assess interspecies variability. Terrill et al. (1989) was the only published furan toxicity study that investigated the toxicity of inhaled furan, and it evaluated only one species (rat). Therefore, insufficient empirical data were available to examine species differences in response to inhaled furan. A PBPK simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5-fold higher, respectively, than that in humans, while the integrated liver exposure to furan metabolites would be ~6- and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that the rat is more sensitive than the mouse despite PBPK modeling predictions that the mouse would have a 3-fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than the rat. Therefore, there are too many uncertainties about the response of the rat, mouse, and human liver to furan to base an uncertainty factor on the PBPK modeling predictions. Intraspecies: 3; applied for the following reasons: 1. Assuming death was the result of a progression of the toxicity present at the lower concentrations, the steep dose-response curve for lethality indicates there is not much variability in the response (0/10 rats died at 1,014 or 2,851 ppm, while 9/10 rats died at 4,049 ppm). The delayed deaths in the high-concentration group suggest that hepatotoxicity was the cause of death. 2. If no hepatotoxicity is present, the clinical signs are likely due to a direct contact effect, which is not expected to vary much among individuals. 3. If the effect is hepatotoxicity, it is due to the reactive metabolite produced in the liver. PBPK modeling data indicate that production of the metabolite is blood flow limited. Therefore, variations in cytochrome P-450 2E1 levels are not likely to be a significant factor (Kedderis and Held 1996). Additionally, when using heptatocytes as the basis, PBPK modeling indicates that when adults and children (ages 6, 10, and 14 years) are exposed to the same furan concentrations, the blood concentration of furan is likely to be greater in children than in adults by a factor of only 1.5 (at steady state), and the maximum factor of adult-child differences in liver concentration of furan metabolite is about 1.25 (Price et al. 2003). (Continued)

OCR for page 136
171 Furan AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 35 ppm 24 ppm 19 ppm 4.8 ppm 2.4 ppm Modifying Factor: 5; applied to account for a limited data set (only one data set addressing furan toxicity after inhalation exposure was available; this study was not repeated; there was no information on furan toxicity in other species. Animal to Human Dosimetric Adjustment: Not applicable Time-scaling: Cn × t = k, where the default value of n = 1 was used for extrapolating from shorter to longer exposure periods and a value of n = 3 was used to extrapolate from longer to shorter exposure periods. Data Adequacy: Only limited data were available to assess the inhalation toxicity of furan.

OCR for page 136
172 Acute Exposure Guideline Levels APPENDIX C Category Plot for Furan FIGURE 3-1 Category plot of animal toxicity data for furan compared with AEGL values.