ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR ...herbpedia.wdfiles.com/local--files/attachments/...BASF Gewerbehygiene und Toxikologie. Unpublished 22 23 BASF. 1990. Range-finding Study

PIPERIDINE INTERIM 1: 09/2007

ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR

PIPERIDINE

(CAS No. 110-89-4)


ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR

PIPERIDINECAS No. 110-89-4


i

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the1National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances2(NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and3other scientific data and develop AEGLs for high priority, acutely toxic chemicals.4

5AEGLs represent threshold exposure limits for the general public and are applicable to emergency6

exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1, AEGL-2 and AEGL-37— are developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and8are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as9follows:10

11AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter12

[ppm or mg/m3]) of a substance above which it is predicted that the general population, including13susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic,14non-sensory effects. However, the effects are not disabling and are transient and reversible upon15cessation of exposure.16

17AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 18

which it is predicted that the general population, including susceptible individuals, could experience19irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.20

21AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is22

predicted that the general population, including susceptible individuals, could experience life-threatening23health effects or death.24

25Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and26

progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain27asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a28progressive increase in the likelihood of occurrence and the severity of effects described for each29corresponding AEGL. Although the AEGL values represent threshold levels for the general public,30including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and31those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses,32could experience the effects described at concentrations below the corresponding AEGL.33


ii

TABLE OF CONTENTS12

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i34

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii56

EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv78

1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1910

2. HUMAN TOXICITY DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3112.1. Acute Lethality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3122.2. Nonlethal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

2.2.1. Experimental studies, case reports, and anecdotal data . . . . . . . . . . . . . . . . . . . . . . . . . . 3142.2.2. Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

2.6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31617

3. ANIMAL TOXICITY DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3183.1 Acute Lethality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3193.2. Nonlethal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5203.3. Developmental/Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7213.4. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8223.5. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8233.6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824

254. SPECIAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126

4.1. Metabolism/Disposition/Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11274.2. Mechanism of Toxicity28

29. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1130

4.3. Structure/Activity Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12314.4. Other Relevant Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1232

4.4.3. Concentration-Exposure Duration Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . 12334.4.4. Concurrent Exposure Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334

355. DATA ANALYSIS AND PROPOSED AEGL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336

5.1. Human Data Relevant to AEGL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13375.2 Animal Data Relevant to AEGL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13385.3. Derivation of AEGL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339


6.1. Human Data Relevant to AEGL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14426.2. Animal Data Relevant to AEGL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14436.3. Derivation of AEGL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1544



iii

7.1 Human Data Relevant to AEGL-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157.2. Animal Data Relevant to AEGL-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1517.3. Derivation of AEGL-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

38. SUMMARY OF PROPOSED AEGLs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

8.1. AEGL Values and Acute Toxicity Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1658.2. Comparison of AEGLs with Other Standards and Criteria . . . . . . . . . . . . . . . . . . . . . . . . . 1768.3. Data Quality and Research Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

89. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

10APPENDIX A: DERIVATION OF AEGL VALUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211

12APPENDIX B: Derivation Summaries for Piperidine AEGL Values . . . . . . . . . . . . . . . . . . . . . . . . . . . 2613

14APPENDIX C: CATEGORY PLOT FOR PIPERIDINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3015

16LIST OF TABLES17

181. Physical/Chemical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192. Lethality data for Piperidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4202. Summary of Acute Inhalation Toxicity Data in Laboratory Animals . . . . . . . . . . . . . . . . . . . . . . . . . 10215. AEGL-2 Values for Piperidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15226. AEGL-3 Values for Piperidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16237. Proposed AEGL Values for Piperidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1724

2526


iv

EXECUTIVE SUMMARY1

Piperidine is a cyclic pyridine that behaves like a secondary amine. It is a clear colorless2flammable liquid that produces vapors that reach explosive concentrations at room temperature. 3Piperidine has a pK b of 2.88 and a pH of 12.6 (100g/L, 20EC). Therefore, it is expected to be very4corrosive. Its odor is strong pepper- or amine-like and pungent. Piperidine has many commercial uses,5some of which include use as a solvent, a curing agent for rubber and epoxy resins, an intermediate in6organic synthesis, a food additive and a constituent in the manufacturing of pharmaceuticals.7

8Daily exposure to piperidine is evidenced by its presence in our food supply and its excretion in9

human urine. Piperidine is a natural constituent in white and black pepper. Piperidine is formed naturally10in the body from the degradation of lysine, cadaverine, and pipecolic acid. Exogenous piperidine is11absorbed from the respiratory tract, gastrointestinal tract, and skin. It is found in most tissues in the body12including the brain and is excreted as unchanged piperidine or its metabolites. Studies in rats showed that13nasal irritation and signs of eye irritation occur at the lower concentrations of piperidine followed by14corrosion around the nose and dyspnea at higher concentrations. Corneal damage, central nervous system15(CNS) toxicity, and prostration occurred at the highest concentrations; however, death occurred only at16concentrations that caused dyspnea, CNS toxicity, and prostration. Therefore, the severity of effects due17to inhalation exposure to piperidine shows a very clear continuum ranging from nasal irritation to death. 18Piperidine has no demonstrated carcinogenic activity, it is not genotoxic in Salmonella, and it is not toxic19to the developing rat fetus at the concentrations tested. The database on effects of inhaled piperidine in20humans is very small. Inhalation exposure to piperidine may cause sore throat, coughing, labored21breathing, and dizziness. The odor threshold is reported to be <2 ppm and 2–5 is reported to be tolerated22by unacclimated individuals for only a brief time because of its pungent odor. The irritation threshold for23humans was reported as 26 ppm. Using 0.37 ppm as the odor threshold gives a Level of Distinct Odor24Awareness (LOA) of 5.9 ppm (van Doorn et al., 2002). 25

26The AEGL-1 values were based on the no-effect-level (20 ppm for 6 hours) for nasal irritation in27

rats. Uncertainty factors (UF) of 3 for interspecies sensitivity and 3 for intraspecies variability (total UF28= 10) were applied to the 20-ppm exposure. The rationale for selecting interspecies and intraspecies UFs29of 3 is as follows: (1) the effect observed at 50 ppm was mediated by direct contact of piperidine30(corrosive agent) with the nasal epithelium without involvement of other regions of the respiratory tract,31and (2) the cell composition of the nasal mucosa is similar among species and among individuals within32the population, although the cell distribution and nasal morphology differ among species. In addition, the33linear correlation coefficient for the concentration vs time for LC50 values for three species is -0.96 and34the concentration × time relationships are similar, not varying by more than 30%, indicating the response35is similar among the three species. After applying a total uncertainty factor of 10, the resulting value of 536ppm was time scaled based on the equation, Cn × t = k, where n = 1.5. The value of n was derived from a37regression analysis of the LC50 values for the mouse, guinea pig, and rat. 38

39The AEGL-2 values were based on exposure of rats to piperidine at 200-ppm for 6 hours, which40

caused nasal irritation without salivation or evidence of eye irritation. The rationale for selecting41uncertainty factors and the time scaling procedure were the same as described for derivation of AEGL-142values.43

44The AEGL-3 values were based on the LC01 calculated from a 4-hour acute inhalation study in45

rats. The LC01 of 448 ppm for the 4-hour exposure is below the lowest concentration that caused one46


v

death among 20 rats (5% lethality) and above than the highest concentration that caused no deaths orclinical signs indicative of death. Therefore, the LC01 appears to be a a good estimate of the threshold for1lethality. Uncertainty factors of 3 for interspecies sensitivity and 3 for intraspecies variability (total UF =210) were applied to the LC01. The rationale for selecting the uncertainty factors are the same as described3for AEGL-1. In addition, the uncertainty factor of 10 for either intraspecies variability or interspecies4sensitivity 10 would produce AEGL values for 4 and 8 hours lower than the irritation threshold of 265ppm. The time scaling procedure also was the same as described for AEGL-1.6

7The AEGL values are summarized below:8

9Summary of Proposed AEGL Values for Piperidine10

Classification11 10 minutes 30 minutes 1 hour 4 hours 8 hours Endpoint/ Reference

AEGL-1 12(Nondisabling)13

10 ppm(38 mg/m3)

10 ppm(38 mg/m3)

6.6 ppm(32 mg/m3)

2.6 ppm(20 mg/m3)

1.7 ppm(13 mg/m3)

NOEL for nasalirritation/ BASF, 1993

AEGL-2 14(Disabling)15

50 ppm(172 mg/m3)

50 ppm(172 mg/m3)

33 ppm(114 mg/m3)

13 ppm(45 mg/m3)

8.3 ppm(29 mg/m3)

nasal irritation /BASF,1990

AEGL-3 16(Lethal)17

370 ppm (1276mg/m3)

180 ppm(621 mg/m3)

110 ppm(379 mg/m3)

45 ppm(157 mg/m3)

28 ppm(97 mg/m3)

threshold for lethalityBASF, 1980

18References:19BASF. 1980. Determination of the Acute Inhalation Toxicity LC50 of piperidine as vapor in Sprague-Dawley Rats20

After a 4-Hour Exposure. BASF Gewerbehygiene und Toxikologie. Unpublished2122

BASF. 1990. Range-finding Study on the Inhalation Toxicity of Piperidin as Vapor in Rats: 5-day Study. Project23No. 3010523-89017, BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Unpublished.24

25BASF. 1993. Study on the Inhalation Toxicity of Piperidin as a vapor in rats: 28-day Test. Project No. 4610523-26

89065. BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Unpublished.2728


1

1. INTRODUCTION1

Piperidine is a cyclic pyridine ( Ducatman and Coumbis, 1991) that behaves like a secondary2amine (HSDB, 1997). It is flammable (Trochimowicz et al., 1994) and produces explosive vapors at3room temperature (HSDB, 1997). Piperidine is a clear colorless liquid and has a strong pepper- or4amine-like pungent odor (Lewis, 1993; Trochimowicz et al., 1994). Piperidine is a very strong base with5a pKb of 2.88 (Reed, 1990), and is therefore, a very corrosive agent. The vapor pressure indicates that6exposure could occur by the inhalation route under ambient conditions.7

8Piperidine has many commercial uses. It is used as a solvent, curing agent for rubber and epoxy9

resins, catalyst in silicone esters, intermediate in organic synthesis, and wetting agent. It is used in the10manufacture of pharmaceuticals (analgesics, anesthetics, and germicides) and as a food additive (Reed,111990, Trochimowicz et al., 1994, HSDB, 1997). In 1983, the U.S. produced 2.75 × 108 g piperidine12(~606,000 pounds) (HSDB, 1997).13

14Humans are exposed to piperidine on a daily basis, as evidenced by its wide presence in our food15

supply and, consequently, in human urine. As a food additive, piperidine is found at 3 ppm in16nonalcoholic beverages, 5 ppm in candy, 0.05–5 ppm in baked goods, and 0.05 ppm in condiments,17meats, and soups (HSDB, 1997). Piperidine also occurs naturally in food products including vegetables18(Neurath et al., 1977). Pulverized white pepper contains as much as 1322 ppm, and black pepper contains19<703 ppm (Lin et al., 1981). Baked ham contains 0.2 ppm of piperidine, milk 0.11 ppm, and dry coffee 120ppm (Reed, 1990). Piperidine is also found in boiled beef (Golovnya et al., 1979, cited from abstract). 21von Euler (1945) reported that humans excrete 7.6–8.5 mg of piperidine in a 24-hour period, and more22recently, Tricker et al. (1992) reported excretion rates of 26.1–31.7 mg/day.23

24The database for piperidine is very limited consisting of anecdotal human data and a small25

amount of animal data.26


2

Table 1. Physical/Chemical Data for Piperidine1

Parameter2 Value Reference

Chemical Name3 Piperidine

Synonym4 azacyclohexane, cyclopentimine,hexahydropyridine, UN2401

RTECS, 1997

CAS Registry No.5 110-89-4 RTECS, 1997

Chemical Formula6 C5H11N Budavari et al., 1996

Molecular Weight7 85.15 Budavari et al., 1996

Physical State8 colorless liquid Lewis, 1993

Vapor Pressure9 32.1 mm Hg @ 25EC40 mm Hg @ 29.2EC

Howard and Meylan, 1997Trochimowicz et al., 1994

Vapor Density 10 3.0 (air = 1) Trochimowicz et al., 1994

Specific gravity11 0.8622 at 20EC Reed, 1990

Freezing point 12 -13 to -7EC Budavari et al., 1996

Boiling point13 106.3EC Howard and Meylan, 1997

Solubility14 1.6 × 106 mg/L of water @ 20EC Howard and Meylan, 1997

Flash point15 16.11EC (61EF) Trochimowicz et al., 1994

Refractive index (no)16 1.4530 Weast, 1985

pH17 12.6 @ 100g/L, 20EC BCI, 2001

pKb18 2.88 Reed, 1990

log P19 0.84 Howard and Meylan, 1997

Conversion factors20 1 ppm = 3.5 mg/m3 @ 25EC, 1 atm1 mg/m3 = 0.29 ppm

2122


3

2. HUMAN TOXICITY DATA1

2.1. Acute Lethality23

No data were found on the acute lethality of piperidine in humans in the literature searched.45

2.2. Nonlethal Toxicity67

2.2.1. Experimental studies, case reports, and anecdotal data89

Bazarova and Migoukina (1975) reported an irritation threshold for piperidine of 90 mg/m3 (2610ppm) for human volunteers. No additional details were provided. 11

12Concentrations of 2–5 ppm were measured in a semi-closed environment as piperidine was13

transferred from drums. The report stated that unacclimated individuals could tolerate the pungent odor14for only a brief time, although irritation was not perceived (Nawakowski, 1980, unpublished, cited by15Trochimowicz et al., 1994). No additional details were provided.16

17The following secondary information had no associated exposure concentrations. Piperidine is a18

strong local irritant that can cause permanent injury after a short exposure to small amounts (U.S. EPA,191985). Inhalation exposure causes sore throat, coughing, labored breathing, and dizziness (DASE, 1980). 20No exposure concentrations were provided.21

222.2.2. Other Studies23

24No human studies were found in the literature searched for neurotoxicity, developmental toxicity,25

reproductive toxicity, carcinogenicity, and genetic toxicity.2627

2.6. Summary2829

No lethality data were found in the literature searched. The threshold for irritation is 26 ppm. 30Inhalation exposure to piperidine causes sore throat, coughing, labored breathing, and dizziness. 31Piperidine concentrations of 2–5 ppm are not irritating, but could be tolerated for only a brief time32because of its pungent odor. These data indicate that the odor threshold for piperidine is less than 2 ppm. 33

343. ANIMAL TOXICITY DATA35

363.1. Acute Lethality37

38BASF (1980) conducted an acute inhalation study in groups of 10 male and 10 female Sprague-39

Dawley rats exposed to piperidine (99%) as a vapor at analytical concentrations of 7540, 5300, 4100,402800, or 1000 mg/m3 (2167, 1523, 1178, 805, 287 ppm, respectively) for 4 hours and observed for 1441days. The rats were exposed to piperidine vapor (whole body) in a glass-steel chamber under dynamic42conditions. The vapor was generated with an evaporation unit at 69EC and mixed with fresh air to obtain43the desired concentration. Clinical signs, mortality, food consumption, body weights, and gross and44microscopic findings were evaluated during or after exposure. Multiple clinical signs were observed at all45concentrations. Prostration was observed only at 5300 and 7540 mg/m3. Corrosion around the nose,46


4

smoky-milky clouded cornea, crouched position, tremors, and clonic convulsions were observed atconcentrations $4100 mg/m3. Rubbing of the snout, dyspnea, and corrosion around the nose were1observed at concentrations $2800 mg/m3. Corrosion around the nose was observed in only one rat (male)2at 2800 mg/m3. A strong watery-reddish or reddish secretion from the eyes and nose, lid closure, and3ragged fur were observed at all concentrations ($1000 mg/m3), and spasmodic respiration was observed4only at 1000 mg/m3. No clinical signs were observed more than 2 days after exposure to 1000 mg/m3. 5Mortality data are summarized in Table 2. The data for male rats showed a clear dose-response6relationship, but not that for the female rats. The LC50 values for piperidine in rats were 4600, 4900, and74800 mg/m3 for males, females, and both sexes combined, respectively. None of the rats exposed to 75408mg/m3 survived until day 7. All male and female rats that did not survive until the end of the observation9period died before day 7 except for one female rat exposed to 5300 mg/m3 and three female rats exposed10to 4100 mg/m3 that died after day 7. Male and female rats exposed to 4100 and 5300 mg/m3 and females11exposed to 2800 mg/m3 lost weight during the first week of observation, gained weight during the second12week, and the males weighed 13-29% less than controls and the females weighed 14-19% less than13controls at the end of the observation period. A postmortem evaluation was conducted, but the data were14not provided.15

16Table 2. Lethality data for Piperidine17

Nominal Concentration18[ mg/m3 (ppm)]19

Mortality response

Males Females Males + Females

1000 (287)20 0/10 0/10 0/20

2800 (805)21 0/10 1/10 1/20

4100 (1178)22 3/10 7/10 10/20

5300 (1523)23 6/10 1/10 7/20

7540 (2167)24 10/10 10/10 20/20

LC50 [mg/m3 (ppm)]a25 4600 (1322) 4900 (1408) 4800 (1379)26

Source: BASF, 198027aCalculated using Number Cruncher Statistical System Survival Analysis Version 5.5, Published by Jerry L. Hintze, July 1991.. 28

29BASF (1981, cited in BCI, 2001) reported that 2/12 and 3/6 Wistar rats died after exposure to an30

atmosphere of saturated piperidine vapor at 20EC (~45,000 ppm) for 3 or 10 minutes, respectively. No31additional details were available.32

33Smyth et al. (1962) reported no deaths among six rats that inhaled 2000 ppm of piperidine for 434

hours. However, 6/6 rats died after inhaling 4000 ppm of piperidine for the same length of time. Smyth35et al. (1962) also reported that inhalation of concentrated piperidine vapor for 15 minutes killed 6/6 rats;36the actual exposure concentration was not reported. 37

38Zayeva et al. (1968, as translated by Tanya Kurtiz, Oak Ridge National Laboratory) reported an39

LT50 of 80 minutes for an unknown mammalian species exposed to an unknown concentration of40piperidine by inhalation. Bazarova and Migoukina (1975) reported an LC50 of 6500 mg/m3 for an41unidentified mammalian species exposed for an unknown period of time. The LC50 for a 2-hour exposure42


5

for the mouse was reported as 1723 ppm (6000 mg/m3) (AIHA, 2001; BCI, 2001); the 1-hour LC50 for theguinea pig was 3444 ppm (AIHA, 1982). The LC50 values for the mouse and guinea pig were cited from1a secondary source; the primary sources could not be located for verification of the values.2

33.2. Nonlethal Toxicity4

53.2.1. Rats6

7Groups of five male and five female Wistar rats were exposed to piperidine (99.4% purity) vapor8

at nominal concentrations of 0, 50, 100, and 200 ppm (174, 348, and 696 mg/m3, respectively), 69hours/day for 5 days (BASF, 1990). Analytical concentrations were 0, 49, 102, and 203 ppm,10respectively. No animals died during the study. Clinical signs, which were both concentration- and time-11dependent, were observed during or immediately after exposure. Nasal secretions and bloody12encrustation on the edge of the nares were observed at all exposure concentrations (50-200 ppm). 13“Stretched respiration posture”, lid closure, and salivation also were observed at 200 ppm. Males exposed14to 100 and 200 ppm had decreased body weights after the first days of exposure, but body weight and15body weight gain were not affected in females. No treatment-related changes in clinical pathology or16postmortem pathology were observed at any exposure concentration. Because clinical signs were17observed and recorded after each exposure, this study can be used for derivation of AEGL values.18

19In a 28-day study, two groups of five male and five female Wistar rats each were exposed to20

piperidine (99.4% purity) vapor at concentrations of 0 (air only), 5, 20, or 100 ppm ( 0, 17.4, 69.6, and21348 mg/m3, respectively) for 6 hours/day, 5 days/week, for 28 days (BASF, 1993). The rats received 2022exposures. Additional groups of five males and five females exposed similarly to 0 or 100 ppm were23maintained for an additional 2 weeks without exposure to piperidine vapor to evaluate recovery. The24animals were exposed whole body under dynamic conditions in a glass-steel inhalation chamber. The25atmosphere in the breathing zones of the animals was monitored approximately every 20 minutes using a26total hydrocarbon analyzer equipped with a flame ionization detector. The rats were observed daily for27clinical signs before, during, and after exposure, and body weights were measured at the beginning of the28study and at 1-week intervals thereafter. Subgroups of five animals/sex/group were subjected to a very29extensive battery of neurofunctional tests before exposure and on days 2, 8, 14, and 28. Subgroups of30five rats/sex/group were used for clinical pathology evaluations of blood and urine. The postmortem31evaluations consisted of gross examination, organ weight measurements, and microscopic examination of32selected tissues.33

34Treatment-related clinical signs at 100 ppm consisted of a reddish crust (positive for blood)35

observed on the nasal edges of three male rats on day 2 of the study, all males from day 3 to the and of the36study, two females on day 3, one female rat on day 4, and almost all females starting on day 8 increasing37to all females by the end of the study. The reddish crust is indicative of upper respiratory tract irritation. 38Each subgroup of five male rats exposed to 100 ppm weighed 3.4% (N.S.) and 5.7% (N.S.) less than39controls. Females exposed to 100 ppm did not show a trend toward decreased body weights. The only40notable effects on the neurofunctional battery were increased hindlimb grip strength in 100-ppm males on41day 8 and decreased response to the hot plate test on day 14 in 5- and 100-ppm males. Because these42effects were transient or showed no dose-related trend, they are unlikely to be treatment related. No43treatment-related effects were observed on the eyes, hematologic or clinical chemistry parameters, or44postmortem findings. Treatment-related effects were not observed at 5 or 20 ppm (BASF, 1993). This45study is marginal for deriving AEGL values, because adverse effects were observed after the second46


6

exposure but not after the first exposure. BASF (1993) reported no nervous system effects; however,Bazarova and Migoukina (1975, as translated by Tanya Kurtiz, Oak Ridge National Laboratory) reported1an acute-exposure threshold of 20 mg/m3 (5.8 ppm) for nervous system response in rats. No additional2details were available in the translation. 3

4Bazarova (1973, as translated by Tanya Kurtiz, Oak Ridge National Laboratory) conducted a5

study in which rats were exposed to piperidine vapors at analytically measured concentrations of60.002±0.0003 or 0.01±0.001 mg/L (2 or 10 mg/m3 = 0.58 or 2.9 ppm) for 4 hours/day, 5 days/week for 47months followed by a 1-month recovery period. Groups of 20 rats (strain and sex not reported) were8exposed to the vapor, and a group of 20 rats served as the control. The animals were exposed in a 700-L9dynamic chamber (not otherwise described), and chamber atmospheres were measured eight times during10each 4-hour exposure. The investigators assessed body weight changes, blood vessel penetrability,11erythrocyte parameters, liver and kidney function, testicular morphology, and neural activity. 12

13Rats exposed to 10 mg/m3 weighed 14% less than the controls after 14 exposures and 16% less14

than controls at the end of the recovery period. The rats showed evidence of increased neural and15muscular excitability after exposure to 10 mg/m3 for 1.5 months or 2 mg/m3 for 2.5 months. Respiration16was decreased after exposure to 2 mg/m3 for 1.5 months and increased after exposure to 10 mg/m3 for 2.517months. At both concentrations, blood vessels in the skin showed decreased penetrability (measured after18application of xylol) during the early phase of the study followed by increased penetrability during the19late phase of the study that remained evident until the end of the recovery period. In addition, blood20vessel stability was decreased throughout the study in the 10-mg/m3 group as measured by increased21petechia (submucosal hemorrhage). In rats exposed to 10 mg/m3, the erythrocyte count (80% of control)22and hemoglobin concentration (89% of control) were decreased at the beginning of exposure and23remained lower after 1.5 months, but were increased compared with controls at the end of the recovery24period in rats exposed to. The leukocyte count was decreased after 2.5 months (53% of control) due to a25decrease in the lymphocyte count (47.9% of control) in rats exposed to 10 mg/m3. Blood pressure was26significantly decreased in rats exposed to 10 mg/m3 after 2.5 and 4 months. At the end of exposure, an27effect on liver function was evidenced by a 47% decrease in urine hippuric acid, and effects on kidney28function were evidenced by a 46% decrease in urine volume, increase in specific gravity of urine, and2965% increase in urine protein. At 10 mg/m3, histopathological examination showed a decrease in the30number of normal spermatogonia and degeneration of the seminiferous tubules in the testes, focal31swelling of the interalveolar septa in the lungs, albuminous degeneration in the liver, hyalin droplet and32albuminous degeneration in the kidney, stromal atrophy in the spleen, and necrosis and scaring in the33cardiac muscle (Bazarova, 1973). Adequate descriptive detail were lacking for an adequate evaluation of34this study. Information for this study were also obtained from BCI (2001).35

363.2.2. Rabbits37

38In the report cited above, Bazarova (1973, as translated by Tanya Kurtiz, Oak Ridge National39

Laboratory) also exposed groups of 6 rabbits under the same conditions: 0.01 or 0.002 mg/L (10 and 240mg/m3, respectively) for 4 hours/day, 5 days/week, for 4 months followed by a 1-month recovery period. 41The only effect described specifically for the rabbit was a 29 and 27% decrease in arterial blood pressure42after exposure to 10 and 2 mg/m3, respectively for 14 days and an 8% increase in arterial blood pressure43after exposure to 10 mg/m3 for 4 months.44

453.3. Developmental/Reproductive Toxicity46


7

Hughes et al. (1990) reported on the developmental effects in rats exposed to piperidine vaporduring organogenesis. Groups of 25 pregnant Crl:CD®(SD) GR VAF/Plus strain rats were exposed whole1body to piperidine vapor at concentrations of 0, 5, 20, or 80 ppm ( 0, 17.4, 69.6, and 278.4 mg/m3,2respectively) during gestation days (GD) 6-15 inclusive for 6 hours/day. The dams were observed daily3for clinical signs, weighed on GD 2, 3, 6, and at 2-day intervals until GD 20 and had food consumption4measured for intervals between weigh days. The dams were killed on GD 20 and the ovaries and uteri5were examined. All dams survived to the end of the study. During each exposure to 80 ppm, clinical6signs included a lack of response to noise (a knock on chamber door), closed or half closed eyes during7each exposure, Other signs observed during exposure to 80 ppm included licking the inside of the mouth8and piloerection (frequency not reported), hunched posture during almost all exposures, and increased9respiration, salivation, and rubbing the chin and paws on the cage were observed during one or two10exposures. After daily exposures to 80 ppm, some rats had red/brown staining on the fur, two had11“snuffles”, and one showed sneezing and salivation. During exposure to 20 ppm, lack of response to a12knock on the chamber door was noted on each occasion, and closed or half-closed eyes and hunched13posture were observed once during the study. No clinical signs were reported after daily exposure to 2014ppm, and no clinical signs related to exposure to piperidine were observed at 5 ppm. Body weights and15weight gain at 80 ppm were reduced compared with controls during the exposure period and showed16signs of recovery after exposure was terminated after GD 15 and was similar to controls at study17termination. Food consumption also was reduced at 80 ppm during the exposure period and remained18reduced after exposure was terminated. No treatment-related effects were observed on body weights or19food consumption at 5 or 20 ppm and no treatment-related necropsy findings were observed at any20exposure concentration. The lack of response to a knock on the chamber door was the only clinical sign21observed daily in rats exposed to 20 ppm. It is doubtful that this nonspecific clinical signs is treatment22related or toxicologically significant in the absence of any corroborating evidence of CNS toxicity. 23BASF (1993) observed no treatment-related effects in their battery of neurofunctional tests conducted in a2428-day study in rats exposed repeatedly to piperidine up to 100 ppm. Nevertheless, this study can be used25for AEGL derivation because of the maternal clinical signs observed at 80 ppm.26

27No treatment-related effects were observed on any litter parameter: litter size, postimplantation28

loss, mean litter weight, or mean fetal weight at any exposure concentration. In addition, the incidences29of visceral and skeletal malformations were similar for all exposed and control groups (Hughes et al.,301990). Therefore, effects were observed in developing fetuses of female rats exposed to piperidine31concentrations up to 80 ppm during organogenesis.32

33In a study by Timofievskaya and Silantyeva (1975, as translated by Tanya Kurtiz, Oak Ridge34

National Laboratory), groups of 6 to 13 pregnant rats were exposed to piperidine vapor at concentrations35of 0, 3, 15, or 100 mg/m3 (0, 0.87, 4.4, or 29 ppm, respectively) throughout pregnancy or on GD 9 or to 336or 100 mg/m3 on GD 4. Two control groups were included in this study. The dams were killed on GD 2137for assessment of maternal and fetal parameters. The duration of each exposure was not reported so it is38assumed that animals were exposed continuously throughout gestation or continuously for 24 hours on39GD 4 or 9. No behavioral effects were noted for the dams, but body weight gain was lower for dams40exposed to 15 and 100 mg/m3 than in the controls (no other data available). For rats exposed to 10041mg/m3 on GD 4, the number of fetuses per dam (5.5 vs 8.5 and 11.08 for the two controls) and the number42of implantation sites (6.1 vs 9.4 for control) were significantly decreased compared with controls. 43Exposure to 100 mg/m3 on GD 9 or throughout pregnancy caused no effect on these parameters. Fetal44body weights were decreased for dams exposed to all concentrations throughout pregnancy (66–78% of45control fetal weight). Fetal body weights were 76% of control weights after exposure to 3 mg/m3 on GD46


8

4 or 9; no significant reductions in fetal weights were observed after exposure to 100 mg/m3 on day 4 or 9or 15 mg/m3 on day 9. The decreases in fetal body weights appear to be unrelated to exposure to1piperidine. A concentration-response relationship was not observed for the single exposures. In addition,2no corresponding changes were observed in other fetal parameters consistent with pronounced decreases3in fetal weights. Fetal length and placental size did not show concentration-response relationships. 4However, the placenta coefficient (not described) was significantly decreased at all concentrations for5exposure throughout gestation, at 3 mg/m3 for exposure on GD 4, and at 3 and 15 mg/m3 for exposure on6GD 9. This study lacks adequate descriptions of details to be used for AEGL derivation. Some of the7information for this study was obtained from BCI (2001).8

93.4. Carcinogenicity10

11No inhalation carcinogenicity studies were found in the literature. Lijinsky and Taylor (1977)12

conducted a study in which groups of 15 male and 15 female Sprague-Dawley rats were administered130.09% piperidine in drinking water with and without 0.2% sodium nitrite for 50 week. No treatment14related neoplasms developed during the lifetime of either test group. Oral studies have shown no15evidence of carcinogenicity piperidine administered to rats in drinking water with or without sodium16nitrite.17

183.5. Genotoxicity19

20Piperidine was negative in Salmonella typhimurium assay using strains TA98, TA100, and21

TA1537 with and without metabolic activation with S9 from phenobarbital-induced mouse liver;22piperidine was tested at concentrations of 1.25–25 mM (Riebe et al., 1982). Green and Savage (1978)23tested piperidine in the Ames and mouse host-mediated mutagenicity assays. Piperidine was negative in24the Ames assay using S. typhimurium strains TA1531, TA1532, TA1964, and TA1530 with and without25mouse liver S9 and in the host-mediated assay using S. typhimurium strains TA1534, TA1950, TA1951,26and TA1952. Riebe et al. (1982) also obtained negative results when they tested piperidine in the27Escherichia coli pol A+/pol A– recombination assay. Nevertheless, piperidine was mutagenic in the28mouse lymphoma assay without metabolic activation with rat liver S9, but negative with S9 activation29(Wangenheim and Bolcsfoldi, 1988). Garber et al (1988) reported that piperidine induced DNA strand30breaks in mouse lymphoma cells with rat liver S9, but not alkaline unwinding with or without S9.31

323.6. Summary33

34Inhalation toxicity data are summarized in Table 3. The LT50 for mice exposed to an unknown35

preset absolute concentration of piperidine was 80 minutes (Zayeva et al., 1968). The 4-hour LC50 for36rats ranged from 4600-4900 mg/m3 for males, females, and both sexes combined, respectively (BASF,371980). Smyth et al. (1962) reported, however, that no rats died after exposure to 2000 ppm (6960 mg/m3)38of piperidine for 4 hours, but 6/6 died after exposure to 4000 ppm (13920 mg/m3) for 4 hours. The LC5039for an unidentified mammalian species exposed for an unknown period of time was reported as 650040mg/m3 (1885 ppm) (Bazarova and Migoukina, 1975). A 2-hour LC50 for the mouse was reported as 172341ppm (6000 mg/m3) and a 1-hour LC50 for the guinea pig was 3444 ppm (1195 mg/m3) (AIHA, 1982).42

43Male and female rats exposed to piperidine at concentrations ranging from 50 to 200 ppm for 644

hour/day caused nasal irritation at 50 and 200 ppm; signs of eye irritation and salivation also were45observed after each daily exposure to 200 ppm (BASF, 1990, 1993; Hughes et al., 1990). More severe46


9

nasal irritation and eye irritation were observed in rats exposed to 1000 mg/m3 (287 ppm) for 4 hoursfollowed by the first evidence of corrosion around the nose and dyspnea at 2800 mg/m3 (805 ppm). CNS1toxicity, coneal damage, and more severe corrosion around the nose were observed at $4100 mg/m3 (11782ppm) followed by prostration at 5300 and 7540 mg/m3 (1523 and 2167 ppm) (BASF, 1980). Clinical3signs likely associated with death included prostration, CNS toxicity, and dyspnea, and the lowest4concentration causing death of one rat was the lowest concentration that caused dyspnea. These data5showed an exposure related continuum that increased in severity from nasal irritation to death. Other6studies were not reliable Bazarova (1973) reported that repeated exposure of rats to much lower7concentrations 2 or 10 mg/m3 (0.58 and 2.9 ppm) for 4 months caused multiple effects in rats including8neurotoxicity, cardiovascular toxicity, hematologic, liver, kidney, and testicular effects at one or both9concentrations. Insufficient details were available for adequately evaluating this study for AEGL10derivation. 11

12Two developmental toxicity studies were available. Hughes et al. (1990) found no effects on the13

fetuses of rat dams exposed to piperidine up to 80 ppm 6 hour/day during organogenesis. Timofievskaya14and Silantyeva (1975) reported inconsistent results regarding the effect of piperidine on the fetuses of rat15dams exposed to concentrations of 0.87–29 ppm throughout gestation or on GD 9 or to 0.87 or 29 ppm on16GD 4.17

18No studies were found on the carcinogenicity of piperidine administered by inhalation exposure. 19

Carcinogenic activity was not observed in rats administered 0.09% piperidine in their drinking water for2050 weeks (Lijinsky and Taylor, 1977). Genotoxicity studies showed that piperidine was not mutagenic in21Salmonella with or without metabolic activation with either the Ames or the host-mediated assay (Riebe22et al., 1982). Piperidine also was negative in the E. coli recombination assay (Riebe et al., 1982), but was23positive in mouse lymphoma cell assay without metabolic activation (Wangenheim and Bolcsfoldi, 1988). 24Piperidine induced DNA strand breaks in mouse lymphoma cells (Garber et al., 1988).25

26


10

Table 3. Summary of Acute Inhalation Toxicity Data in Laboratory Animals

Species1 Exposure Conditions Effects Reference

Mouse2 2-h LC100 LT50 = 80 min Zayeva et al., 1968

2 h LC50 = 1723 ppm AIHA, 1982

Rat3 1000-7540 mg/m3 (287-2167ppm) for 4 h

respiratory irritation at all concentrations; deaths at$2800 mg/m3 (812 ppm)LC50 = 4600 mg/m3 (1334 ppm) (males); 4900 mg/m3

(1421 ppm) (females), and 4800 mg/m3 (1392ppm)(males and females)

BASF, 1980

2000 ppm for 4 h 0/6 deaths Smyth et al., 1962

4000 ppm for 4 h 6/6 deaths Smyth et al., 1962

Concentrated vapor: 15 min10 min3 min

6/6 deaths3/62/12

Smyth et al., 1962BASF, 1991BASF, 1991

NR4 NR LC50 = 6500 mg/m3 (1885 ppm) Bazarova andMigoukina, 1975

Rats5 50 100, 200 ppm (174-696mg/m3), 6 h/d, 5 d

upper respiratory tract irritation at all concentrationsfor each exposure; closed eyes and salivation at 200ppm

BASF, 1990

5, 20, 100 ppm (17.4-348mg/m3), 6 h/d, 28 d

upper respiratory tract irritation at 100 ppm on day 2 BASF, 1993

10 mg/m3 (2.9 ppm), 4 h/d, 5d/wk, 4 mo

no effects after a single exposure; body wt. decreases,neural and muscular, cardiovascular, RBC and WBC,respiratory effects; liver, kidney, testicular, spleen, andcardiac muscle toxicity after repeated exposures

Bazarova, 1973

2 mg/m3 (0.58 ppm), 4 h/d, 5d/wk, 4 mo

cardiovascular, respiratory, neural and muscular effectsafter multiple exposures

Bazarova, 1973

Rabbit6 2 or 10 mg/m3 (0.58 or 2.9ppm), 4 h/d, 5 d/wk, 4 mo

decreased arterial blood pressure at both concentrations Bazarova, 1973

NR7 20 mg/m3 (5.8 ppm) threshold for nervous system response Bazarova andMigoukina, 1975

Rat, pregnant8 5, 20, 80 ppm (17.4, 69.6, 278.4mg/m3), GD 6-15

dams: 80 ppm:, respiratory and eye irritation,salivation during or after first exposure, hunchedposture after most exposures; 20 ppm: eye irritationand hunched posture observed once fetuses: no effects

Hughes et al., 1990

Guinea pig9 1 h LC50 = 3444 ppm AIHA, 198210

GD = gestation day11NR = not reported12

13


11

4. SPECIAL CONSIDERATIONS4.1. Metabolism/Disposition/Kinetics1

2Piperidine is absorbed from the respiratory tract, digestive tract, and skin (Gehring, 1983). 3

Piperidine is also synthesized endogenously from lysine, cadaverine, and pipecolic acid. Pipecolic acid is4a product of lysine degradation, and homogenates of brain tissue can convert pipecolic acid to piperidine. 5Radioactive piperidine is recovered from rat brain after intraperitoneal injection of radioactive pipecolic6acid. Piperidine has been found in muscle, liver, heart, kidney, spleen, testes, small intestine, lung of rats7and mice at concentrations ranging from 0.115–0.440 nmol/g tissue. However, the highest endogenous8concentrations are found in the brain, where concentrations reported for whole mouse and rat brain9ranged from 0.016–3.28 nmol/g tissue depending on the extraction and analysis procedures. The10concentration in whole human brain was reported as 1.8 nmol/g tissue. The concentrations of piperidine11in the cerebellum was 3.92–5.18 nmol/g of tissue for the dog, 3.07–3.17 nmol/g of tissue for the mouse,120.8 nmol/g of tissue for the cat, and 0.047 nmol/g of tissue for the rat. The concentration in other brain13regions varied considerably (Giacobini, 1976). Perry et al. (1964) discovered that piperidine also was14found in human cerebral spinal fluid at very low levels.15

16Piperidine and its metabolites are excreted in urine. Unchanged piperidine, 3-hydroxypiperidine,17

4-hydroxypiperidine, and two unidentified metabolites were found in urine collected over 72 hours after18i.p. injection of rats with [3H]piperidine (Okano et al., 1978).19

20von Euler (1945) used a colorimetric method to determine the amount piperidine in the urine of21

non-smoking human subjects (eight male and four female medical students). Male subjects had an22average of 0.49 mg piperidine/dL of urine and females had 0.88 mg piperidine/dL in 24-hour pooled23specimen; the total amount excreted in 24 hours was 8.5 mg for males and 7.6 mg for females.24

254.2. Mechanism of Toxicity26

27Piperidine is a very strong alkaline agent with a pKb of 2.88 at 25EC; consequently, it is severely28

corrosive to skin producing severe third degree burns in a human after less than 3 minutes contact (Linch,291965). Linch (1965) considered piperidine to be more corrosive than “strong primary irritants.” Because30of its corrosive properties, piperidine is expected to cause irritation to the eyes and respiratory tract. 31Piperidine is found naturally in the brain and other tissues of vertebrates and invertebrates; it is a biogenic32amine and acts as a neuromodulator (Giacobini, 1976). Piperidine stimulates and blocks actions on33ganglia, chemoreceptors, and neuromuscular junctions. It acts on chemoreceptors, which stimulates34respiration; acts on sympathetic ganglia releasing catecholamines, which raises blood pressure; acts on35parasympathetic ganglia, which stimulates contraction of smooth muscle; and acts on end plates, which36stimulates contraction of skeletal muscle (Kase and Miyata, 1976). Piperidine interacts with cholinergic37receptor sites of muscle end plates and with nicotinic receptors on sympathetic and parasympathetic38ganglia to cause effects mimicking those of acetylcholine (Giacobini, 1976). Piperidine also acts on the39central nervous system (CNS) where it also mimics the nicotinic effects of acetylcholine on synaptic sites40in the brain (Kase and Miyata, 1976). Piperidine affects CNS responses related to emotional behavior,41physiological processes of sleep, and extrapyramidal motor function (ataxia, head turning, and42nystagmus) (Giacobini, 1976; Kase and Miyata, 1976).43

44


12

4.3. Structure/Activity Relationship1

Pyrrolidine (CAS No. 123-75-1) is a five-membered alicyclic secondary amine structurally2similar to piperidine (Trochimowicz et al., 1994). It produces CNS effects similar to those of piperidine3(Giacobini, 1976). The LC50 for a 2-hour exposure to mice is 1300 mg/m3; inhalation exposure causes4irritation, excitement, and convulsions. The oral LD50 is 300 mg/kg for rats, 450 mg/kg for mice, and 2505mg/kg for rabbits and guinea pigs. Intravenous administration of pyrrolidine causes increases in blood6pressure and respiration in dogs and cats (Trochimowicz et al., 1994). Piperazine (CAS No. 110-85-0) is7a six-membered alicyclic amine structurally similar to piperidine (Trochimowicz et al., 1994). Piperazine8produced signs of respiratory irritation in rats after inhaling 40 mg/L (4000 mg/m3) for 2 hours (Dupont ,91968, cited by Trochimowicz et al., 1994). Mice showed changes in motor activities and muscle10contraction after inhaling 5400 mg/m3 for 2 hours ( Timofievskaya, 1979, cited by Trochimowicz et al.,111994). The oral LD50's range from 2050–3000 mg/kg for rats and from 600–1900 mg/kg for the mouse. 12Administration of piperazine caused an initial fall in blood pressure and heart rate followed by a transient13rise in both in rats (cited by Trochimowicz et al., 1994).14

154.4. Other Relevant Information16

17One case was reported in the literature concerning chemical burns associated with skin contact18

with piperidine. This report involved a worker who was sprayed with piperidine when transferring the19chemical under room temperature conditions. The worker suffered first degree burns on the face, left ear,20and neck; second degree burns on the forearms and abdomen, and third-degree burns on the chest. 21Contact time with the chemical was <3 minutes (Linch, 1965).22

23Smyth et al. (1962) reported an oral LD50 for piperidine of 520 mg/kg for the rat; values reported24

by Trochimowicz et al. (1994) ranged from 133 to 337 mg/kg. Oral administration of piperidine causes25weakness, respiratory distress, and convulsions. van den Heuvel et al. (1990) reported LD50 values of 44526mg/kg for male and female rats combined; clinical signs associated with dosing included ptosis,27respiratory effects, lethargy, ataxia, tremors, salivation, and lacrimation.28

294.4.1. Species variability30

31Very few data elements were available for evaluation species variability concerning exposure to32

piperidine vapor. The LC50 is 3444 ppm for a 1-hour exposure to the guinea pig, 1723 ppm for a 2-hour33exposure to the mouse, and 1379 ppm for a 4-hour exposure to the rat. The linear correlation for the34concentration vs time for these three species is -0.96, indicating the response does not vary because of35species.36

374.4.2. Susceptible Populations38

39No data were available for determining human variability to inhalation exposure to piperidine.40

414.4.3. Concentration-Exposure Duration Relationship42

43Data were not available from a single species for establishing a concentration-exposure duration44

relationship for piperidine. However, LC50 data were available for three different species that allowed a45derivation of the n-value used for extrapolating to the pertinent time frames. The 1-hour LC50 for the46


13

3.1

3.2

3.3

3.4

3.5

3.6

Log

Con

cent

ratio

n (p

pm)

1.7 1.8 1.9 2 2.1 2.2 2.3 2.4 Log Time (min)

Best Fit Concentration x Time Curve

Figure 1. Mouse, Rat, and Guinea Pig Data: Time Curve for LC50Values for Piperidine

guinea pig is 3444 ppm (AIHA, 1982); the 2-hour LC50 for the mouse is 1723 ppm (AIHA, 2001, BCI,2001); and the 4-hour LC50 for the rat is 1379 ppm (BASF, 1980). The correlation coefficient is -0.96 and1the value of n derived from these data is 1.5. Figure 1 shows the concentration-exposure duration2relationship.3

456789

101112131415161718192021222324

4.4.4. Concurrent Exposure Issues2526

There are no known concurrent exposure issued related to inhalation exposure to piperidine.2728

5. DATA ANALYSIS AND PROPOSED AEGL-12930

5.1. Human Data Relevant to AEGL-13132

Piperidine has a amine-like pungent (Trochimowicz et al., 1994) or pepper-like odor (Lewis,331993, Trochimowicz et al., 1994). The odor of 2–5 ppm of piperidine was reported to be tolerated for34only a brief time by unacclimated individuals and the odor threshold for piperidine was reported to be <235ppm (Nawakowski, 1980, cited by Trochimowicz et al., 1994) and 0.37 ppm by van Doorn et al. (2002). 36Bazarova and Migoukina (1975) reported that the irritation threshold for inhalation exposure to piperidine37was 90 mg/m3 (26 ppm). These are cited from secondary sources and are not verified.38

395.2. Animal Data Relevant to AEGL-140

41Bazarova and Migoukina (1975) reported that the acute inhalation threshold for nervous system42

response to piperidine was 20 mg/m3 (5.7 ppm) for an unidentified species. In a repeat exposure study by43Bazarova (1973), no effects were described in rats after the first exposure to 0.58 or 2.9 ppm of piperidine44for 4 h. A concentration-related increase in the severity of nasal irritation (secretions and bloody45encrustation) was observed during or after each 6-hour exposure to 50-200 ppm for 5 days and eye lid46


14

closure and salivation were observed at 200 ppm (BASF, 1990). Nasal irritation also was observed afterthe second 6-hour exposure to 100 ppm in a 28-day inhalation study with piperidine, (BASF, 1993); no1effects were observed after exposure to 5 or 20 ppm. In a developmental toxicity study, Hughes et al.2(1990) observed eye closure, increased respiration, hunched posture, piloerection, salivation, a lack of3response to a knock on the chamber door after the first exposure to 80 ppm in pregnant female rats4exposed 6 hours/day during GD 6-15; a lack of response to a knock on the chamber door at 20 ppm; and5no clinical signs at 5 ppm. The very extensive battery of neurofunctional test showed no treatment-6related CNS toxicity after repeated 6-hour daily exposures at concentrations up to 100 ppm. The BASF7(1990, 1993) and Hughes et al. (1990) studies appeared to follow standard protocol for repeat exposure8studies and were conducted under Good Laboratory Practice. 9

105.3. Derivation of AEGL-111

12The data for odor detection, threshold, or tolerance as well as the data for irritation threshold were13

obtained from secondary sources. The primary sources were not available. Three studies showed nasal14secretions, bloody or reddish encrustation/crust or other evidence of upper respiratory tract irritation,15evidence of eye irritation, or general discomfort in rats exposed to 50-200 ppm (Hughes et al., 1980,16BASF, 1990, BASF, 1993). The lowest concentration causing nasal irritation was 50 ppm for a 6-hour17exposure in rats (BASF, 1990), and no nasal irritation was observed in rats exposed to 20 ppm for 6 hours18(BASF, 1993). A lack of response to a knock was observed at 20 ppm in pregnant rats exposed to 20 ppm19for 6 hours, but the toxicologic significance of this observation is uncertain because a functional20observation battery showed no treatment-related effects after repeated exposures to 100 ppm for 6 hours. 21A no-effect-level (20 ppm for 6 hours) for nasal irritation was selected as the endpoint for deriving22AEGL-1 values. Uncertainty factors of 3 for interspecies sensitivity and 3 for intraspecies variability23(total uncertainty factor = 10) were applied to the 20-ppm exposure for 6 hours. The rationale for24selecting interspecies and intraspecies uncertainty factors of 3 is as follows: (1) the effects are mediated25by direct contact of piperidine (corrosive agent) with the nasal epithelium without involvement of other26regions of the respiratory tract, and (2) the cell composition of the nasal mucosa is similar among species27and individuals in the population, although the cell distribution and nasal morphology differ among28species. Additional data supporting an intraspecies uncertainty factor of 3 is obtained by an analysis of29the LC50 data for 3 species exposed for three different time periods. The LC50 values are 3444 ppm for a301-hour exposure to the guinea pig, 1723 ppm for a 2-hour exposure to the mouse, and 1379 ppm for a 4-31hour exposure to the rat. The linear correlation coefficient for regression analysis of the LC50 values for32the three species is -0.96 and the concentration × time relationships are similar among the three species,33not varying by more than 30%, indicating the response is similar among the three species. Therefore,34these data support an interspecies uncertainty factor of 3. After applying a total uncertainty factor of 10,35the resulting value of 2 ppm was time scaled based on the equation, Cn × t = k, where n = 1.5. The value36of n was derived from a regression analysis of the LC50 values for the mouse, guinea pig, and rat as37discussed above. The 30-minute AEGL-1 value was retained for the 10-minute exposure because of the38uncertainty of scaling from a 6-hour exposure to a 10-minute exposure. The resulting AEGL values are39presented in Table 4. All values are below the irritation threshold of 26 ppm reported by Bazarova and40Migoukina (1975).41


15

TABLE 4. AEGL-1 Values for Piperidine110-minute2 30-minute 1-hour 4-hour 8-hour

10 ppm3(38 mg/m3)4

10 ppm(38 mg/m3)

6.6 ppm(32 mg/m3)

2.6 ppm(20 mg/m3)

1.7 ppm(13 mg/m3)



9There were no human data found that were specifically associated with AEGL-2 endpoints. The10

irritation threshold for piperidine is reported as 26 ppm (Bazarova and Migoukina, 1975); no information11was provided on how this value was derived. Secondary sources reported that exposure to piperidine can12cause sore throat, signs of respiratory tract irritation (coughing, labored breathing), and dizziness13(probably CNS related); exposure concentrations and durations were not reported14


17Smyth et al. (1962) observed no deaths among 6 rats exposed to 2000 ppm of piperidine for 418

hours and BASF (1980) reported no deaths among 20 rats exposed to 287 ppm (1000 mg/m3) for 4 hours. 19Nasal secretions and bloody encrustation were observed after exposure to 50-200 ppm for 6 hours20(BASF, 1990). In addition, eye closure (may be indicative of eye irritation) and salivation (probably due21to attempted mouth breathing) occurred in rats during each exposure to 200 ppm piperidine. The severity22of nasal and eye irritation and general discomfort showed a concentration-related increase at piperidine23concentrations ranging from 50-200 ppm. Clinical signs observed at 287 ppm included eye and nasal24irritation, spasmodic respiration (probably due to attempted mouth breathing because of the pungent25odor), and ragged fur; none of these clinical signs were indicative of death. Thus, the clinical signs26observed in rats exposed to 287 ppm for 4 hours are similar but slightly more severe than those observed27in rats exposed to 200 ppm for 4 hours. In rats exposed to 10 mg/m3 (2.9 ppm), 4 hours/day for 4 months,28Bazarova (1973) noted cardiovascular and hematologic effects at the beginning of exposure (not29otherwise described) but did not state whether or not effects were observed after the first exposure and the30results have not been corroborated in another study. The BASF (1980, and 1990) studies appeared to31have been conducted under standard protocol for acute inhalation and repeat exposure studies.32

33No developmental toxicity was in rat fetuses after exposure of the dam to 0.87, 4.4, or 29 ppm34

piperidine throughout gestation, on GD 4, or on GD 9 (Timofievskaya and Silantyeva, 1975). 35Developmental toxicity also was not observed after exposure of pregnant rats to 5, 20, or 80 ppm, 636hours/day during GD 6-15 (Hughes et al., 1990).37


40AEGL-2 values can be derived from the study showing nasal irritation but no salivation or eye41

closure, which may be indicative of eye irritation, in rats exposed to 100 ppm for 6 hours (BASF, 1990). 42The uncertainty factors, justification for uncertainty factors, and time scaling are the same as described43for AEGL-1 derivation (Section 5.3). AEGL-2 values for 10-minute, 30-minute, 1-hour, 4-hour, and 8-44hour exposure durations are summarized in Table 5. 45


16

TABLE 5. AEGL-2 Values for Piperidine

10 minutes1 30 minutes 1 hour 4 hour 8 hour

50 ppm2(172 mg/m3)3

50 ppm(172 mg/m3)

33 ppm(114 mg/m3)

13 ppm(45 mg/m3)

8.3 ppm(29 mg/m3)

45



No human lethality data were found in the literature searched.1011


Zayeva et al. (1968) reported an LT50 of 80 minutes, but an exposure concentration was not14associated with the time. Bazarova and Migoukina (1975) reported an LC50 of 1868 ppm (6500 mg/m3)15for an unknown species exposed for an unknown duration. BASF (1991) reported that exposure of rats to16a saturated piperidine atmosphere at 20EC resulted in the death of 2/12 animals after 3 minutes and 3/617animals after 10 minutes. The 4-hour LC50 for rats is 1379 ppm (4800 mg/m3); no rats died after exposure18to 289 ppm (1000 mg/m3) and 20/20 died after exposure to 2167 ppm (7540 mg/m3) (BASF, 1980) No19deaths occurred after exposure of six rats to 2000 ppm (6960 mg/m3) of piperidine for 4 hours, but 6/620rats died after exposure to 4000 ppm (13,920 mg/m3) of piperidine for 4 hours (Smyth et al., 1962). LC5021values of 1723 ppm (6000 mg/m3) were reported for a 2-hour exposure to the mouse and 3444 ppm22(11985 mg/m3) for a 1-hour exposure to the guinea pig. The mouse and guinea pig values were cited23from secondary sources; the primary sources could not be located. 24


27One acute inhalation study showing increased mortality with exposure concentration was28

available for deriving AEGL-3 values for piperidine. Clinical signs at lethal doses affected the eyes,29upper and lower respiratory tract, and the CNS; however, dyspnea, tremors, clonic convulsions, and30prostration were the most severe signs that appeared to be associated with death. One death occurred31among the 20 rats exposed to 812 ppm and dyspnea was the only clinical sign that was potentially related32to the cause of death. The 4-hour LC50 for inhalation exposure to piperidine is 1379 ppm. The lethality33threshold (LC01) estimated by probit analysis 4-hour LC01 was 448 ppm (1560 mg/m3) (NCSS,34Version 5.5). The LC01 (BMD01) estimated from the Probit Model using EPA’s Benchmark Dose35Software, Version 1.3.2 (U.S. EPA, 2003) was 415 ppm and the BMDL05 is 474 ppm. AEGL-3 values36were derived from the LC01 of 448 ppm for a 4-hour exposure. This value is below the lowest37concentration (805 ppm) that caused one death among 20 rats (5% lethality) and above than the highest38concentration (287 ppm) that caused no deaths or clinical signs indicative of death. Therefore, the LC0139appears to be a good estimate of the threshold for lethality. The rationale for applying an uncertainty40factor of 3 for intraspecies variability the LC01 and the time scaling method are the same as described for41AEGL-1. An uncertainty factor of 3 for interspecies sensitivity was applied because the linear correlation42for the concentration vs time for LC50 values for three species is -0.96 and the concentration × time43relationships are similar, not varying by more than 30%, indicating the response is similar among the44


17

three species. In addition, an uncertainty factor of 10 for either interspecies sensitivity or intraspeciesvariability would lower the AEGL-3 values for 4 and 8 hours below the irritation threshold of 26 ppm1(Bazarova and Migoukina, 1975). AEGL-3 values are summarized in Table 6.2

3TABLE 6. AEGL-3 Values for Piperidine4

10 minutes5 30 minutes 1 hour 4 hour 8 hour

370 ppm 6(1276 mg/m3)7

180 ppm(621 mg/m3)

110 ppm(379 mg/m3)

45 ppm(157 mg/m3)

28 ppm(97 mg/m3)

89

8. SUMMARY OF PROPOSED AEGLs1011

8.1. AEGL Values and Acute Toxicity Endpoints1213

No human data were available for deriving any AEGL values. AEGL1- values were based on the14no-effect level (20 ppm for a 6-hour exposure) for nasal irritation in rats exposed to piperidine. 15Uncertainty factors of 3 each for interspecies sensitivity and intraspecies variability were applied to the16exposure concentration and time scaling was based on an n value equal to 1.5. AEGL- 2 values were17based on the highest concentration of 100 ppm for 6 hours that caused nasal irritation but no salivation or18eye closure. AEGL-3 values were based on the LC01 derived from a 4-hour acute lethality study in rats. 19The LC01 (448 ppm) was below the lowest concentration associated with death and clinical signs20indicative of death (805 ppm) and above than the highest concentration that caused no deaths nor clinical21signs indicative of death (287 ppm). Uncertainty factors and time scaling methods for AEGL-2 and -322were the same as described for AEGL-1 values. In addition, the interspecies uncertainty factor for23AEGL-3 was based on the analysis of LC50 values for three species.24

25Table 7. Proposed AEGL Values for Piperidine26

Classification27 10 minutes 30 minutes 1 hour 4 hours 8 hours Endpoint/ Reference

AEGL-1 28(Nondisabling)29

10 ppm(38 mg/m3)

10 ppm(38 mg/m3)

6.6 ppm(32 mg/m3)

2.6 ppm(20 mg/m3)

1.7 ppm(13 mg/m3)

nasal irritation/ BASF, 1993

AEGL-2 30(Disabling)31

50 ppm(172 mg/m3)

50 ppm(172 mg/m3)

33 ppm(114 mg/m3)

13 ppm(45 mg/m3)

8.3 ppm(29 mg/m3)

nasal irritation /BASF,1990

AEGL-3 32(Lethal)33

370 ppm (1276 mg/m3)

180 ppm(621 mg/m3)

110 ppm(379 mg/m3)

45 ppm(157 mg/m3)

28 ppm(97 mg/m3)

threshold for lethality/BASF, 1980

348.2. Comparison of AEGLs with Other Standards and Criteria35

36The only recommended standards for piperidine are the Workplace Environmental Exposure37

Level (WEEL) established by the American Industrial Hygiene Association (AIHA) and the United38Kingdom Occupational Exposure Level (OEL). The WEEL for piperidine is 1 ppm (8-hour time-39weighted-average) with a skin notation (AIHA, 2001, 2002). AIHA based their value on secondary40sources and comparison to standards for 2-aminopyridine, which has an ACGIH-TLV, NIOSH-REL, and41OSHA-PEL of 2 mg/m3 (0.5 ppm) and an IDLH of 20 mg/m3 (5 ppm). It appears that the data used to42


18

derive the AEGL values were not available to the organizations that derived the standards andrecommended values.1

2American Industrial Hygiene Association Emergency Response Planning Guidelines (ERPGs),3

National Research Council Permissible Exposure Levels (PELs), Spacecraft Maximum Allowable4Concentrations (SMACs), National Institute for Occupational Safety and Health (RELS and IDLHs),5Occupational Safety and Health Association (PELs), American Conference of Governmental Industrial6Hygienists (TLVs), and German or Dutch Maximum Allowable Workplace Concentrations are not7available for piperidine.8

98.3. Data Quality and Research Needs10

11The studies by Bazarova and coworkers, Zayeva et al., and Timofievskaya and Silantyeva did not12

provide adequate experimental detail and explanation of results. The BASF and Hughes et al. studies13were well conducted and useful for deriving the three AEGL levels. Overall, the BASF and Hughes et al.14studies showed an exposure-response continuum from 5 to 2167 ppm; therefore, the database for15piperidine provided sufficient data for deriving AEGLs. Nevertheless, the evaluation and conclusions16regarding the acute inhalation toxicity of piperidine vapor and AEGL derivations could be strengthen17with definitive data on the odor and irritation threshold in humans and with 1- and 8-hour acute inhalation18toxicity studies at concentrations in rats that would encompass lethal and non-lethal endpoints.19

209. REFERENCES21

22AIHA (American Industrial Hygiene Association). 1982. Workplace Environmental Exposure Level23

Guide: Piperidine. Am. Ind. Hyg. Assoc. J. 43: B-91-92.2425

AIHA (American Industrial Hygiene Association). 2001. Workplace Environmental Exposure Level26Guide: Piperidine. In: 2001 WEELs Complete Set. AIHA Press, Fairfax, VA.27

28AIHA (American Industrial Hygiene Association). 2002. The AIHA 2002 Emergency Response29

Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American30Industrial Hygiene Association, AIHA Press, Fairfax, VA. p. 32.31

32BASF. 1980. Determination of the Acute Inhalation Toxicity LC50 of piperidine as vapor in Sprague-33

Dawley Rats After a 4-Hour Exposure. BASF Gewerbehygiene und Toxikologie. Unpublished3435

BASF. 1990. Range-finding Study on the Inhalation Toxicity of Piperidin as Vapor in Rats: 5-day36Study. Project No. 3010523-89017, BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. 37Unpublished.38

39BASF. 1981. Akutes Inhalationsrisiko. BASF Gewerbehygiene und Toxikologie. Unpublished40

41BASF. 1993. Study on the Inhalation Toxicity of Piperidin as a vapor in rats: 28-day Test. Project No.42

4610523-89065. BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Unpublished.4344


19

Bazarova, L.A. 1973. [Evaluation of general toxic and specific effects of piperidine at chronic exposure]. Toksikol. Nov. Prom. Khim. Veshchestv. No. 13: 100-107. (translated by T. Kuritz ,Oak Ridge,1National Laboratory)2

3Bazarova, L.A.; Migoukina, N.V. 1975. [Comparative evaluation of the toxicity, hazards and mode of4

action of piperidine and morpholine]. Toksikol. Nov. Khim. Veshchestv. No. 14:90-95. (Translated5by T. Kuritz, Oak Ridge National Laboratory)6

7BCI [Berufsgenossenschaft der Chemischen Industrie (Employment Accident Insurance Fund of8

theChemical Industry],eds., 2001, Toxicological Evaluations, Piperidine, Nr.72-E, Heidelberg,9Germany, 2001.10

11Budavari, S.; O’Neil, M.J.; Smith, A.; Heckelman, P.E.; Kinneary, J.F. (Eds.) 1996. The Merck Index:12

An Encyclopedia of Chemicals, Drugs, and Biologicals, 12th ed., Merck & Co., Inc.,Whitehouse13Station, NJ. p. 1285.14

15DASE (Dutch Association of Safety Experts). 1980). Piperidine. In: Handling Chemicals Safely - 1980. 16

2nd ed. Published by: Dutch Assoc. of Safety Factors, Dutch Chemistry Industrial Association, and17Dutch Safety Institute. p. 757.18

19Ducatman, A.M.; Coumbis, J.J. 1991. Chemical hazards in the biotechnology industry. Occupational20

Medicine: State of the Art Reviews. 6(2):193-208.2122

DuPont Company. 1968. Unpublished Report, HLR 158-68. (cited in Trochimowicz et al., 1994)2324

Garberg, P.; Akerblom, E.-L.; Bolcsfoldi, G. 1988. Evaluation of a genotoxicity test measuring DNA-25strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution. Mutat.26Res. 203:155-176.27

28Gehring, P.J. 1983. Pyridine, homologues and derivatives. In: Encyclopaedia of Occupational Health29

and Safety. Vol. 2, 3rd ed., L. Parmeggiani (Ed.), International Labour Organization, Geneva, pp.301810-1812.31

32Giacobini, E. 1976. Piperidine: A new neuromodulator or a hypnogenic substance? Adv. Biochem.33

Pyschopharmacol. 15:17-56.3435

Golovnya, R.V.; Zhuravleva, I.L.; Kapustin, Y.P. 1979. Gas chromatographic analysis of volatile36nitrogen bases of boiled beef as possible precursors of N-nitrosamines. Prikl. Biokhim. Mifrobiol. 3715: 295-302. (cited from abstract)38

39Green, N.R.; Savage, J.R. 1978. Screening of safrole, eugenol, their ninhydrin positive metabolites and40

selected secondary amines for potential mutagenicity. Mutat. Res. 57:115-121.4142

Howard, P.H.; Meylan, W.M. (Eds.) 1997. Handbook of Physical Properties of Organic Chemicals. 43CRC Press, Boca Raton, FL. p. 203.44

45HSDB (Hazard Substance Data Bank). Online Database. Retrieved July 8, 1997.46


20

Hughes, E.W., Homan, B.A., John, D.M., et al. 1990. A study of the Effect of Piperidine on Pregnancyof the Rats. Report No. BGH 9/9097. Huntingdon Research Centre, Ltd., Huntingdon,1Cambridgeshire, PE18 6ES, England.2

3Kase, Y.; Niyata, T. 1976. Neurobiology of piperidine: Its relevance to CNS function. Adv. Biochem.4

Pyschopharmacol. 15:5-16.56

Lewis, R.J., Sr. 1993. Hawley’s Condensed Chemical Dictionary, 12th ed., Van Nostrand Reinhold Co.,7New York, p. 919.8

9Lijinsky, W.; Taylor, H.W. 1977. Feeding tests in rats on mixtures of nitrite with secondary and tertiary10

amines of environmental importance. Fd. Cosmet. Toxicol. 15:269-274.1112

Lin, J.-K.; Hwa, J.J.; Lee, Y.-J. 1981. Chemical toxicants in Chinese foods: 4.. The contents and13biological significance of piperidine in black pepper, white pepper, red pepper and other species. 14Nat. Sci. Counc. Mon. 9:557-566 (cited from abstract).15

16Linch, A.L. 1965. Piperidine—A hazardous chemical. Am. Ind. Hyg. Assoc. J. 26:95-96.17

18Nawakowski, A.C. 1980. Unpublished data, The Upjohn Company, Kalamazoo, MI. (cited in19

Trochimowicz et al., 1994)2021

Neurath, G.B.; Dünger, Pein, F.G., et al. 1977. Primary and secondary amines in the human22environment. Fd. Cosmet. Toxicol. 15: 275-282.23

24Okano, Y.; Miyata, T.; Hung, S.-H.; et al. 1978. Metabolites of piperidine in rat urine. Jpn. J.25

Pharmacol. 28:41-47.2627

Perry, T.L.; Hansen, S.; Jenkins, L.C. 1964. Amine content of normal human cerebrospinal fluid. J.28Neurochem. 11:49-53.29

30Reed, R.L. 1990. Piperidine. In: Ethel Browning’s Toxicity and Metabolism of Industrial Solvents, Vol.31

II: Nitrogen and Phosphorus Solvents, 2nd. ed., D.R. Buhler and D.J. Reed, Eds., Elsevier, New32York, pp. 251-258.33

34Riebe, M.; Westphal, K.; Fortnagel, P. 1982. Mutagenicity testing, in bacterial test systems, of some35

constituents of tobacco. Mutat. Res. 101;39-43.3637

RTECS. 1997. Online Database. Retrieved July 8, 1997.3839

Smyth, H.F., Jr.; Carpenter, C.P.; Weil, C.S.; et al. 1962. Range-finding toxicity data: List VI. Am. Ind.40Hyg. Assoc. J. 23:95-107.41

42Timofievskaya, L.A.; Silantyeva, I.V. 1975. [Study of the effect of piperidine on embryogenesis]. 43

Toksikol. Nov. Prom. Khim. Veshchestv. 14: 40-46. (Translated by T. Kuritz, Oak Ridge National44Laboratory)45

46


21

Trochimowicz, H.J.; Kennedy, G.L., Jr.; Krivanek, N.D. 1994. Heterocyclic and miscellaneous nitrogencompounds. In: Patty’s Industrial Hygiene and Toxicology, 4th edition, Vol. 2, Pt. E. G.D. Clayton1and F.E. Clayton, (Eds.), John Wiley &Sons, New York. pp. 3312-3315.2

3Tricker, A.R.; Pfundstein, B.; Kaelble, T.; Preussmann, R. 1992. Secondary amine precursor in human4

saliva, gastric juice, blood, urine and faeces. Carcinogenesis. 13:563-568.56

U.S. EPA. 1985. Piperidine. In: EPA Chemical Profile. 78

U.S. EPA. 2003. EPA’s Benchmark Dose Software, Verison 1.3.2. 9http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=2016710

11van den Heuvel, M.J.; Clark, D.G.; Fielder, R.J.; et al. 1990. The international validation of a fixed-dose12

procedure as an alternative to the classical LD50 test. Fd. Chem. Toxicol. 28:469-482.1314

von Euler, U.S. 1945. The occurrence and determination of piperidine in human and animal urine. Acta15Pharmacol. 1:29-49.16

17Wangenheim, J.; Bolcsfoldi, G. 1988. Mouse lymphoma L5178Y thymidine kinase locus assay of 5018

compounds. Carcinogenesis 3:193-205.1920

Weast, R.C.; Astle, M.J.; Beyer, W.H. (Eds.) (1985) CRC Handbook of Chemistry and Physics. 66th21edition, CRC Press, Inc.,22

23Zayeva, G.N.; Timofievskaya, L.A.; Stasenkova, K.P.; Bazarova, L.A. 1968. [Use of time/effect plots in24

toxicological experiments]. Toksikol. Nov. Prom. Khim. Veshchestv. 10:5-9. (Translated by T.25Kuritz, Oak Ridge National Laboratory)26


22

APPENDIX A: DERIVATION OF AEGL VALUES1


23

AEGL-1 1

Key Study: BASF, 199023

Toxicity Endpoint: no-effect level for nasal irritation45

Time Scaling: Cn × t = k; n = 1.5 (derived by regression analysis of LC50 data for rats,6guinea pigs, and mice)7

8Uncertainty Factors: 10: 3 for interspecies sensitivity because the effects are mediated by9

direct contact with nasal epithelium, which has similar cell composition10among species although different cell distribution and nasal morphology;11linear correlation for the concentration vs time for LC50 values for three12species is -0.96 and the concentration × time relationships are similar,13not varying by more than 30%, indicating that the response was similar14among the three species153 for intraspecies variability because the nasal epithelium does not vary16among individuals in the population.17

18AEGL Calculations: C = 20 ppm/10 (total UF) = 2 ppm19

Cn × t = k; C = 2 ppm, t = 360 minutes, n = 1.520k = 1018.2338 ppmCminutes21

2210-minute Same as the 30-minute values23

2430 minutes C = (k/t)1/3 = (1018.2338 ppmCminutes/30 min)1/1.525

C = 10 ppm2627

1 hour C = (k/t)1/1.5 = (1018.2338 ppmCminutes/60 min)1/1.528C =6.6 ppm29

304 hours C = (k/t)1/1.5 = (1018.2338 ppmCminutes/240 min)1/1.531

C = 2.6 ppm3233

8-hour AEGL C = (k/t)1/1.5 = (1018.2338 ppmCminutes/480 min)1/1.534C = 1.7 ppm35


24

AEGL-2 1


Toxicity Endpoint: nasal irritation without eye closure or salivation45


8Uncertainty Factors: 10: 3 for interspecies sensitivity because the effects are mediated by9

direct contact with nasal mucosa, which has similar cell composition10among species but different cell distribution and nasal morphology11differ; the data only small variations in LC50 values for 3 different12species133 for intraspecies variability because the nasal epithelium does not vary14among individuals in the population.15

16AEGL Calculations: C = 100 ppm/10 (total UF) = 10 ppm17

Cn × t = k; C = 10 ppm, t = 360 minutes, n = 1.518k = 11384.1996 ppmCminutes19

2010-minute Same as the 30-minute value21

2230 minutes C = (k/t)1/1.5 = (11384.1996 ppmCminutes/30 min)1/1.523

C = 50 ppm2425

1 hour C = (k/t)1/1.5 = (11384.1996 ppmCminutes/60 min)1/1.526C = 33 ppm27

284 hours C = (k/t)1/1.5 = (11384.1996 ppmCminutes/240 min)1/1.529

C = 13 ppm3031

8-hour AEGL C = (k/t)1 = (11384.1996 ppmCminutes/480 min)132C =8.3 ppm33

34


25

AEGL-31


Toxicity Endpoint: LC01 (lethality threshold) calculated by probit analysis45


8Uncertainty Factors: 10: 3, because the data showed only small variations in LC50 values for9

three species103 for intraspecies variability because a UF of 10 produces unusually low11values that are not supported by available data12

13AEGL Calculations: C = 448 ppm/10 (total uncertainty factor) = 44.8 ppm14

Cn × t = k; C = 44.8 ppm, t = 240 minutes, n = 3 (default)15k = 71966.1488 ppmCminutes16

1710-minute C = (k/t)1/1.5 = (71966.1488 ppmCminutes/10 min)1/1.518

C = 370 ppm1920

30 minutes C = (k/t)1/1.5 = (71966.1488 ppmCminutes/30 min)1/1.521C = 180 ppm22

231 hour C = (k/t)1/1.5 = (71966.1488 ppmCminutes/60 min)1/1.524

C = 110 ppm2526

4 hours C = (k/t)1/1.5 = (71966.1488 ppmCminutes/240 min)1/1.527C = 45ppm28

298 hours C = (k/t)1.5 = (71966.1488 ppmCminutes/240 min)1/1.530

C = 28 ppm31


26

APPENDIX B: DERIVATION SUMMARIES FOR PIPERIDINEAEGL VALUES1

2


27

ACUTE EXPOSURE GUIDELINES FOR PIPERIDINE1

AEGL -1 VALUES2

10 minutes3 30 minutes 1 hour 4 hours 8 hours

10 ppm4(38 mg/m3)5

10 ppm(38 mg/m3)

6.6 ppm(32 mg/m3)

2.6 ppm(20 mg/m3)

1.7 ppm(13 mg/m3)

Reference: BASF. 1993. Study on the Inhalation Toxicity of Piperidin as a vapor in rats: 28-day Test. Project6No. 4610523-89065. BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Unpublished.7

Test Species/Strain/Number: male and female rat/Wistar/ 5 of each sex8

Exposure Route/Concentration/Durations: inhalation/ 0, 20, 100 ppm, 6 hours/day, 28 days9

Effects: nasal irritation (red crusts on nasal edge) at 100 ppm starting at day 2; no effect at 20 ppm10

Endpoint/Concentration/Rationale: no-effect level for nasal irritation at 100 ppm for 6 hours11

Uncertainty Factors/Rationale:12Total uncertainty factor:1013

Interspecies: 3, the effects are mediated by direct contact with nasal epithelium, which has similar cell14composition among species, although cell distribution and nasal morphology differ; the15linear correlation coefficient for the concentration vs time for LC50 values for three16species is -0.96 and the concentration × time relationships are similar, not varying by17more than 30%, indicating the response is similar among the three species18

Intraspecies: 3, the nasal epithelium does not vary among individuals in the population;.19

Modifying Factor: none20

Animal to Human Dosimetric Adjustment: none21

Time Scaling: n = 1.5 based on regression analysis of LC50 values for the rat exposed for 4 hours, the mouse22exposed for 2 hours, and the guinea pig exposed for 1 hour.23

Confidence and Support of AEGL Values: Time scaling was based on LC50 values of three different species. 24The key study was a 28-day study in which the animals were observed daily for clinical signs. The exposure25concentration from which the AEGL values were derived was a no-effect level for nasal irritation in a well-26conducted study; concentrations #50 ppm of piperidine vapor caused exposure-related effects on the upper27respiratory tract and eyes. The AEGL values are below the reported irritation threshold of 26 ppm. 28

2930


28

AEGL -2 VALUES1


50 ppm3(172 mg/m3)4

50 ppm(172 mg/m3)

33 ppm(114 mg/m3)

13 ppm(45 mg/m3)

8.3 ppm(29 mg/m3)

Reference: BASF. 1990. Range-finding Study on the Inhalation Toxicity of Piperidin as Vapor in Rats: 5-day5Study. Project No. 3010523-89017, BASF Aktiengesellschaft, Ludwigshafen/Rhein, Germany. Unpublished6

Test Species/Strain/Number: male and female rat/Wistar/5 of each sex7

Exposure Route/Concentration/Durations: inhalation/ 0, 50, 100, 200 ppm, 6 hours/day, 5 days8

Effects: nasal irritation at all concentrations (severity increased with concentration and time); “stretched9respiration posture”, lid closure, salivation at 200 ppm10

Endpoint/Concentration/Rationale: 100 ppm for 6 hours was the highest concentration at which nasal irritation11(reddish crusts on the nasal edge) was observed without eye closure or salivation. The severity of nasal12irritation in the rat with increasing exposure concentration, but there was no involvement of other regions of the13respiratory tract.14

Uncertainty Factors/Rationale:15Total uncertainty factor: 1016

Interspecies: 3, the effects are mediated by direct contact with nasal epithelium, which has similar17cellular composition among species although cell distribution and morphology differ; the18linear correlation coefficient for the concentration vs time for LC50 values for three19species is -0.96 and the concentration × time relationships are similar, not varying by20more than 30%, indicating the response is similar among the three species21

Intraspecies: 3, the nasal epithelium does not vary among individuals in the population22

Modifying Factor: none23


Time Scaling: n = 1.5 based on regression analysis of LC50 values for the rat exposed for 4 hours, the mouse25exposed for 2 hours, and the guinea pig exposed for 1 hour.26

Confidence and Support of AEGL Values: Time scaling was based on LC50 values of three different species. 27The key study used for deriving AEGL-2 values was conducted according to standard protocol . The resulting28AEGL-2 values for 10-60 minutes are above the reported irritation threshold for humans. Nasal irritation was29the most sensitive endpoint in rats inhaling piperidine vapor. The concentration of piperidine at which nasal30irritation occurred and from which AEGL-2 values were derived caused no respiratory effects that extended31beyond the nasal region and did not cause eye closure or salivation. The experimental concentration did not32cause CNS toxicity. Therefore, the AEGL-2 values are well within the limits that would protect from long-term33or irreversible effects of piperidine vapor.34

353637


29

AEGL -3 VALUES1


370 ppm 3(1276 mg/m3)4

180 ppm(621 mg/m3)

110 ppm(379 mg/m3)

45 ppm(157 mg/m3)

28 ppm(97 mg/m3)

Reference: BASF. 1980. Determination of the Acute Inhalation Toxicity LC50 of piperidine as vapor in5Sprague-Dawley Rats After a 4-Hour Exposure. BASF Gewerbehygiene und Toxikologie. Unpublished6

Test Species/Strain/Number: rats/Sprague-Dawley/10 of each sex7

Exposure Route/Concentration/Durations: inhalation/ 100, 2800, 4100, 5300, and 7540 mg/m3 (287, 805, 1178,81523, 2167 ppm) for 4 hours (single exposure)9

Effects: 1000 mg/m3 - 0/20 deaths, nasal and eye irritation102800 mg/m3 - 1/20 deaths, nasal and eye irritation, corrosion around the nose (1 rat), dyspnea114100 mg/m3 - 10/20 deaths, nasal and eye irritation, corneal damage, corrosion around the nose,12

dyspnea, CNS toxicity135300 mg/m3 - 7/20 deaths, prostration plus effects noted at 4100 mg/m3147540 mg/m3 - 20/20 deaths, effects same at 5300 mg/m315

Endpoint/Concentration/Rationale: lethality threshold (LC01)at 1560 mg/m3 (448 ppm). The LC01 appears to be16a good estimate of the lethality threshold because it is below the lowest concentration (2800 mg/m3) where 1 of1720 rats died and had signs of dyspnea, which could be associated with death, and above the highest18concentration (1000 mg/m3) that caused no deaths nor clinical signs indicate of death19

Uncertainty Factors/Rationale:20Total uncertainty factor:1021

Interspecies: 3, The linear correlation coefficient for the concentration vs time for LC50 values for three22species is -0.96 and the concentration × time relationships are similar, not varying by23more than 30%, indicating the response is similar among the three species.24

Intraspecies: 3, an UF of 10 would produce AEGL values for 4 and 8 hours that are lower than the25irritation threshold 26

Modifying Factor: 127


Time Scaling: default: n = 1.5 based on regression analysis of LC50 values for the rat exposed for 4 hours, the29mouse exposed for 2 hours, and the guinea pig exposed for 1 hour.30

Confidence and Support of AEGL Values Time scaling was based on LC50 values of three different species. 31The acute inhalation study was conducted according to standard protocol and showed a reasonable32concentration-response relationship for lethality and a clear concentration-response relationship for severity of33clinical signs. The LC01 was a good approximation of the lethality threshold; therefore, the AEGL-3 values34should be within the limits that would protect humans from lethal exposure to piperidine vapor.35

3637


30

APPENDIX C: CATEGORY PLOT FOR PIPERIDINE1


31

1.0

10.0

100.0

1000.0

10000.0

ppm

0 60 120 180 240 300 360 420 480 Minutes

Human - No Effect

Human - Discomfort

Human - Disabling

Animal - No Effect

Animal - Discomfort

Animal - Disabling

Animal - Some Lethality

Animal - Lethal

AEGL

Chemical Toxicity - TSD All DataPiperidine

AEGL-3

AEGL-1

AEGL-2

1

Documents

ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR ...herbpedia.wdfiles.com/local--files/attachments/...BASF Gewerbehygiene und Toxikologie. Unpublished 22 23 BASF. 1990. Range-finding Study