2
Propylene Glycol Dinitrate1,2

Acute Exposure Guideline Levels

SUMMARY

Otto Fuel II, a liquid propellant used exclusively by the U.S. Navy in torpedoes and other weapon systems, is a mixture of three synthetic compounds: 1,2-propylene glycol dinitrate (PGDN) (a nitrate ester explosive), dibutyl sebacate (a desensitizer), and 2-nitrodiphenylamine (a stabilizer). The

1  

Also appropriate for Otto Fuel II (CAS Reg. No. 106602–80–60).

2  

This document was prepared by the AEGL Development Team comprising Sylvia Talmage (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances including William Bress (Chemical Manager) and Robert Snyder, William Pepelko, and Kenneth Still (Chemical Reviewers). The NAC reviewed and revised the document and AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes 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; NRC 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 2 Propylene Glycol Dinitrate1,2 Acute Exposure Guideline Levels SUMMARY Otto Fuel II, a liquid propellant used exclusively by the U.S. Navy in torpedoes and other weapon systems, is a mixture of three synthetic compounds: 1,2-propylene glycol dinitrate (PGDN) (a nitrate ester explosive), dibutyl sebacate (a desensitizer), and 2-nitrodiphenylamine (a stabilizer). The 1   Also appropriate for Otto Fuel II (CAS Reg. No. 106602–80–60). 2   This document was prepared by the AEGL Development Team comprising Sylvia Talmage (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances including William Bress (Chemical Manager) and Robert Snyder, William Pepelko, and Kenneth Still (Chemical Reviewers). The NAC reviewed and revised the document and AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes 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; NRC 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 primary component and the one responsible for the toxicity of Otto Fuel II is PGDN, a volatile liquid with a disagreeable odor. Because PGDN is the primary and most toxic component of Otto Fuel II and because only PGDN is relatively volatile compared with the other components, AEGLs have been derived in terms of PGDN with the notation that the values are appropriate for Otto Fuel II. PGDN is a systemic toxicant with effects on the cardiovascular and central nervous systems. Its vasodilatory action results in headaches during human exposures. Dizziness, loss of balance, nasal congestion, eye irritation, palpitations, and chest pains have also been reported. Methemoglobinemia has been reported at the high concentrations used in studies with animals. The air-odor threshold in healthy subjects is 0.2 parts per million (ppm), but warning properties are poor inasmuch as olfactory fatigue sets in after as little as 5 minutes (min) (Stewart et al. 1974). Within 24 hours (h) of exposure, PGDN is rapidly and completely metabolized in vivo and eliminated primarily in the urine as inorganic nitrate. Few data were available that met the definitions of AEGL end points. One inhalation study with 20 human subjects described headaches and slight loss of balance at exposure concentrations of 0.1 to 1.5 ppm for exposure durations of up to 8 h (Stewart et al. 1974). Acute exposure of monkeys for 6 h at concentrations ranging between 70 and 100 ppm resulted in severe signs of toxicity including convulsions but no deaths (Jones et al. 1972). In the same study, exposure of rats at a higher concentration, 189 ppm for 4 h, resulted in no toxic signs. Examination of the relationship between exposure duration and concentration for both mild and severe headaches in humans over periods of 1 to 8 h determined that the relationship is C1×t=k. The AEGL-1 values were based on concentrations at 0.5 ppm and 0.1 ppm, which were the thresholds for mild headaches in healthy individuals at exposure durations of 1 and 6 h, respectively (Stewart et al. 1974). This effect can be considered the threshold for mild discomfort (only one subject was affected at each exposure), which falls within the definition of an AEGL-1. The 0.5-ppm concentration was used to derive the 30-min and 1-h AEGL-1 values, and the 0.1-ppm concentration was used for the 4- and 8-h values. Because the time and concentration values were based on the most susceptible subject, these concentrations were adjusted by an uncertainty factor (UF) of 3 to account for potential differences in human sensitivity and scaled to the appropriate time periods using the C1×t=k relationship. A UF of 3 was considered sufficient as no susceptible populations were identified (the headache effect is the same as that experienced by patients medicated with nitro-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 glycerin for angina, and the calculated concentrations of nitrite arising from inhaled PGDN are far below those inducing methemoglobinemia in infants), and the vasodilatory effects of PGDN, responsible for the headaches, are not expected to vary greatly among individuals. The UF of 3 is supported by the steep dose-response curve for induction of headaches in the key study. (The threshold concentration and the concentration that induced headaches in approximately half of the individuals differed by a factor of 2.) The 10-min AEGL-1 value was set equal to the 30-min value. The AEGL-2 values were based on a 0.5-ppm concentration, which caused severe headaches accompanied by dizziness in one subject and slight loss of equilibrium in two subjects in one of several sensitive equilibrium tests after 6 h of exposure (Stewart et al. 1974). This concentration-exposure duration was considered the threshold for impaired inability to escape as defined by the AEGL-2. The 0.5-ppm concentration was adjusted by an intraspecies UF of 3 to protect susceptible individuals and scaled across time for the 30-min and 1-, 4-, and 8-h time periods using the C1×t=k relationship, as was done for the AEGL-1 derivation. The UF of 3 is supported by the less than 2-fold difference among individuals for the induction of narcosis by central nervous system depressants and by the steep dose-response curve for the induction of headaches in the key study: namely, a 2-fold difference in the threshold concentration and the concentration that induced headaches in the majority of tested individuals. Because of the long exposure duration of 6 h for the chosen end point, time scaling was not performed for the 10-min AEGL-2. The 10-min AEGL-2 was set equal to the 30-min value. The AEGL-3 values were based on the 6-h exposure of squirrel monkeys at concentrations that ranged between 70 and 100 ppm. This exposure resulted in vomiting, pallor, cold extremities, semiconscousness, and clonic convulsions; these signs disappeared upon removal from the exposure chamber (Jones et al. 1972). Because a range of concentrations were encountered during the 6-h exposure, the lower concentration, 70 ppm, was selected as the basis for the AEGL-3. This value may be conservative as rats showed no effects during a 4-h exposure at 189 ppm (Jones et al. 1972). The 70-ppm concentration was adjusted by a total UF of 10. An interspecies UF of 3 was chosen because the monkey is an appropriate model for extrapolation to humans: Both the monkey and human subjects showed changes in electrical activity of the brain at similar PGDN concentrations. An intraspecies UF of 3 was considered sufficient for differences in the threshold for convulsions, which are also attributable to central nervous depression. Because the end point for the AEGL-3 values (convulsions and lethality) is different than the

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 end point for AEGL-1 and AEGL-2 (headache), and no data on the relationship between concentration and exposure duration are available for the end point of convulsions, the more conservative values of n=3 and n=1 were used to scale from 6 h to the shorter (30-min and 1- and 4-h) and longer time periods, respectively. The 10-min AEGL-3 was set equal to the 30-min AEGL-3. The values are supported by the results of additional studies with squirrel monkeys and dogs by Jones et al. (1972). Monkeys and dogs exposed continuously at approximately 15 ppm for 90 days (d) showed no overt clinical signs; systemic toxicity consisted of biochemical and/or non-life-threatening histological changes in the liver, spleen, and kidneys. The values appear in Table 2–1. 1. INTRODUCTION Otto Fuel II is a liquid propellant used exclusively by the U.S. Navy in MK-46 and MK-48 torpedoes and other weapon systems (Rivera 1974; Gaworski et al. 1985). It is a mixture of three synthetic compounds. The primary component is the explosive, 1,2-propylene glycol dinitrate (PGDN) (approximately 75%); dibutyl sebacate (23%) is added as a desensitizer, and because pure PGDN is unstable, 2-nitrodiphenylamine (2%) is added as a stabilizer (ATSDR 1995). PGDN, a nitrated ester, is a volatile liquid with a disagreeable odor. Its primary use is as a propellant in Otto Fuel II (Forman 1988). No information on production was located. Wiltshire Chemical Company in Gardena, California, was the only identified producer (ATSDR 1995). Neither Otto Fuel II nor its components are highly acutely toxic, as indicated by oral toxicity data. The oral LD50 for Otto Fuel II in male HA/ICR mice was 1.6 mL/kg (2.24 g/kg) (Litton Bionetics 1979). For PGDN, oral LD50 values for the rat ranged from 0.25–1.19 g/kg (Clark and Litchfield 1969; Jones et al. 1972; Andersen and Mehl 1979). About 10% of topically applied PGDN is absorbed through the skin (Clark and Litchfield 1967). Dibutyl sebacate, a food flavoring agent and plasticizer, has a very low acute oral toxicity; the oral no-effect level for lethality was 16 g/kg in the rat (Bisesi 1994). The low vapor pressure of 3 mm Hg at 180°C severely limits its risk as an inhalation hazard. ATSDR (1995) reported an oral LD50 value for 2-nitrodiphenylamine in rats of 6.15 g/kg. In addition to its use in Otto Fuel II, 2-nitrodiphenylamine is an orange-colored solvent dye (Sudan yellow 1339) with a low vapor pressure of 1×10−5 mm Hg at 25°C (Baughman and Perenich 1988; ATSDR 1995).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 2–1 Summary of AEGL Values for PGDN (Otto Fuel II) (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a 0.33 0.33 0.17 0.05 0.03 Mild headaches in humans (Stewart et al. 1974) (Nondisabling) (2.3) (2.3) (1.1) (0.34) (0.17) AEGL-2 2.0 2.0 1.0 0.25 0.13 Severe headaches and slight unbalance in humans (Stewart et al. 1974) (Disabling) (14) (14) (6.8) (1.7) (0.8) AEGL-3 16 16 13 8.0 5.3 Convulsions in monkeys (Jones et al. 1972) (Lethal) (114) (114) (93) (57) (38) aThe distinctive odor of PGDN will be noticeable to most individuals at the 0.33 and 0.17 ppm concentrations. The vapor pressures of the three components of Otto Fuel II differ considerably. During vapor generation studies with Otto Fuel II, PGDN was the only component vaporized into inhalation exposure chambers in sufficient quantity to allow direct analysis (Stewart et al. 1974; MacEwen and Vernot 1982). In light of the low toxicity of dibutyl sebacate and 2-nitrodiphenylamine and the fact that they do not vaporize to a detectable extent at test compound generation temperatures up to 45°C, the toxicity of Otto Fuel II has been evaluated in terms of PGDN. Chemical and physical data for PGDN are listed in Table 2–2. At low concentrations, PGDN has been reported to cause cardiovascular, irritant, and central nervous system effects including headaches, nasal congestion, eye irritation, and dizziness in humans (Stewart et al. 1974; Hovath et al. 1981). In animal studies that used higher concentrations, methemo-globinemia occurred (Jones et al. 1972). The acute and subchronic effects of PGDN were studied in monkeys, dogs, rats, and guinea pigs. Several studies with humans as well as with monkeys and rats addressed neurotoxicity. The air-odor threshold in healthy subjects is 0.2 ppm, but warning properties are poor inasmuch as olfactory fatigue sets in after as little as 5 min (Stewart et al. 1974).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 2–2 Chemical and Physical Dataa Parameter Value Reference Synonyms (PGDN) 1,2-Propylene glycol dinitrate; propylene glycol dinitrate; 1,2-propanediol, dinitrate; propylene dinitrate; isopropylene nitrate; methynitroglycol ATSDR 1995 Chemical formula C3H6N2O6 Gingell et al. 1994 Structure   ATSDR 1995 Molecular weight 166 Gingell et al. 1994 CAS registry number 6423–43–4 (PGDN) 106602–80–6 (Otto Fuel II) ATSDR 1995 Physical state Liquid ATSDR 1995 Color Colorless (PGDN) red-orange (Otto Fuel II) ACGIH 1991 Gaworski et al. 1985 Solubility in water 1.3 g/L ACGIH 1991 Vapor pressure (25°C) 0.087 mm Hg Gaworski et al. 1985 Vapor density (air=1) No data   Liquid density (water=1) 1.4 Gingell et al. 1994 Melting point No data   Boiling point 92°C Decomposes above 121°C Gingell et al. 1994 Gaworski et al. 1985 Odor Disagreeable (PGDN) Distinctive (Otto Fuel II) ACGIH 1991 Gaworski et al. 1985 Conversion factors 1 ppm=7.14mg/m3 1 mg/m3=0.14 ppm ATSDR 1995 aData are for propylene glycol dinitrate (PGDN) unless specified otherwise.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Although sudden deaths due to circulatory failure have been reported among workers exposed chronically to nitrated esters such as nitroglycerin and ethylene glycol dinitrate (Carmichael and Lieben 1963), no deaths attributable to cardiovascular effects were reported for U.S. Navy personnel involved in torpedo maintenance work (Horvath et al. 1981; Forman et al. 1987). The sudden deaths for workers in the explosives industry were attributed to a compensatory vasospasm that may produce coronary insufficiency upon withdrawal from nitrate ester exposure. 2.2. Nonlethal Toxicity 2.2.1. Occupational Exposures Horvath et al. (1981) evaluated the neurophysiologic effects of acute and chronic exposure to PGDN of 87 workers employed in U.S. Navy torpedo facilities. Prior to the evaluation, the subjects reported subjective symptoms of frequent or occasional headaches (65% of respondents), nasal congestion (31%), eye irritation (26%), and dizziness (13%). Palpitations, dyspnea, chest pain, and loss of balance were reported by small percentages of workers. For the chronic exposure, evaluation of the workers included both quantitative oculomotor functions (saccades or synchronized eye tracking movements) and ataxia tests; comparison was made with a control group consisting of 21 nonexposed personnel from the same facilities. Results of the tests indicated no evidence of chronic neurotoxicity in either the study population or a subgroup of 28 workers with the longest exposure to PGDN. In the same study (Horvath et al. 1981), acute effects were evaluated in a subgroup of 29 workers by comparing test values before and after a torpedo maintenance procedure, or “turnaround.” The maintenance procedures lasted 30–60 min. During this time, PGDN concentrations, as indicated by approximately 400 grab samples (instantaneous atmospheric samples) taken in the work area, ranged from 0.00 to 0.22 ppm (average value of 0.06 ppm; 88% were ≤0.1 ppm, 50% were ≤0.05 ppm, and only one sample was above the ACGIH TLV-Ceiling value of 0.2 ppm, which was in effect at that time).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 There were no decrements in the three ataxia tests (although the mean score in one test was increased), but mean saccade velocity was statistically significantly decreased (by 37.3 degrees per second [s]), and mean saccade delay time was statistically significantly increased (by 6.4 milliseconds). There were no changes in saccade accuracy or (eye) smooth pursuit index. The changes in the saccade test parameters did not correlate with peak PGDN levels measured during the turnaround procedure. The workers involved in the turnaround did not complain of headache or nasal congestion, although one individual involved in a spill developed a headache. Forman et al. (1987) (see also Helmkamp et al. [1984] for preliminary study) evaluated cardiac morbidity among U.S. Navy “torpedoman’s mates,” a group potentially exposed to PGDN while engaged in torpedo maintenance work. Cardiovascular events in this group were compared with both a nonexposed group of torpedomen and a nonexposed group in the job category “fire control technician”. The torpedoman’s mate group consisted of 1,352 men, with an average yearly population of 822; hospitalization records were available for 1970 through 1979. The nonexposed-torpedomen control group consisted of 14,336 individuals over the 10-y period with a yearly average of 4,906. The fire control technician control group consisted of 29,129 individuals with a yearly average of 11,198. Measured concentrations of PGDN included those of the Horvath et al. (1981) study and current surveys in which 8-h time-weighted averages were below 0.05 ppm. Cardiac incidences considered were myocardial infarction, angina pectoris, and cardiac arrhythmia. Age-adjusted incidence rates and relative risk were calculated for each group. There were higher incidences of hospitalizations for myocardial infarctions and angina pectoris but not cardiac arrhythmias in the torpedoman’s mates than in either control group. Relative risk was significant for myocardial infarction and angina pectoris when compared with the torpedoman control group (2.6 and 3.8, respectively; p<0.05) but not when compared with the fire control technicians. When incidences of myocardial infarction and angina pectoris were combined, relative risk was significant when compared with both the unexposed torpedoman and fire control technician control groups (2.6 and 2.9, respectively; p<0.05). Deaths attributable to cardiovascular events occurred in the control groups but not in the torpedoman’s mate group. The authors discuss biases in the study, including the healthy worker syndrome and the small number of actual hospitalizations. For example, only four hospitalizations for myocardial infarction and two hospitalizations for angina pectoris occurred in the torpedoman’s mates group over the 10-y period.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 2.2.2. Experimental Studies Stewart et al. (1974) exposed human volunteers to PGDN in a controlled environment chamber. “Each group underwent a training program in the chamber. The experiments were conducted in a double-blind mode. However, in those experiments in which the odor of PGDN was detectable, both the subjects and the research staff were aware that exposure to PGDN was occurring, although the magnitude of the exposure was not disclosed to them.” Exposure concentrations were 0.0 (control), 0.03, 0.1, 0.2 (range, 0.21–0.26), 0.35 (range, 0.33–0.37), 0.5, or 1.5 (1.2 and 1.5) ppm, and exposures lasted from 1 to 8 h. The exposures at 0.2 ppm were repeated on a daily basis for 5 d. Selected exposure concentrations, exposure durations, and the number of subjects tested are summarized in Table 2–3. Seventeen healthy male subjects (ages 22–25), usually in groups of three, participated in the exposures. In addition, one of the exposures (to 0.5 ppm) included two male members of the research staff, ages 45 and 51, and a 24-y-old female for a total of 20 subjects. PGDN was generated from a sample of Otto Fuel II by blowing air across a Pyrex reservoir of the compound to the return air duct of the air conditioner. Eighty percent of the air was recirculated. The concentration of PGDN in the air was monitored continuously by an infrared spectrophotometer and by a gas chromatograph fitted with an electron capture detector. The vaporized Otto Fuel II was 99% pure PGDN as measured by infrared analysis. Testing of the subjects consisted of both subjective evaluations and physiological and central nervous system responses observed under medical supervision. The lowest concentration at which odor was detected was 0.2 ppm (four of nine subjects), but the ability to detect the odor disappeared within 5 min. Subjective symptoms consisted of headache and eye irritation. At 0.1 ppm, two of the subjects experienced mild headache (Table 2–3). One of these subjects had developed headache during each of the control exposures and during the exposure at 0.03 ppm. The other subject developed headache after 6 h, and the headache continued for several hours postexposure. Of the nine subjects exposed at 0.21–0.26 ppm (18 exposures; all nine subjects took part in the 8-h exposures, and three of the nine were exposed for 8 h on two separate occasions), seven developed headaches of varying intensity. The headaches were mild in intensity for two of three subjects during the 2-h exposure. During the twelve 8-h exposures, there were five incidences of mild headache and six incidences of severe headache. The number of subjects in each category of headache could not be ascertained from the data. The

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 2–3 Human Responses to PGDN   0.0 ppm 0.03 ppm 0.1 ppm 0.21–0.26 ppm 0.35 ppm 0.5 ppm 1.5 ppm   1–8 h 1 h 4 h 8 h 1 h 4 h 8 h 1 h 2 h 8 h 1 h 2 h 8 h 1 h 2 h 7.3 h 1 h 3.2 h Number of subjects 2–6a 2 3 3 2 3 3 3 3 9b 3 3 3 3 3 3 2 6 Number detecting odor 0 0 0 0 0 0 0 2 3 2 1 2 2 1 1 2 2 6 Number developing mild headache 1 0 1c 0 0 1c 1 0 2 5 0 3 1 1 2 0 0 0 Number developing severe headache 0 0 0 0 0 0 0 0 0 6 0 0 2 0 1 3 2 6 Number developing eye irritation 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 2 6 aGroups of eight and nine male subjects participated in a series of 4-h training sessions and all 17 male subjects, in groups of two to six, participated in a series of control exposures lasting from 1 to 8 h. bNine subjects participated in 12 exposures; numbers in column immediately below refer to incidences per 12 exposures rather than individuals. cThis individual developed a mild headache during each of the control exposures. Source: Modified from Stewart et al. (1974).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 visual evoked response (VER), a complex waveform representing the summed electrical activity of many neurons, was minimally altered in the majority of subjects but with no consistent pattern of response. No decrements in test performance or alterations in monitored physiological parameters occurred at this concentration. Subjects repeatedly exposed to this concentration developed tolerance to the induction of headache, but the alteration in visual evoked response morphology appeared cumulative. At 0.35 ppm, all three subjects exposed for 2 h developed mild headaches, and one of three subjects exposed for 8 h developed a mild headache. Two of three subjects exposed for 8 h developed severe headaches. One subject also developed slight eye irritation, which persisted throughout the 2 h exposure. Four of the nine subjects detected the odor of the compound, which they described as mild at this concentration; however, the odor was not detectable after 5 min of exposure. The morphology of the visual evoked response, while variable, was altered, particularly in three subjects exposed for 8 h. The exposure produced an increase in the peak-to-peak amplitude of the 3–4–5 wave complex. The authors interpreted the VER changes as consistent with the VER changes produced by central nervous system depression. Groups of three subjects were exposed at 0.5 ppm for time periods of 1, 2, or 7.3 h. Seven of the nine subjects developed headaches during these exposures, beginning with a mild headache after 1 h of exposure (Table 2–3). After exposure for 6.25 h, balance became impaired in two of three subjects (heel-to-toe test with eyes closed), and at 7.3 h, all three subjects had abnormal modified Romberg tests (postural stability with the eyes closed) as well as abnormal heel-to-toe tests with their eyes closed. One subject was unable to perform a normal heel-to-toe test with his eyes open. The authors compared the equilibrium disturbance with ethanol intoxication, which produced a blood alcohol concentration in the 100–150 mg/100 mL range. These three subjects also had a mean elevation of diastolic blood pressure of 12 mm Hg, which was not accompanied by alterations in pulse or cardiac rhythm. Headaches became increasingly severe and throbbing for all three subjects during exposure, and one of the three subjects reported dizziness and nausea after 6 h of exposure. Three members of the research staff, two males and one female, were exposed at this concentration for a period of 1.25 h and all developed a mild headache. These latter three exposures appear to be in addition to that of the nine subjects described above. All eight subjects exposed at 1.5 ppm reported eye irritation (without conjunctivitis or excessive lacrimation) after 40 min of exposure. All of the subjects developed severe headaches, three after 30 min of exposure and the remaining five after 40–90 min of exposure. Headaches became so severe that

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Appendixes

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX A DERIVATION OF AEGL VALUES Derivation of AEGL-1 Key study: Stewart et al. 1974 Toxicity end point: Mild headache (threshold); 1 h at 0.5 ppm and 6 h at 0.1 ppm Scaling: C1×t=k based on concentrations and exposure durations for the end points of mild and severe headache in the key study. Uncertainty factor: 3; no unusually susceptible populations were identified and the end point was a threshold effect. More severe headaches are known to occur in some patients medicated with other nitrate esters and the threshold for vasodilatation in the key study did not vary greatly among individuals. Calculations: C×t=k 30-min and 1-h AEGL-1: (0.5 ppm/3)×1 h= 0.167 ppm·h 4- and 8-h AEGL-1: (0.1 ppm/3)×6 h=0.2 ppm·h 10-min AEGL-1: Set equal to the 30-min value 30-min AEGL-1: C×t=k C×1/2 h=0.167 ppm·h C=0.33 ppm 1-h AEGL-1: 0.5 ppm/3=0.17 ppm 4-h AEGL-1: C×t=k C×4 h=0.2 ppm·h C=0.05 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 8-h AEGL-1: C×t=k C×8 h=0.2 ppm·h C=0.03 ppm Derivation of AEGL-2 Key study: Stewart et al. 1974 Toxicity end point: Severe headache and threshold for central nervous system effects after 6-h exposure at 0.5 ppm Scaling: C1×t=k based on concentrations and exposure durations for the end points of mild and severe headache in the key study Uncertainty factor: 3; severe headaches are known to occur in angina patients medicated with nitroglycerin and the threshold for vasodilatation does not vary greatly among individuals. The effect was also a threshold effect for central nervous systems depression (no change in cognitive abilities; slight imbalance in one of several sensitive motor tests). Individual variation in susceptibility to central nervous system depressants such as anesthetics varies no more than 2-fold. Calculations: C×t=k (0.5 ppm/3)×6 h=1 ppm·h 10-min AEGL-2: Set equal to the 30-min value 30-min AEGL-2: C×t=k C×1/2 hour=1 ppm·h C=2 ppm 1-h AEGL-2: C×t=k C×1 h=1 ppm·h C=1 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 4-h AEGL-2: C×t=k C×4 h=1 ppm·h C=0.25 ppm 8-h AEGL-2: C×t=k C×8 h=1 ppm·h C=0.13 ppm Derivation of AEGL-3 Key study: Jones et al. 1972 Toxicity end point: Severe effects (vomiting, pallor, cold extremities, semiconscousness, and clonic convulsions) in monkeys exposed at 70–100 ppm for 6 h; no effects in rats exposed at 189 ppm for 4 h Scaling: Default values of n=3 for shorter exposure durations and n=1 for longer exposure durations Uncertainty factors: Interspecies: 3—The monkey was more susceptible than the rat; the lowest concentration in a range was chosen (70 ppm); humans and monkeys showed changes in the visual evoked response at similar concentrations; the monkey is a good model for the human. The concentration inducing central nervous system depression does not vary greatly among mammalian species. Intraspecies: 3—Individual variation in susceptibility to central nervous system depressants such as anesthetics varies no more than 2-fold. Calculations: 30-min and 1- and 4-h exposure durations: C3×t=k (70 ppm/10)3×6 h=2,058 ppm·h 8-h exposure duration: C×t=k

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2   (70 ppm/10)×6 h=42 ppm·h 10-min AEGL-3: Set equal to the 30-min value 30-min AEGL-3: C3×t=k C3×1/2 h=2,058 ppm·h C=16 ppm 1-h AEGL-3: C3×t=k C3×1 h=2,058 ppm·h C=13 ppm 4-h AEGL-3: C3×t=k C3×4 h=2,058 ppm·h C=8.0 ppm 8-h AEGL-3: C×t=k C×8 h=42 ppm·h C=5.3 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX B Potential Methemoglobin Formation in Infants Calculation of N released from exposure to PGDN at the 8-h AEGL concentrations: Assumptions: a breathing rate in infants of 4.5 m3/day (U.S. EPA Exposure Factors Handbook) 100% of the PGDN that enters the lung is absorbed into the circulatory system 1 molecule of N per molecule of PGDN (M.W.=14/166) (the 2-mononitrate is the predominant metabolite in the blood) 4.5 m3×8 h/24 h×0.17 mg/m3=0.26×14/166=0.02 mg 4.5 m3×8 h/24 h×0.8 mg/m3=0.12×14/166=0.10 mg 4.5 m3×8 h/24 h×38 mg/m3=57×14/166=4.8 mg EPA’s reference dose for nitrate-nitrogen (NO3−) is based on a clinical study in newborn infants. That study showed that ingestion of 6.4 mg/d of nitratenitrogen did not cause an increase in the circulating methemoglobin in infants. The NOEL of 6.4 mg/d for methemoglobin formation in infants is higher than the amount of nitrogen released from PGDN even assuming complete systemic bioavailability upon inhalation and complete in vivo conversion of PGDN to NO3− during exposure to the 8-h AEGL-3.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX C DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS PROPYLENE GLYCOL DINITRATE (CAS No. 6423–43–4) AEGL-1 10 min 30 min 1 h 4 h 8 h 0.33 ppm 0.33 ppm 0.17 ppm 0.05 ppm 0.03 ppm Key reference: Stewart, R.D., J.E.Peterson, P.E.Newton, C.L.Hake, M.J. Hosko, A.J.Lebrun, and G.M.Lawton. 1974. Experimental human exposure to propylene glycol dinitrate. Toxicol. Appl. Pharmacol. 30:377–395. Test species/Strain/Number: 20 human subjects Exposure route/Concentrations/Durations: Inhalation; 0.0, 0.03, 0.1, 0.2, 0.35, 1.2, or 1.5 ppm for periods of 1 to 8 h. Subjective evaluations and physiological and central nervous system responses reported. Effects: No headache: 0.03 ppm for 8 h 0.1 ppm for 3–4 h 0.2 ppm for 1 h 0.35 ppm for 1 h Mild headache: 0.1 ppm after 6 h 0.2 ppm (0.21–0.26 ppm) for 2 h 0.35 ppm for >2 h 0.5 ppm for 1 h End point/Concentration/Rationale: Threshold for mild headache in 1 of 3 subjects after a 6-h exposure at 0.1 ppm and after a 1-h exposure at 0.5 ppm. The threshold for mild headache falls within the AEGL-1 definition of mild discomfort. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: Not applicable; human subjects tested. Intraspecies: 3—no unusually susceptible populations were identified. Because the time and concentration values were based on a threshold, these concentrations were adjusted by an uncertainty factor of 3 to account for differences in human sensitivity. More severe headaches are often experienced by heart patients medicated with nitroglycerin for angina and these concentrations are far below those inducing methemoglobinemia in infants.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable; human data used. Time scaling: Cn×t=k where n=1 (k=0.167 ppm·hour for the 30-min value and 0.2 ppm·h for the 4- and 8-h values). Data from the key study suggest that the relationship between exposure concentration and exposure duration for end points of both mild and severe headaches is approximately linear (i.e., mild headaches induced by 6, 2, 2, and 1 h at exposure concentrations of 0.1, 0.2, 0.3, and 0.5 ppm, respectively, and severe headaches induced at 8, 8, 2, and 1 h at exposure concentrations of 0.2, 0.3, 0.5, and 1.5 ppm, respectively). The concentration×time product is approximately 0.5 for mild headaches and approximately 1.6 for severe headaches. The linear relationship is consistent with an n value of 1 in the relationship between concentration and time, Cn×t=k. The 1-h value was used to extrapolate to the shorter duration (30 min) and the 6-h value was used to extrapolate to the longer durations (4 and 8 h). The 10-min value was set equal to the 30-min value. Data adequacy: The key study was well designed, conducted, and documented; used 20 human subjects; and utilized a range of concentrations and exposure durations. Occupational exposures support the 8-h AEGL value. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-2 10 min 30 min 1 h 4 h 8 h 2.0 ppm 2.0 ppm 1.0 ppm 0.25 ppm 0.13 ppm Key reference: Stewart, R.D., J.E.Peterson, P.E.Newton, C.L.Hake, M.J. Hosko, A.J.Lebrun, and G.M.Lawton. 1974. Experimental human exposure to propylene glycol dinitrate. Toxicol. Appl. Pharmacol. 30:377–395. Test species/Strain/Sex/Number: 20 human subjects Exposure route/Concentrations/Durations: Inhalation; 0.0, 0.03, 0.1, 0.2, 0.3, 0.35, 1.2, or 1.5 ppm for periods of 1 to 8 h. Subjective evaluations and physiological and central nervous system responses reported. Effects: Severe headache: 0.21–0.26 ppm for 8 h 0.35 ppm for 8 h 0.5 ppm for 2 h 1.5 ppm for 1 h Change in visual evoked response: 0.35 ppm for 8 h Threshold for impairment of balance: 0.5 ppm for 6 h Threshold for abnormal cognitive test: 1.5 ppm for 3.2 h End point/Concentration/Rationale: A 6-h exposure at 0.5 ppm which resulted in severe headache and was the threshold for loss of equilibrium falls within the AEGL-2 definition of threshold for impaired ability to escape. Uncertainty Factors/Rationale: Total uncertainty factor: 3 Interspecies: Not applicable; human subjects tested. Intraspecies: 3—no unusually susceptible populations were identified. The threshold for vasodilatation does not vary greatly among individuals. Furthermore, severe headaches are often experienced by heart patients medicated with nitroglycerin for angina and these concentrations are far below those inducing methemoglobinemia in infants. The threshold for anesthetic effects also does not differ greatly among individuals. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable, human data used. Time scaling: Cn×t=k where n=1 and k=1 ppm·h. Data from the key study suggest that the relationship between exposure concentration and exposure duration for end points of both mild and severe headaches is approximately linear (i.e., mild headaches induced by 6, 2, 2, and 1 h at exposure concentrations of 0.1, 0.2, 0.3, and 0.5 ppm, respectively, and severe headaches induced at 8, 8, 2, and 1 h at exposure concentrations of 0.2, 0.3, 0.5, and 1.5

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 ppm, respectively). The concentration × time product is approximately 0.5 for mild headaches and approximately 1.6 for severe headaches. The linear relationship is consistent with an n value of 1 in the relationship between concentration and time, Cn×t=k. Because of the long exposure duration of the key study, the 10-min AEGL-2 was not time-scaled, but was set equal to the 30-min value. Data adequacy: The key study was well designed, conducted and documented; used 20 human subjects; and utilized a range of concentrations and exposure durations. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-3 10 min 30 min 1 min 4 min 8 min 16 ppm 16 ppm 13 ppm 8.0 ppm 5.3 ppm Key reference: Jones, R.A., J.A.Strickland, and J.Siegel. 1972. Toxicity of propylene glycol 1,2-dinitrate in experimental animals. Toxicol. Appl. Pharmacol. 22:128–137. Test species/Strain/Sex/Number: Squirrel monkeys (number and sex not stated) Exposure route/Concentrations/Durations: Inhalation; 70–100 ppm for 6 h Effects: Severe effects (vomiting, pallor, cold extremities, semiconsciousness, and clonic convulsions) End point/Concentration/Rationale: The 6-h exposure at 70–100 ppm was a NOEL for lethality in monkeys Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—the monkey was more susceptible than the rat, the lowest concentration in a range was chosen, humans and monkeys showed changes in the visual evoked response at similar concentrations, and the monkey is a good model for the human. Intraspecies: 3—the threshold for central nervous system effects (narcosis) does not vary greatly among individuals. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applied. Time scaling: Default values of n=3 and n=1 for shorter and longer time-scaling durations, respectively, with respective k value of 2,058 ppm·h and 42 ppm·h, because no data were available for time scaling the central nervous system end points of convulsions and narcosis. Because of the long exposure duration of the key study, the 10-min value was not time scaled but was set equal to the 30-min AEGL-3. Data adequacy: Although the key study lacked details of methodology, the AEGL-3 values are supported by the additional observation of no adverse effects in rats exposed at a concentration of 189 ppm for 4 h (Jones et al. 1972). The AEGL-3 values are also supported by subchronic and chronic exposures of several animal species at concentrations up to 34 ppm with no life-threatening effects.