6

Piperidine1

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 are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or 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

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1This document was prepared by the AEGL Development Team composed of Kowetha Davidson (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Managers Mark A. McClanahan and Susan Ripple (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). 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 guidelines reports (NRC 1993, 2001).



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6 Piperidine1 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 are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or 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 Kowetha Davidson (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Managers Mark A. McClanahan and Susan Ripple (National Advisory Com- mittee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and re- vised 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 devel- oped in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 167

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168 Acute Exposure Guideline Levels 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 concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Piperidine is a cyclic aliphatic amine (Eller et al. 2000). It is a clear, color- less, and flammable liquid that produces vapors that reach explosive concentra- tions at room temperature. Piperidine has a dissociation constant (pKb) of 2.88 and a pH of 12.6 (100 g/L, 20°C). Therefore, it is expected to be very corrosive. It has a strong pepper- or amine-like and pungent odor. Piperidine has many commercial uses, including use as a solvent, a curing agent for rubber and epoxy resins, an intermediate in organic synthesis, a food additive, and a constituent in the manufacturing of pharmaceuticals. Daily exposure to piperidine is evidenced by its presence in the food sup- ply and its excretion in human urine. It is a natural constituent in white and black pepper. Piperidine is formed naturally in the body from the degradation of lysine, cadaverine, and pipecolic acid. Exogenous piperidine is absorbed from the respiratory tract, gastrointestinal tract, and skin. It is found in most tissues of the body, including the brain, and is excreted as unchanged piperidine or its me- tabolites. Studies in rats showed that nasal irritation and signs of ocular irritation oc- cur at the lower concentrations of piperidine followed by corrosion around the nose and dyspnea at higher concentrations. Corneal damage, central nervous system (CNS) toxicity, and prostration occurred at the highest concentrations;

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Piperidine 169 however, death occurred only at concentrations that caused dyspnea, CNS toxic- ity, and prostration. Therefore, the severity of effects from piperidine shows a clear continuum ranging from nasal irritation to death. Piperidine has no demon- strated carcinogenic activity, it is not genotoxic in Salmonella typhimurium, and it is not toxic to the developing rat fetus at the concentrations tested. The database on piperidine in humans is very small. Inhalation exposure to piperidine may cause sore throat, coughing, labored breathing, and dizziness. The odor threshold is reported to be <2 ppm, and 2-5 ppm is reported to be tol- erated by unacclimated individuals for only a brief time because of its pungent odor. The irritation threshold for humans was reported to be 26 ppm. At an odor threshold of 0.37 ppm, a level of distinct odor awareness would be 5.9 ppm (van Doorn et al. 2002). AEGL-1 values were based on the no-effect level (20 ppm for 6 h) for na- sal irritation in rats. Uncertainty factors of 3 for interspecies differences and 3 for intraspecies variability were applied. The rationale for selecting those factors included the following: (1) the effect observed at 50 ppm was mediated by direct contact of piperidine with the nasal epithelium without involvement of other regions of the respiratory tract; and (2) the cell composition of the nasal mucosa is similar between species and among individuals within the population, al- though the cell distribution and nasal morphology differ among species. In addi- tion, the relationship between concentration vs. time for LC50 (lethal concentra- tion, 50% lethality) values was similar in mice, guinea pigs, and rats; they did not vary by more than 30%. The linear correlation coefficient was -0.96. After applying a total uncertainty factor of 10, the resulting value of 5 ppm was time scaled based on the equation, Cn × t = k, where n = 1.5. The value of n was de- rived from a regression analysis of the LC50 values for the mouse, guinea pig, and rat. AEGL-2 values were based on exposure of rats to piperidine at 200 ppm for 6 h, which caused nasal irritation without salivation or evidence of ocular irritation. The rationale for selecting uncertainty factors and the time-scaling procedure were the same as those described for the AEGL-1 values. AEGL-3 values were based on the LC01 (lethal concentration, 1% lethal- ity) calculated from a 4-h acute inhalation study in rats. The LC01 of 448 ppm is less than the lowest concentration that caused one death among 20 rats (5% le- thality) and greater than the highest concentration that caused no deaths or clini- cal moribund signs. Therefore, the LC01 appeared to be a good estimate of the threshold for lethality. Uncertainty factors of 3 for interspecies differences and 3 for intraspecies variability were applied to the LC01. The rationale for selecting the uncertainty factors was the same as described for AEGL-1 values. In addi- tion, larger factors for interspecies differences or intraspecies variability would have produced values for the 4-h and 8-h durations that were lower than the irri- tation threshold of 26 ppm. The time-scaling procedure was the same as de- scribed for AEGL-1 values. AEGL values for piperidine are presented in Table 6-1.

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170 Acute Exposure Guideline Levels TABLE 6-1 Summary of AEGL Values for Piperidine End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 10 ppm 10 ppm 6.6 ppm 2.6 ppm 1.7 ppm No nasal irritation (nondisabling) (35 mg/m3) (35 mg/m3) (23 mg/m3) (9 mg/m3) (6 mg/m3) (BASF 1993) AEGL-2 50 ppm 50 ppm 33 ppm 13 ppm 8.3 ppm Nasal irritation (disabling) (175 (175 (116 (46 (29 (BASF 1990) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 370 ppm 180 ppm 110 ppm 45 ppm 28 ppm Threshold for (lethal) (1,295 (630 (385 (158 (98 lethality mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (BASF 1980) 1. INTRODUCTION Piperidine is a cyclic aliphatic amine (Eller et al. 2000). It is flammable (Trochimowicz et al. 1994) and produces explosive vapors at room temperature (HSDB 2008). Piperidine is a clear, colorless liquid and has a strong pepper- or amine-like pungent odor (Lewis 1993; Trochimowicz et al. 1994). Piperidine is a very strong base with a dissociation constant (pKb) of 2.88 (Reed 1990); thus, it is a very corrosive agent. The vapor pressure indicates that exposure to piperidine could occur by the inhalation route under ambient conditions. Chemi- cal and physical properties of piperidine are presented in Table 6-2. Piperidine has many commercial uses. It is used as a solvent, a curing agent for rubber and epoxy resins, a catalyst in silicone esters, an intermediate in organic synthesis, and a wetting agent. It is used in the manufacture of pharma- ceuticals (analgesics, anesthetics, and germicides) and as a food additive (Reed 1990; Trochimowicz et al. 1994; HSDB 2008). In 1983, the United States pro- duced 2.75 × 108 g (~606,000 pounds) of piperidine (HSDB 2008). Humans are exposed to piperidine on a daily basis, as evidenced by its wide presence in the food supply and, consequently, in human urine. As a food additive, piperidine is found at 2.5-3.33 ppm in nonalcoholic beverages, 4-5.67 ppm in candy, 9.69 ppm in baked goods, and 0.04-1.66 ppm in condiments, meats, and soups (HSDB 2008). Piperidine also occurs naturally in food prod- ucts, including vegetables (Neurath et al. 1977). Pulverized white pepper con- tains as much as 1,322 ppm of piperidine, and black pepper up to 703 ppm (Lin et al. 1981). Baked ham contains 0.2 ppm of piperidine, milk 0.11 ppm, and dry coffee 1 ppm (Reed, 1990). Piperidine also is found in boiled beef (Golovnya et al. 1979). von Euler (1945) reported that humans excrete 7.6-8.5 mg of piperidine in a 24-h period; more recently, Tricker et al. (1992) reported excre- tion rates of 26.1-31.7 mg/day. The toxicology database on piperidine consists of anecdotal human data and a small amount of animal data.

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Piperidine 171 TABLE 6-2 Chemical and Physical Data on Piperidine Parameter Value Reference Chemical name Piperidine Synonyms Azacyclohexane, cyclopentimine, RTECS 2009 hexahydropyridine, UN2401 CAS registry no. 110-89-4 RTECS 2009 Chemical formula C5H11N Budavari et al. 1996 Molecular weight 85.15 Budavari et al. 1996 Physical state Colorless liquid Lewis 1993 Boiling point 106.3°C Howard and Meylan 1997 Freezing point -13 to -7°C Budavari et al. 1996 Vapor density 3.0 (air = 1) Trochimowicz et al. 1994 Specific gravity 0.8622 at 20°C Reed 1990 6 Solubility 1.6 × 10 mg/L of water at 20°C Howard and Meylan 1997 Vapor pressure 32.1 mm Hg at 25°C Howard and Meylan 1997 40 mm Hg at 29.2°C Trochimowicz et al. 1994 Flash point 16.11°C (61°F) Trochimowicz et al. 1994 Refractive index (no) 1.4530 Weast et al. 1985 pH 12.6 at 100 g/L at 20°C BG Chemie 2000 pKb 2.88 Reed 1990 Log P 0.84 Howard and Meylan 1997 Conversion factors 1 ppm = 3.5 mg/m3 at 25°C, 1 atm 1 mg/m3 = 0.29 ppm 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data were found on the acute lethality of piperidine in humans. 2.2. Nonlethal Toxicity 2.2.1. Experimental Studies, Case Reports, and Anecdotal Data Bazarova and Migoukina (1975) reported an irritation threshold for piperidine of 90 mg/m3 (26 ppm) in human volunteers. No additional details were provided.

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172 Acute Exposure Guideline Levels Concentrations of 2-5 ppm (7.0-17.5 mg/m3) were measured in a semi- closed environment as piperidine was transferred from drums. The report stated that unacclimated individuals could tolerate the pungent odor for only a brief time, although irritation was not perceived (A.C. Nawakowski, Upjohn Com- pany, unpublished material, 1980, as cited in Trochimowicz et al. 1994). No additional details were provided. EPA (1985) reported that piperidine is a strong local irritant that can cause permanent injury after a short exposure to small amounts. DASE (1980) re- ported that inhalation exposure causes sore throat, coughing, labored breathing, and dizziness. No exposure concentrations were provided in either report. 2.2.2. Other Studies No human studies were found on the neurotoxicity, developmental toxic- ity, reproductive toxicity, carcinogenicity, or genetic toxicity of piperidine. 2.3. Summary No human lethality data were found on piperidine. The irritation threshold for piperidine is 26 ppm (90 mg/m3). Inhalation exposure to piperidine causes sore throat, coughing, labored breathing, and dizziness. Piperidine at 2-5 ppm (7.0-17.5 mg/m3) is not irritating, but could be tolerated for only a brief time because of its pungent odor. These data indicate that the odor threshold for piperidine is less than 2 ppm (7.0 mg/m3). 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality BASF (1980) exposed groups of 10 male and 10 female Sprague-Dawley rats to piperidine (99%) at analytic concentrations of 2,190, 1,540, 1,190, 810, or 290 ppm (7,540, 5,300, 4,100, 2,800, or 1,000 mg/m3, respectively) for 4 h, and the rats were observed for 14 days. Rats were exposed (whole body) in a glass-steel chamber under dynamic conditions. Vapor was generated with an evaporation unit at 69°C and mixed with fresh air to obtain the desired concen- tration. Clinical signs, mortality, food consumption, body weights, and gross and microscopic findings were evaluated during or after exposure. Multiple clinical signs were observed at all concentrations. Prostration was observed only at 1,540 and 2,190 ppm. Corrosion around the nose, smoky-milky clouded cornea, crouched position, tremors, and clonic convulsions were observed at concentra- tions >1,190 ppm. Rubbing of the snout, dyspnea, and corrosion around the nose were observed at concentrations >810 ppm; nasal corrosion was observed in

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Piperidine 173 only one male rat. A strong watery-reddish or reddish secretion from the eyes and nose, lid closure, and ragged fur were observed at all concentrations, and spasmodic respiration was observed only at 290 ppm. No clinical signs were observed more than 2 days after exposure at 290 ppm. Mortality data are sum- marized in Table 6-3. A clear dose-response relationship was shown for male rats but not female rats. LC50 (lethal concentration, 50% lethality) values for piperidine in rats were 1,330, 1,420, 1,390 ppm (4,600, 4,900, and 4,800 mg/m3) for males, females, and both sexes combined, respectively. None of the rats exposed at 2,190 ppm survived until day 7. All male and female rats that did not survive until the end of the observation period died before day 7, except for one female rat exposed at 1,540 ppm and three female rats exposed at 1,190 ppm. Male and female rats exposed at 1,190 ppm and 1,540 ppm and females exposed at 810 ppm lost weight during the first week of observation, gained weight during the second week, and the males weighed 13-29% less than controls and the females weighed 14-19% less than controls at the end of the observation period. A post- mortem evaluation was conducted, but no data were provided. BASF (1981, as cited in BG Chemie 2000) reported that two of 12 and three of six Wistar rats died after exposure to an atmosphere of saturated piperidine vapor at 20°C (~45,000 ppm) for 3 or 10 min, respectively. No addi- tional details were available. Smyth et al. (1962) reported no deaths among six rats exposed to piperidine at 2,000 ppm (7,000 mg/m3) for 4 h. However, six of six rats died after exposure to piperidine at 4,000 ppm (14,000 mg/m3) for 4 h. The investiga- tors also reported that inhalation of concentrated piperidine vapor for 15 min killed six of six rats; the exposure concentration was not reported. Zayeva et al. (1968) reported a median lethal time (LT50) of 80 min for an unknown mammalian species exposed to an unknown concentration of piperidine by inhalation. Bazarova and Migoukina (1975) reported an LC50 of 1,885 ppm (6,500 mg/m3) for an unidentified mammalian species exposed for an unknown period of time. A 2-h LC50 in mice was reported to be 1,740 ppm (6,000 mg/m3) (BG Chemie 2000; AIHA 2001), and a 1-h LC50 in guinea pigs was 3,480 ppm (12,000 mg/m3) (AIHA 2001). Those lethality values were cited in a secondary source, and the primary sources could not be located to verify the values. 3.2. Nonlethal Toxicity 3.2.1. Rats Groups of five male and five female Wistar rats were exposed to piperidine vapor (99.4% purity) at nominal concentrations of 0, 50, 100, and 200 ppm (175, 350, and 700 mg/m3, respectively) for 6 h/day for 5 days (BASF

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174 Acute Exposure Guideline Levels TABLE 6-3 Lethality Data for Piperidine Mortality Concentration, ppm (mg/m3) Males Females Males and Females 290 (1,000) 0/10 0/10 0/20 810 (2,800) 0/10 1/10 1/20 1,190 (4,100) 3/10 7/10 10/20 1,540 (5,300) 6/10 1/10 7/20 2,190 (7,540) 10/10 10/10 20/20 3 a LC50 [ppm (mg/m )] 1,330 (4,600) 1,420 (4,900) 1,390 (4,800) a Calculated using Number Cruncher Statistical System Survival Analysis, Version 5.5, published by Jerry L. Hintze, July 1991. Source: BASF 1980. 1990). Analytic concentrations were 0, 49, 102, and 203 ppm (0, 170, 360, and 710 mg/m3), respectively. No animals died during the study. Clinical signs were observed during or immediately after exposure, and were concentration- and time-dependent. Nasal secretions and bloody encrustation on the edge of the nares were observed at all concentrations. “Stretched respiration posture,” lid closure, and salivation were observed at 200 ppm. Males exposed at 100 and 200 ppm had decreased body weights after the first days of exposure, but body weight and weight gain were not affected in females. No treatment-related changes in clinical pathology or post-mortem pathology were observed at any concentration. Because clinical signs were observed and recorded after each exposure, this study can be used for derivation of AEGL values. In a 28-day study, two groups of five male and five female Wistar rats each were exposed to piperidine vapor (99.4% purity) at concentrations of 0, 5, 20, or 100 ppm (0, 18, 70, and 350 mg/m3, respectively) for 6 h/day, 5 days/week for 28 days (BASF 1993). The rats received 20 exposures. Additional groups of five male and five female rats exposed similarly at 0 or 100 ppm (0 and 350 mg/m3) were maintained for an additional 2 weeks without exposure to piperidine to evaluate recovery. The animals were exposed whole body under dynamic condi- tions in a glass-steel inhalation chamber. The atmosphere in the breathing zones of the animals was monitored approximately every 20 min using a total hydrocarbon analyzer equipped with a flame ionization detector. Rats were observed daily for clinical signs before, during, and after exposure, and body weights were measured at the beginning of the study and at 1-week intervals thereafter. Subgroups of five animals/sex/group were subjected to an extensive battery of neurofunctional tests before exposure and on days 2, 8, 14, and 28. Subgroups of five rats/sex/group were used for clinical pathology evaluations of blood and urine. Post-mortem evaluations consisted of gross examination, organ weight measurements, and mi- croscopic examination of selected tissues.

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Piperidine 175 Treatment-related clinical signs at 100 ppm consisted of a reddish crust (positive for blood) observed on the nasal edges of three male rats on day 2 of the study, all males from day 3 to the end of the study, two females on day 3, one female on day 4, almost all females starting on day 8, and all females by the end of the study. The reddish crust was indicative of upper respiratory tract irri- tation. Each subgroup of five male rats exposed at 100 ppm weighed 3.4% (n.s.) and 5.7% (n.s.) less than controls. Females exposed at 100 ppm did not show a trend toward decreased body weights. The only notable effects on the neuro- functional battery were increased hindlimb grip strength on day 8 in males ex- posed at 100 ppm and decreased response to the hot plate test on day 14 in males exposed at 5 and 100 ppm. Because these effects were transient or showed no dose-related trend, they are unlikely to be treatment related. No treatment- related effects were observed on ocular, hematologic, or clinical chemistry pa- rameters, or on post-mortem findings. Treatment-related effects were not ob- served at 5 or 20 ppm (BASF 1993). This study is of marginal use for deriving AEGL values, because adverse effects were observed after the second exposure but not after the first exposure. BASF (1993) reported no nervous system ef- fects; however, Bazarova and Migoukina (1975) reported an acute-exposure threshold of 5.8 ppm (20 mg/m3) for nervous system response in rats. No addi- tional details were available in the translation. Bazarova (1973) conducted a study in which groups of 20 rats (strain and sex not specified) were exposed to piperidine vapors at analytically measured concentrations of 0.002 ± = 0.0003 or 0.01 ± 0.001 mg/L (2 or 10 mg/m3 [0.6 or 3 ppm]) for 4 h/day, 5 days/week for 4 months followed by a 1-month recovery period. A group of 20 rats served as the control. Animals were exposed in a 700- L dynamic chamber (not otherwise described), and chamber atmospheres were measured eight times during each 4-h exposure. The investigators assessed body weight changes, blood vessel penetrability, erythrocyte parameters, liver and kidney function, testicular morphology, and neural activity. Rats exposed at 10 mg/m3 weighed 14% less than the controls after 14 ex- posures and 16% less than controls at the end of the recovery period. Evidence of increased neural and muscular excitability was observed after exposure at 10 mg/m3 for 1.5 months or at 2 mg/m3 for 2.5 months. Respiration was decreased after exposure at 2 mg/m3 for 1.5 months and increased after exposure at 10 mg/m3 for 2.5 months. At both concentrations, blood vessels in the skin showed decreased penetrability (measured after application of xylol) during the early phase of the study, followed by increased penetrability during the late phase of the study that remained evident until the end of the recovery period. In addition, blood vessel stability was decreased throughout the study in the 10-mg/m3 group, as measured by increased petechia (submucosal hemorrhage). Decreases in erythrocyte count (80% of control) and hemoglobin concentration (89% of control) were observed in this group at the beginning of exposure and remained lower after 1.5 months, but were increased compared with controls at the end of the recovery period. Leukocyte count was decreased after 2.5 months (53% of control) due to a decrease in the lymphocyte count (47.9% of control) in rats

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176 Acute Exposure Guideline Levels exposed at 10 mg/m3. Blood pressure was significantly decreased in rats ex- posed at 10 mg/m3 after 2.5 and 4 months. At the end of exposure, an effect on liver function was evidenced by a 47% decrease in urinary hippuric acid, and effects on kidney function were evidenced by a 46% decrease in urinary volume, increase in specific gravity of the urine, and 65% increase in urinary protein. Histopathologic findings in the 10 mg/m3 group included a decrease in the num- ber of normal spermatogonia and degeneration of the seminiferous tubules in the testes, focal swelling of the interalveolar septa in the lungs, albuminous degen- eration in the liver, hyalin droplet and albuminous degeneration in the kidney, stromal atrophy in the spleen, and necrosis and scaring in the cardiac muscle (Bazarova 1973). Descriptive details were lacking for an adequate evaluation of this study; some information about this study was also obtained from BG Che- mie (2000). 3.2.2. Rabbits Bazarova (1973) exposed groups of six rabbits under the same conditions as rats to piperidine at 0.01 or 0.002 mg/L (10 and 2 mg/m3, respectively) for 4 h/day, 5 days/week for 4 months, followed by a 1-month recovery period. The only effect described for the rabbit was a 29% and 27% decrease in arterial blood pressure after exposure at 10 and 2 mg/m3, respectively, for 14 days, and an 8% increase in pressure after exposure at 10 mg/m3 for 4 months. 3.3. Developmental and Reproductive Toxicity Hughes et al. (1990) reported on the developmental effects in rats exposed to piperidine vapor during organogenesis. Groups of 25 pregnant Crl:CD(SD) GR VAF/Plus strain rats were exposed whole body to piperidine at concentra- tions of 0, 5, 20, or 80 ppm (0, 18, 70, and 280 mg/m3, respectively) for 6 h/day on gestation days 6-15. Dams were observed daily for clinical signs, weighed on gestation days 2, 3, and 6 and at 2-day intervals until gestation day 20, and had food consumption measured at intervals between weighing days. Dams were killed on gestation day 20 and their ovaries and uteri were examined. All dams survived to the end of the study. No treatment-related effects were observed on any litter parameter examined, including litter size, post-implantation loss, mean litter weight, or mean fetal weight. In addition, the incidences of visceral and skeletal malformations were similar between the exposed and control groups. Therefore, no effects were observed in developing fetuses of female rats ex- posed to piperidine concentrations up to 80 ppm during organogenesis. However, a number of maternal effects were observed. During each expo- sure to piperidine at 80 ppm, clinical signs in dams included a lack of response to noise (a knock on chamber door) and closed or half-closed eyes. Other signs observed during exposure at that concentration included licking the inside of the

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Piperidine 177 mouth (frequency not reported), piloerection (frequency not reported), hunched posture during almost all exposures, and increased respiration, salivation, and rubbing the chin and paws on the cage during one or two exposures. After daily exposures at 80 ppm, some rats had red/brown staining on the fur, two had “snuffles,” and one showed sneezing and salivation. At 20 ppm, lack of response to a knock on the chamber door was noted on each exposure occasion, and closed or half-closed eyes and hunched posture were observed once during the study. No clinical signs were reported after daily exposure to piperidine at 20 ppm, and no clinical signs related to exposure were observed at 5 ppm. Body weights and weight gain at 80 ppm were reduced compared with controls during the exposure period, but showed signs of recovery after exposure ended and was similar to controls at the end of the study. Food consumption also was reduced at 80 ppm during the exposure period and remained reduced after exposure ended. No treatment-related effects were observed on body weights or food con- sumption in the 5- or 20-ppm groups and no treatment-related necropsy findings were observed at any exposure concentration. The lack of response to a knock on the chamber door was the only clinical sign observed daily in rats exposed at 20 ppm. It is doubtful that this nonspecific clinical signs is treatment related or toxicologically significant in the absence of any corroborating evidence of cen- tral nervous system toxicity. BASF (1993) observed no treatment-related effects in their battery of neurofunctional tests conducted in a 28-day study of rats ex- posed repeatedly to piperidine at concentrations up to 100 ppm. Nevertheless, this study can be used for AEGL derivation because of the maternal clinical signs observed at 80 ppm. In a study by Timofievskaya and Silantyeva (1975), groups of 6-13 preg- nant rats were exposed to piperidine vapor at concentrations of 0, 0.9, 4, or 30 ppm (0, 3, 15, or 100 mg/m3, respectively) throughout pregnancy or on gestation day 9 or at 0.9 or 30 ppm on gestation day 4. Two control groups were included in this study. Dams were killed on gestation day 21 for assessment of maternal and fetal parameters. The duration of each exposure was not reported, so it was assumed that animals were exposed continuously. No behavioral effects were noted in the dams, but body weight gain was lower in dams exposed at 4 and 30 ppm compared with controls. In rats exposed at 30 ppm on gestation day 4, sig- nificant decreases in the number of fetuses per dam (5.5 vs. 8.5 and 11.08 for the two control groups) and in the number of implantation sites (6.1 vs. 9.4 for con- trol) were observed. Piperidine at 30 ppm on gestation day 9 or throughout pregnancy had no effect on these parameters. Fetal body weights were decreased in dams exposed at all concentrations throughout pregnancy (66-78% of control fetal weight). Fetal body weights were 76% of control weights after exposure at 0.9 ppm on gestation day 4 or 9; no significant reductions in fetal weights were observed after exposure at 30 ppm on gestation day 4 or 9 or at 4 ppm on gesta- tion day 9. Decreases in fetal body weights appeared to be unrelated to exposure to piperidine. A concentration-response relationship was not observed for the single exposures. In addition, no corresponding changes were observed in other

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Piperidine 191 9. REFERENCES AIHA (American Industrial Hygiene Association). 1996. Workplace Environmental Ex- posure Level Guide: Piperidine. American Industrial Hygiene Association, Fairfax, VA. AIHA (American Industrial Hygiene Association). 2001. Workplace Environmental Ex- posure Level Guide: Piperidine (CAS Reg. No. 110-89-4). In 2001 WEELs Com- plete Set. American Industrial Hygiene Association, Fairfax, VA. AIHA (American Industrial Hygiene Association). 2007. Piperidine (CAS Reg. No. 110- 89-4). P. 8 in The AIHA 2007 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association, Fairfax, VA. BASF. 1980. Determination of the Acute Inhalation Toxicity LC50 of Piperidine as Vapor in Sprague-Dawley Rats after a 4-Hour Exposure [in German]. BASF Gewerbehy- giene und Toxikologie. November 17, 1980. BASF. 1981. Piperidin-akutes inhalationsrisiko. BASF Gewerbehygiene und Toxikologie (as cited in BG Chemie 2000). BASF. 1990. Range-finding Study on the Inhalation Toxicity of Piperidine as Vapor in Rats: 5-Day Study [in German]. Project No. 3010523-89017. BASF Aktiengesell- schaft, Ludwigshafen/Rhein, Germany. January 2, 1990. BASF. 1993. Study on the Inhalation Toxicity of Piperidine as a Vapor in Rats: 28-Day Test Including an About 2-Week Post-Exposure Observation Period Including Neurotoxicological Examinations. Project No. 4610523-89065. BASF Aktienge- sellschaft, Ludwigshafen/Rhein, Germany. Bazarova, L.A. 1973. Evaluation of general toxic and specific effects of piperidine at chronic exposure [in Russian]. Toksikol. Nov. Prom. Khim. Veshchestv. 13:100-107. Bazarova, L.A., and N.V. Migoukina. 1975. Comparative evaluation of the toxicity, haz- ards and mode of action of piperidine and morpholine [in Russian]. Toksikol. Nov. Khim. Veshchestv. 14:90-95. BG Chemie. 2000. Piperidine (CAS Reg. No. 110-89-4). Toxicological Evaluations No.72 [in German]. Berufsgenossenschaft der Chemischen Industrie (Employment Accident Insurance Fund of the Chemical Industry), Heidelberg, Germany [online]. Available: http://www.bgrci.de/fileadmin/BGRCI/Downloads/DL_Praeve ntion/Fachwissen/Gefahrstoffe/TOXIKOLOGISCHE_BEWERTUNGEN/Bewertun gen/ToxBew072-L.pdf [accessed Nov. 1, 2012]. Budavari, S., M.J. O’Neil, A. Smith, P.E. Heckelman, and J.F. Kinneary, eds. 1996. P. 1285 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 12th Ed. Whitehouse Station, NJ: Merck. DASE (Dutch Association of Safety Experts). 1980. Piperidine. P. 757 in Handling Chemicals Safely. Dutch Association of Safety Experts, Dutch Chemistry Indus- trial Association, and Dutch Safety Institute, The Hague. DuPont Company. 1968. Report HLR 158-68 (as cited in Trochimowicz et al. 1994). Eller, K., E. Henkes, R. Rossbacher, and H. Höke. 2000. Amines, aliphatic. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH [online]. Available: http://onlinelibrary.wiley.com/doi/10.1002/14356007.a02_001/abstract;jsessionid= 7E07931380494CD0DB64275764D4B544.d01t01 [accessed Nov. 1, 2012]. EPA (U.S. Environmental Protection Agency). 1985. Chemical Profile: Piperidine (CAS Reg. No. 110-89-4). U.S. Environmental Protection Agency, Washington, DC.

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192 Acute Exposure Guideline Levels EPA (U.S. Environmental Protection Agency). 2003. EPA’s Benchmark Dose Software, Version 1.3.2. U.S. Environmental Protection Agency: Washington, DC. Garberg, P., E.L. Akerblom, and G. Bolcsfoldi. 1988. Evaluation of a genotoxicity test measuring DNA-strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution. Mutat. Res. 203(3):155-176. Gehring, P.J. 1983. Pyridine, homologues and derivatives. Pp. 1810-1812 in Encyclope- dia of Occupational Health and Safety, Vol. 2, 3rd Ed., L. Parmeggiani, ed. Ge- neva, Switzerland: International Labour Organization. Giacobini, E. 1976. Piperidine: A new neuromodulator or a hypnogenic substance? Adv. Biochem. Pyschopharmacol. 15:17-56. Golovnya, R.V., I.L. Zhuravleva, and Y.P. Kapustin. 1979. Gas chromatographic analysis of volatile nitrogen bases of boiled beef as possible precursors of N-nitrosamines. Chem. Senses 4(2):97-105. Green, N.R., and J.R. Savage. 1978. Screening of safrole, eugenol, their ninhydrin posi- tive metabolites and selected secondary amines for potential mutagenicity. Mutat. Res. 57(2):115-121. Howard, P.H., and W.M. Meylan, eds. 1997. P. 203 in Handbook of Physical Properties of Organic Chemicals. Boca Raton, FL: CRC Press. HSDB (Hazard Substance Data Bank). 2008. Piperidine (CAS Reg. No. 110-89-4). TOXNET, Specialized Information Services. U.S. National Library of Medicine: Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? HSDB [accessed Nov. 1, 2012]. Hughes, E.W., B.A. Homan, D.M. John, T.J. Kenny, D.W. Coombs, and C.J. Hardy. 1990. A Study of the Effect of Piperidine on Pregnancy of the Rats. Report No. BGH 9/9097. PE18 6ES. Huntingdon Research Centre, Ltd., Huntingdon, England. Kase, Y., and T. Miyata. 1976. Neurobiology of piperidine: Its relevance to CNS func- tion. Adv. Biochem. Pyschopharmacol. 15:5-16. Lewis, R.J., Sr. 1993. P. 919 in Hawley’s Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Reinhold Co. Lijinsky, W., and H.W. Taylor. 1977. Feeding tests in rats on mixtures of nitrite with secondary and tertiary amines of environmental importance. Food Cosmet. Toxi- col. 15(4):269-274. Lin, J.K., J.J. Hwa, and Y.J. Lee. 1981. Chemical toxicants in Chinese foods: 4. The con- tents and biological significance of piperidine in black pepper, white pepper, red pepper and other species. Nat. Sci. Counc. Mon. 9(7):557-566. Linch, A.L. 1965. Piperidine - A hazardous chemical. Am. Ind. Hyg. Assoc. J. 26(1):95-96. Neurath, G.B., M. Dünger, F.G. Pein, D. Ambrosius, and O. Schreiber. 1977. Primary and secondary amines in the human environment. Food Cosmet. Toxicol. 15(4):275-282. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Acad- emy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. Okano, Y., T. Miyata, S.H. Hung, T. Motoya, M. Kataoka, K. Takahama, and Y. Kasé. 1978. Metabolites of piperidine in rat urine. Jpn. J. Pharmacol. 28(1):41-47. Perry, T.L., S. Hansen, and L.C. Jenkins. 1964. Amine content of normal human cerebro- spinal fluid. J. Neurochem. 11(1):49-53.

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Piperidine 193 Reed, R.L. 1990. Piperidine. Pp. 251-258 in Ethel Browning’s Toxicity and Metabolism of Industrial Solvents, Vol. II: Nitrogen and Phosphorus Solvents, 2nd Ed., D.R. Buhler, and D.J. Reed, eds. New York: Elsevier. Riebe, M., K. Westphal, and P. Fortnagel. 1982. Mutagenicity testing, in bacterial test systems, of some constituents of tobacco. Mutat. Res. 101(1):39-43. Royal Society. 1987. Piperidine. Pp. 207-210 in Chemical Safety Data Sheets (as cited in AIHA 1996). RTECS (Registry of Toxic Effects of Chemical Substances). 2009. Piperidine. RTECS No. TM3500000 National Institute for Occupational Safety and Health [online]. Avail- able: http://www.cdc.gov/niosh-rtecs/tm3567e0.html [accessed Nov. 1, 2012]. Smyth, H.F., Jr., C.P. Carpenter, C.S. Weil, U.C. Pozzani, and J.A. Striegel. 1962. Range-finding toxicity data: List VI. Am. Ind. Hyg. Assoc. J. 23:95-107. Timofievskaya, L.A. 1979. Comparative evaluation of the toxicity of piperazine and N- methyl piperazine in Russian]. Toksikol. Nov. Prom. Khim. Veshchestv. 15:116-123. Timofievskaya, L.A., and I.V. Silantyeva. 1975. Study of the effect of piperidine on em- bryogenesis [in Russian]. Toksikol. Nov. Prom. Khim. Veshchestv. 14:40-46. Trochimowicz, H.J., G.L. Kennedy, Jr., and N.D. Krivanek. 1994. Heterocyclic and mis- cellaneous nitrogen compounds. Pp. 3285-3521 in Patty’s Industrial Hygiene and Toxicology, Vol. IIB, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Tricker, A.R., B. Pfundstein, T. Kaelble, and R. Preussmann. 1992. Secondary amine precursor in human saliva, gastric juice, blood, urine and faeces. Carcinogenesis 13(4):563-568. van den Heuvel, M.J., D.G. Clark, R.J. Fielder, P.P. Koundakjian, G.J. Oliver, D. Pelling, N.J. Tomlinson, and A.P. Walker. 1990. The international validation of a fixed- dose procedure as an alternative to the classical LD50 test. Food. Chem. Toxicol. 28(7):469-482. van Doorn, R., M. Ruijten, and T. van Harreveld. 2002. Guidance for the Application of Odor in 44 Chemical Emergency Responses, Version 2.1. August 29, 2002. Pre- sented at the NAC/AEGL Meeting, September 2002. von Euler, U.S. 1945. The occurrence and determination of piperidine in human and ani- mal urine. Acta Pharmacol. Toxicol. 1(1):29-49. Wangenheim, J., and G. Bolcsfoldi. 1988. Mouse lymphoma L5178Y thymidine kinase locus assay of 50 compounds. Mutagenesis 3(3):193-205. Weast, R.C., M.J. Astle, and W.H. Beyer, eds. 1985. CRC Handbook of Chemistry and Physics, 66th Ed. Boca Raton: CRC Press. Zayeva, G.N., L.A. Timofievskaya, K.P. Stasenkova, and L.A. Bazarova. 1968. Use of time/effect plots in toxicological experiments [in Russian]. Toksikol. Nov. Prom. Khim. Veshchestv. 10:5-9.

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194 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR PIPERIDINE Derivation of AEGL-1 Values Key study: BASF. 1993. Study on the Inhalation Toxicity of Piperidine as a Vapor in Rats: 28-day Test. Project No. 4610523-89065. BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Toxicity end point: No-effect level for nasal irritation (20 ppm for 6 h). Time scaling: Cn × t = k; n = 1.5 (derived by regression analysis of LC50 data for rats, guinea pigs, and mice). Uncertainty factors: 3 for interspecies differences because the effects are mediated by direct contact with nasal epithelium, which has similar cell composition among species but different cell distribution and nasal morphology; linear correlation for the concentration vs. time relationship for LC50 values for three species is -0.96 and the concentration-time relationships are similar, not varying by more than 30%, indicating that the response was similar among the three species 3 for intraspecies variability because the nasal epithelium does not vary among individuals in the population. Calculations: C = 20 ppm ÷ 10 (total uncertainty factor) = 2 ppm Cn × t = k; C = 2 ppm, t = 360 minutes, n = 1.5 k = (2 ppm)1.5 × 360 min = 1,018.2338 ppm-min 10-min AEGL-1: Set equal to the 30-min AGEL-1 values

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Piperidine 195 30-min AEGL-1: C = (1,018.2338 ppm-min ÷ 30 min)1/1.5 C = 10 ppm 1-h AEGL-1: C = (1,018.2338 ppm-min ÷ 60 min)1/1.5 C = 6.6 ppm 4-h AEGL-1: C = (1,018.2338 ppm-min ÷ 240 min)1/1.5 C = 2.6 ppm 8-h AEGL-1: C = (1,018.2338 ppm-min ÷ 480 min)1/1.5 C = 1.7 ppm Derivation of AEGL-2 Values Key study: BASF. 1990. Range-finding Study on the Inhalation Toxicity of Piperidine as Vapor in Rats: 5-day Study. Project No. 3010523- 89017, BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Toxicity end point: Nasal irritation without eye closure or salivation (100 ppm for 6 h). Time scaling: Cn × t = k; n = 1.5 (derived by regression analysis of LC50 data for rats, guinea pigs, and mice). Uncertainty factors: 3 for interspecies differences because the effects are mediated by direct contact with nasal mucosa, which has similar cell composition among species but different cell distribution and nasal morphology; the data indicate only small variations in LC50 values for three different species 3 for intraspecies variability because the nasal epithelium does not vary among individuals in the population. Calculations: C = 100 ppm ÷ 10 (total uncertainty factor) = 10 ppm Cn × t = k; C = 10 ppm, t = 360 min, n = 1.5 k = 11,384.1996 ppm-min

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196 Acute Exposure Guideline Levels 10-min AEGL-2: Set equal to the 30-min AGEL-1 values 30-min AEGL-2: C = (11,384.1996 ppm-min ÷ 30 min)1/1.5 C = 50 ppm 1-h AEGL-2: C = (11,384.1996 ppm-min ÷ 60 min)1/1.5 C = 33 ppm 4-h AEGL-2: C = (11,384.1996 ppm-min ÷ 240 min)1/1.5 C = 13 ppm 8-h AEGL-2: C = (11,384.1996 ppm-min ÷ 480 min)1/1.5 C = 8.3 ppm Derivation of AEGL-3 Values Key study: BASF. 1980. Determination of the Acute Inhalation Toxicity LC50 of Piperidine as Vapor in Sprague-Dawley Rats After a 4-Hour Exposure. BASF Gewerbehygiene and Toxikologie. Toxicity end point: LC01 (lethality threshold) of 448 ppm calculated by probit analysis. Time scaling: Cn × t = k; n = 1.5 (derived by regression analysis of LC50 data for rats, guinea pigs, and mice). Uncertainty factors: 3 for interspecies differences because the data showed only small variations in LC50 values for three species. 3 for intraspecies variability because a factor of 10 produces unusually low values that are not supported by available data. Calculations: C = 448 ppm ÷ 10 (total uncertainty factor) = 44.8 ppm Cn × t = k; C = 44.8 ppm, t = 240 min, n = 1.5 k = 71,966.1488 ppm-min

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Piperidine 197 10-min AEGL-3: C = (71,966.1488 ppm-min ÷ 10 min)1/1.5 C = 370 ppm 30-min AEGL-3: C = (71,966.1488 ppm-min ÷ 30 min)1/1.5 C = 180 ppm 1-h AEGL-3: C = (71,966.1488 ppm-min ÷ 60 min)1/1.5 C = 110 ppm 4-h AEGL-3: C = (71,966.1488 ppm-min ÷ 240 min)1/1.5 C = 45 ppm 8-h AEGL-3: C = (71,966.1488 ppm-min ÷ 480 min)1/1.5 C = 28 ppm

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198 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINES FOR PIPERIDINE Derivation Summary for Piperidine AEGL-1 VALUES 10 min 30 min 1h 4h 8h 10 ppm 10 ppm 6.6 ppm 2.6 ppm 1.7 ppm (35 mg/m3) (35 mg/m3) (32 mg/m3) (9 mg/m3) (6 mg/m3) Reference: BASF. 1993. Study on the Inhalation Toxicity of Piperidine as a Vapor in Rats: 28-day Test. Project No. 4610523-89065. BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Test species/Strain/Number: Rat, Wistar, five of each sex Exposure route/Concentration/Durations: Inhalation; 0, 20, and 100 ppm; 6 h/day for 28 days Effects: Nasal irritation (red crusts on nasal edge) at 100 ppm starting on day 2; no effect at 20 ppm. End point/Concentration/Rationale: No-effect level for nasal irritation at 100 ppm for 6 h Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the effects are mediated by direct contact with nasal epithelium, which has similar cell composition among species, although cell distribution and nasal morphology differ; the linear correlation coefficient for the concentration vs. time relationship for LC50 values for three species is -0.96 and the concentration-time relationships are similar, not varying by more than 30%, indicating the response is similar among the three species Intraspecies: 3, because the nasal epithelium does not vary among individuals in the population Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn × t = k; n = 1.5 based on regression analysis of LC50 values for the rat exposed for 4 h, the mouse exposed for 2 h, and the guinea pig exposed for 1 h. Confidence and support of AEGL values: Time scaling was based on LC50 values of three different species. The key study was a 28-day study in which the animals were observed daily for clinical signs. The exposure concentration from which the AEGL values were derived was a no-effect level for nasal irritation in a well-conducted study; concentrations ≤50 ppm of piperidine vapor caused exposure-related effects on the upper respiratory tract and eyes. The AEGL values are below the reported irritation threshold of 26 ppm.

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Piperidine 199 AEGL-2 VALUES 10 min 30 min 1h 4h 8h 50 ppm 50 ppm 33 ppm 13 ppm 8.3 ppm (175 mg/m3) (175 mg/m3) (116 mg/m3) (46 mg/m3) (29 mg/m3) Reference: BASF. 1990. Range-finding Study on the Inhalation Toxicity of Piperidine as Vapor in Rats: 5-day Study. Project No. 3010523-89017, BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Test species/Strain/Number: Rat, Wistar, five of each sex Exposure route/Concentration/Durations: Inhalation; 0, 50, 100, and 200 ppm; 6 h/day for 5 days Effects: Nasal irritation at all concentrations (severity increased with concentration and time); “stretched respiration posture,” eye closure, and salivation at 200 ppm. End point/Concentration/Rationale: 100 ppm for 6 h was the highest concentration at which nasal irritation (reddish crusts on the nasal edge) was observed without eye closure or salivation. Severity of nasal irritation in the rat increased with increasing exposure concentration, but there was no involvement of other regions of the respiratory tract. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the effects are mediated by direct contact with nasal epithelium, which has similar cellular composition among species, although cell distribution and morphology differ; the linear correlation coefficient for the concentration vs. time relationship for LC50 values for three species is -0.96 and the concentration-time relationships are similar, not varying by more than 30%, indicating the response is similar among the three species. Intraspecies: 3, because the nasal epithelium does not vary among individuals in the population. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn × t = k; n = 1.5 based on regression analysis of LC50 values for the rat exposed for 4 h, the mouse exposed for 2 h, and the guinea pig exposed for 1 h. Confidence and support of AEGL values: Time scaling was based on LC50 values of three different species. The key study used for deriving AEGL-2 values was conducted according to standard protocol. The resulting AEGL-2 values for 10-60 min are greater than the reported irritation threshold for humans. Nasal irritation was the most sensitive end point in rats. The concentration of piperidine at which nasal irritation occurred and from which AEGL-2 values were derived caused no respiratory effects that extended beyond the nasal region and did not cause eye closure or salivation. The experimental concentration did not cause CNS toxicity. Therefore, the AEGL-2 values are well within the limits that would protect against long-term or irreversible effects of piperidine vapor.

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200 Acute Exposure Guideline Levels AEGL-3 VALUES FOR PIPERIDINE 10 min 30 min 1h 4h 8h 370 ppm 180 ppm 110 ppm 45 ppm 28 ppm (1,295 mg/m3) (630 mg/m3) (385 mg/m3) (158 mg/m3) (98 mg/m3) Reference: BASF. 1980. Determination of the Acute Inhalation Toxicity LC50 of Piperidine as Vapor in Sprague-Dawley Rats After a 4-h Exposure. BASF Gewerbehygiene und Toxikologie. Test species/Strain/Number: Rats, Sprague-Dawley, 10 of each sex Exposure route/Concentration/Durations: Inhalation; 290, 810, 1,190, 1,540, and 2,190 ppm; 4 h (single exposure) Effects: 290 ppm: No deaths; nasal and ocular irritation. 810 ppm: One of 20 rats died; nasal and ocular irritation, corrosion around the nose (1 rat), and dyspnea. 1,190 ppm: 10 of 20 rats died; nasal and ocular irritation, corneal damage, corrosion around the nose, dyspnea, and CNS toxicity. 1,540 ppm: seven of 20 rats died; prostration and same effects noted at 1,190 ppm 2,190 ppm: 20 of 20 rats died; effects same as at 1,540 ppm End point/Concentration/Rationale: Lethality threshold (LC01) for piperidine is 448 ppm. That concentration is lower than the lowest concentration (810 ppm) where one of 20 rats died and had signs of dyspnea, which could be associated with death, and is greater than the highest concentration (290 ppm) that caused no deaths or clinical moribund signs. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the linear correlation coefficient for the concentration vs. time relationship for LC50 values for three species is -0.96 and the concentration- time relationships are similar, not varying by more than 30%, indicating the response is similar among the three species. Intraspecies: 3, because a factor of 10 would produce AEGL values for the 4- and 8-h durations that are lower than the irritation threshold. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn × t = k; n = 1.5 based on regression analysis of LC50 values for the rat exposed for 4 h, the mouse exposed for 2 h, and the guinea pig exposed for 1 h. Confidence and support of AEGL values: Time scaling was based on LC50 values of three different species. The acute inhalation study was conducted according to standard protocol and showed a reasonable concentration-response relationship for lethality and a clear concentration-response relationship for severity of clinical signs. The LC01 was a good approximation of the lethality threshold; therefore, the AEGL-3 values should be within the limits that would protect humans from lethal exposure to piperidine vapor.

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Piperidine 201 APPENDIX C CATEGORY PLOT FOR PIPERIDINE Chemical Toxicity - TSD All Data Piperidine 10000.0 Human - No Effect Human - Discomfort 1000.0 Human - Disabling Animal - No Effect ppm 100.0 Animal - Discomfort AEGL-3 Animal - Disabling 10.0 AEGL-2 Animal - Some Lethality Animal - Lethal AEGL-1 1.0 AEGL 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category plot of animal and human toxicity data in relation to AEGL val- ues for piperidine.