6
Propylene Glycol Dinitrate

This chapter summarizes the relevant epidemiologic and toxicologic studies of propylene glycol dinitrate (PGDN). It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for PGDN. The committee’s recommendations for PGDN exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

When freshly prepared, PGDN is a colorless liquid that has “a disagreeable odor” (ACGIH 1991). Pure PGDN is unstable and has properties that are similar to those of ethylene glycol dinitrate, which is flammable, explosive, and shock-sensitive (ACGIH 1991). PGDN is mixed with 2-nitrodiphenylamine as a stabilizer and di-n-butyl sebacate as a desensitizer in Otto fuel II, which has been commonly used in toxicity studies of PGDN (Gaworski et al. 1985). Ruth (1986) reported an odor threshold ranging from 0.18 to 0.23 ppm. Stewart et al. (1974) reported the human odor threshold for PGDN as 0.2 ppm with olfactory fatigue occurring in as little as 5 min. Selected physical and chemical properties are shown in Table 6-1.

OCCURRENCE AND USE

PGDN is the primary component (about 76%) of Otto fuel II, which is used as a torpedo propellant (ATSDR 1995; NSWC 1995). Although the vapor



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6 Propylene Glycol Dinitrate This chapter summarizes the relevant epidemiologic and toxicologic stud- ies of propylene glycol dinitrate (PGDN). It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for PGDN. The committee’s recommenda- tions for PGDN exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES When freshly prepared, PGDN is a colorless liquid that has “a disagree- able odor” (ACGIH 1991). Pure PGDN is unstable and has properties that are similar to those of ethylene glycol dinitrate, which is flammable, explosive, and shock-sensitive (ACGIH 1991). PGDN is mixed with 2-nitrodiphenylamine as a stabilizer and di-n-butyl sebacate as a desensitizer in Otto fuel II, which has been commonly used in toxicity studies of PGDN (Gaworski et al. 1985). Ruth (1986) reported an odor threshold ranging from 0.18 to 0.23 ppm. Stewart et al. (1974) reported the human odor threshold for PGDN as 0.2 ppm with olfactory fatigue occurring in as little as 5 min. Selected physical and chemical properties are shown in Table 6-1. OCCURRENCE AND USE PGDN is the primary component (about 76%) of Otto fuel II, which is used as a torpedo propellant (ATSDR 1995; NSWC 1995). Although the vapor 139

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140 Exposure Guidance Levels for Selected Submarine Contaminants TABLE 6-1 Physical and Chemical Properties of Propylene Glycol Dinitrate Synonyms 1,2-propylene glycol dinitrate, 1,2-propanediol dinitrate, isopropylene nitrate, propylene dinitrate, propylene nitrate, propane-1,2-diyl dinitrate CAS registry number 6423-43-4 Molecular formula C3H6N2O6 Molecular weight 166.09 Boiling point 92°C at 10 mmHg (decomposes above 121°C) Melting point –27.7°C Flash point NA Explosive limits NA Specific gravity NA Vapor pressure 0.07 mmHg at 22°C Solubility 0.13 g/100 mL of water 1 ppm = 6.79 mg/m3; 1 mg/m3 = 0.15 ppm Conversion factors Abbreviation: NA, not available or not applicable. Sources: ACGIH (1991) and HSDB (2005). pressure of PGDN is relatively low, it is the most volatile component of that fuel (NRC 2002). ATSDR (1995) noted that exposure could occur during torpedo- maintenance operations, manufacturing, or transport. However, exposure would not be expected to be substantial because PGDN has a low vapor pressure. Air concentrations of PGDN at four U.S. Navy torpedo facilities were reported to range from 0 to 0.22 ppm (ATSDR 1995). No exposure data on PGDN on sub- marines were located. SUMMARY OF TOXICITY The animal and human toxicity information on PGDN and Otto fuel II have been reviewed by Forman (1988), ACGIH (1991), ATSDR (1995), and NRC (1982, 2002). PGDN is a systemic toxicant with effects on red blood cells, liver, kid- neys, the cardiovascular system, and the central nervous system (CNS) in labo- ratory animals (Jones et al. 1972; NRC 2002). It is rapidly and completely metabolized in vivo within 24 h and eliminated primarily in urine as inorganic nitrate. Monkeys exposed to PGDN at 70-100 ppm for 6 h exhibited signs of acute toxicity, including semiconsciousness and clonic convulsions, but no deaths. Rats exposed to a PGDN mist at 1,350 mg/m3 for 4 h exhibited no overt signs of

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141 Propylene Glycol Dinitrate intoxication; however, methemoglobin concentrations were 23.5% (Jones et al. 1972). The visual evoked response (VER) showed a significant increase in C- wave amplitude in monkeys exposed to PGDN at 2 ppm for 4 h (Mattsson et al. 1981). However, monkeys exposed at 2-33 ppm for 4 h and continuously at 39 ppm (Jones et al. 1972) did not change trained avoidance behavior. In a study with four animals species (squirrel monkeys, beagles, Sprague-Dawley-derived rats, and Hartley-derived guinea pigs) exposed to PGDN at 0, 10, 16, or 35 ppm continuously (24 h/day) for 90 days, hematologic changes were seen in dogs, and fatty livers were reported in multiple species at 10 ppm (Jones et al. 1972). There were no treatment-related increases in tumors in beagles exposed at 0 or 0.2 ppm for 14 months or in rats and mice exposed at 0, 0.2, or 36 ppm for 12 months (Gaworski et al. 1985); however, the studies are of limited value because the exposure durations were relatively short in relationship to the animals’ life- spans, and the exposures may not have been maximized. Methemoglobinemia was observed in rats exposed to PGDN at 36 ppm after only 3 days of exposure and continued until the experiment was terminated. In addition, methemoglo- binemia and hematologic changes were observed in dogs after 2 weeks of expo- sure to PGDN at 0.2 ppm. In a battery of mutagenicity and genotoxicity studies, PGDN produced positive results only in a study with L5178Y mouse lymphoma cells, in which it induced mutations at cytotoxic concentrations (Litton Bionetics 1979, cited in NRC 2002). In humans exposed to PGDN, vasodilation results mainly in mild to severe frontal headaches; dizziness, loss of balance, nasal congestion, eye irritation, palpitations, and chest pain have also been reported (Stewart et al. 1974; Horvath et al. 1981). In contrast with studies in experimental animals, methe- moglobinemia has not been reported in humans as a result of exposure to PGDN (Stewart et al. 1974). That finding may be related partly to the observation that in the presence of PGDN human erythrocytes appear less susceptible to forming methemoglobin than erythrocytes from sensitive test species, especially dogs. It may also be related to the fairly high concentrations (about 35 ppm) needed to produce the effect even in sensitive species; such concentrations would clearly be intolerable to humans because of headaches and sensory symptoms. Changes in VER similar to those observed in monkeys have been observed in humans exposed to PGDN at 0.2-1.5 ppm (Stewart et al. 1974). The VER changes have been interpreted as subclinical disruptions of the extraocular motor system. The VER changes were not reflected in decreased cognitive abilities in humans ex- posed to PGDN at 1.5 ppm except during periods of severe headache (Stewart et al. 1974). An increase in hospitalization for cardiac morbidity has been reported in workers exposed chronically to Otto fuel II during maintenance operations (Forman et al. 1987); however, no deaths of PGDN-exposed workers due to cardiac end points have been reported, and a cause-effect relationship between occupational exposure to PGDN and cardiac morbidity is uncertain because of the paucity of available data.

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142 Exposure Guidance Levels for Selected Submarine Contaminants Effects in Humans Accidental Exposures Although PGDN is a potent vasodilator, reports of significant effects other than headache due to accidental exposure are rare. Human toxicity data on PGDN commonly involve exposure to Otto fuel II. The potential for fire and explosion plays a role in how PGDN and Otto fuel II are handled and conse- quently in the PGDN exposures that occur in the workplace. Humans exposed to Otto fuel II have experienced a number of effects, including headache, loss of balance, poor eye-hand coordination, eye irritation, nasal congestion, nausea, dizziness, and difficulty in breathing; the most common effect reported is head- ache (ATSDR 1995). Sudden deaths due to circulatory failure have been associated with chronic exposure to nitrated esters, such as nitroglycerin and ethylene glycol dinitrate, an analogue of PGDN, in workers in the explosives industry (NRC 2002). The sudden deaths were attributed to compensatory vasospasm that may produce coronary insufficiency on withdrawal from nitrate ester exposure (NRC 2002). No similar cardiovascular deaths have been reported in U.S. Navy personnel during maintenance work on torpedoes, an activity in which accidental expo- sures to PGDN might be expected to occur (Horvath et al. 1981; Forman et al. 1987). Experimental Studies In the only available human experimental study, Stewart et al. (1974) ex- posed human volunteers to Otto fuel II in a controlled-environment chamber. The PGDN exposure concentrations were 0, 0.03, 0.1, 0.2 (0.21-0.26), 0.35 (0.33-0.37), 0.5, or 1.5 (1.2-1.5) ppm. Exposures lasted 1-8 h. The Otto fuel II vapor was 99% pure PGDN as measured with infrared analysis. The volunteers were 17 healthy men (22-25 years old) except for one of the exposures that in- volved two men (45 and 51 years old) and one woman (24 years old) who were members of the research staff. Most of the exposures used three subjects; the range was two to nine. The volunteers underwent a training program in the chamber. The experiments were intended to be double blind to control for bias; however, when the odor of PGDN was detectable, the subjects and the research staff were aware of its presence. The exposures at 0.2 ppm were repeated daily for 5 days. Observations of the volunteers included subjective evaluations (such as for headache and eye irritation) and observation for physiologic and CNS responses under medical supervision (VER, audiometry, clinical neurologic evaluation, electroencephalography (EEG), electrocardiography (EKG), pulse rate, pulse rhythm, pulmonary function, hematology, clinical chemistry, Mar- quette time-estimation test, and Flanagan arithmetic, coordination and inspection

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143 Propylene Glycol Dinitrate tests). The volunteers were under close medical surveillance for 16 h after expo- sure. At 0.03 ppm, one volunteer reported a mild frontal headache after a 1-h exposure; the headache cleared within 1 h. The same person consistently re- ported a headache during control exposures. No headaches were reported by three volunteers exposed to PGDN at 0.03 ppm for 8 h. At 0.1 ppm, the person who reported a headache at 0.03 ppm reported a mild frontal headache after a 3-h exposure; a second person reported a headache after a 6-h exposure, and it lasted several hours after exposure. Two volunteers exposed at 0.1 ppm for 8 h reported no headaches. Black coffee was given im- mediately after exposure to volunteers with headaches and typically ameliorated the headaches. The lowest concentration at which the odor of PGDN was detected was 0.2 ppm; it was detected at this concentration by four of nine subjects. The abil- ity to detect the odor disappeared within 5 min. Headaches were mild in two of three volunteers during a 2-h exposure. Of the nine volunteers who were ex- posed at 0.2 ppm for 8 h, three were exposed for 8 h on two occasions, and seven developed headaches of varying intensity. During the 8-h exposures, there were five incidents of mild headache and six of severe headache; one subject reported eye irritation. The VER was minimally altered in most subjects but with no consistent pattern of response. No abnormalities were detected in test performance or physiologic end points at this concentration. Volunteers who were repeatedly exposed at 0.2-0.3 ppm over a 5-day period developed tolerance of the induction of headache; only mild headaches were reported by three of nine subjects on days 2 and 3, by none on day 4, and by one of nine on day 5. However; the alteration in VER that was observed in subjects exposed for 8 h on 1 day was cumulative in subjects exposed 8 h/day for 5 days; on each day, the baseline values were higher than on the day before. At 0.35 ppm, the three subjects exposed for 2 h developed mild headaches. After an 8-h exposure at 0.35 ppm, one volunteer developed a mild headache, and two developed severe headaches. One subject in the 2-h group developed slight eye irritation that persisted throughout the exposure period but resolved 5 min after exposure. The odor of PGDN was detected by four of nine volunteers but not after 5 min of exposure. The wave form of the VER was altered, particu- larly in three subjects exposed for 8 h, producing an increase in the peak-to-peak amplitude of the 3-4-5 wave complexes. The authors interpreted the changes as consistent with the VER changes produced by CNS depression. At 0.5 ppm, one of three volunteers developed a mild headache during a 1- h exposure; at 2 h, two volunteers reported mild headaches, and one reported a severe headache. By 7.3 h, all three volunteers reported severe headaches. Three members of the research staff exposed at that concentration for 1.25 h developed mild headaches. After exposure for 6.25 h, balance was impaired in two of three volunteers (heel-to-toe test with eyes closed); at 8 h, all three had abnormal modified Romberg tests (postural stability with eyes closed) and abnormal heel- to-toe tests with their eyes closed. One subject could not perform a normal heel-

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144 Exposure Guidance Levels for Selected Submarine Contaminants to-toe test with his eyes open. The authors compared the equilibrium disturbance with ethanol intoxication. The three volunteers with “abnormal neurologic find- ings also showed a narrowing of their pulse pressure due to a rise in diastolic pressure.” The mean increase in diastolic pressure was 12 mmHg and was not accompanied by alterations in heart rate or cardiac rhythm. Headaches were in- creasingly severe and throbbing in all three volunteers during exposure, and one of the three subjects reported dizziness and nausea after 6 h of exposure. VER changes at 0.5 ppm were similar to those observed at 0.35 ppm. At 1.5 ppm, the odor of PGDN was immediately apparent to the subjects as they entered the exposure chamber. The intensity of the odor was graded from mild to strong. None of the subjects could detect it after 20 min. Three of eight subjects reported mild eye irritation within 5 min of exposure; all subjects re- ported eye irritation within 40 min of exposure. Conjunctivitis or excessive lac- rimation did not accompany reports of irritation, and the irritation resolved within 5-8 min after exposure. All the volunteers developed severe frontal head- aches after 30-90 min of exposure, which caused all exposures to be terminated after 3 h. The headaches after a 3-h exposure were described as nearly incapaci- tating. The headaches persisted for 1-7.5 h in the absence of continued exposure. As in early exposure scenarios, black coffee consumed after exposure amelio- rated the headaches in some subjects. Of the cognitive-coordination tests, only the Flanagan coordination test was considered abnormal while the subjects were experiencing severe headaches. The VER in all volunteers showed a dramatic increase (10-70%) in amplitude in the peak-to-peak voltage of the 3-4-5 com- plex after 45-90 min of exposure. There was a shift to control values after 160- 180 min of exposure, but VER patterns were still altered for 48 h after a 3-h exposure to PGDN. None of the exposures resulted in changes in hematology, blood nitrate, methemoglobin, clinical chemistry, urinalysis, serum electrolytes, EEG, pulse rate and sinus rhythm, pulmonary function, visual and auditory acuity, EKG during exercise, or time-estimation tests. Only one of the cognitive tests (Flanagan coordination test) was affected by exposure, and the change occurred only in the four subjects exposed at 1.5 ppm while they were experiencing se- vere headaches. Occupational and Epidemiologic Studies Sudden deaths due to circulatory failure have been reported in workers exposed chronically to nitrated esters, such as nitroglycerin and ethylene glycol dinitrate, an analogue of PGDN (Carmichael and Lieben 1963). Sudden deaths in the explosives industry were attributed to compensatory vasospasm that may produce coronary insufficiency on withdrawal from nitrate ester exposure. No deaths attributable to cardiovascular effects were reported in U.S. Navy person- nel involved in torpedo-maintenance work, as discussed below.

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145 Propylene Glycol Dinitrate Horvath et al. (1981) evaluated the neurophysiologic effects—according to medical and occupational history, neuro-ophthalmologic examination, quanti- tative tests of oculomotor function (saccades or synchronized eye tracking movements), and ataxia—of chronic exposure to PGDN in a population of 87 workers employed in U.S. Navy torpedo-maintenance facilities for an average period of 47.4 months (range, 1-132 months). A control group of 21 workers was used for comparison. A major difference between the exposed and control groups was that the exposed group regularly consumed over twice as much al- cohol as the controls. Exposed workers reported symptoms of frequent or occa- sional headaches (65% of respondents), nasal congestion (31%), eye irritation (26%), and dizziness (13%). Palpitations, dyspnea, chest pain, and loss of bal- ance were reported by small percentages of workers. Results of the tests indi- cated no evidence of chronic neurotoxicity either in the study population com- pared with an unexposed control group in the same plant or in a subgroup of 28 workers with the longest exposure to PGDN. Horvath et al. (1981) also evaluated the acute effects in a subgroup of 29 chronically exposed workers by comparing test values before and after comple- tion of a torpedo-maintenance procedure that lasted 30-60 min. During that time, PGDN concentrations based on multiple grab samples taken in the work area averaged 0.06 ppm (range, 0-0.22 ppm; 88% of values 0.1 ppm or less, 50% of values 0.05 ppm or less, and one sample above 0.2 ppm; Horvath et al. 1981, cited in NRC 2002). There were no decrements in the ataxia tests, and the mean score in one test was increased after exposure. The mean saccade velocity (speed of eye movement) was significantly decreased (by 37.3 deg/s), and the mean saccade delay time (time by which initiation of eye movement in response to a stimulus is delayed) was significantly increased (by 6.4 ms). There were no changes in saccade accuracy or ocular smooth pursuit index. The changes in the saccade test results did not correlate with peak PGDN concentrations measured during the maintenance procedure. The workers involved in the procedure did not complain of headaches or nasal congestion, although one person involved in a spill developed a headache. Forman et al. (1987) and an earlier report of their work by Helmkamp et al. (1984) evaluated cardiac morbidity in U.S. Navy personnel potentially ex- posed to PGDN while engaged in torpedo-maintenance work. Cardiovascular events in this group were compared with events in unexposed groups of torpe- domen and fire-control technicians. The potentially exposed group consisted of 1,352 men with a yearly average of 822; hospitalization records were available for 1970-1979. The group of unexposed torpedomen consisted of 14,336 people over the 10-year period with a yearly average of 4,906, and the group of unex- posed fire-control technicians consisted of 29,129 people with a yearly average of 11,198. Measured concentrations of PGDN included those of the Horvath et al. (1981) study and surveys in the same period in which 8-h time-weighted av- erages were below 0.05 ppm. Cardiac morbidity included myocardial infarction, angina pectoris, and cardiac arrhythmia, and these were used to calculate rela- tive risk and age-adjusted incidences. There were higher incidences of hospitali-

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146 Exposure Guidance Levels for Selected Submarine Contaminants zation for myocardial infarction and angina pectoris but not cardiac arrhythmia in the potentially exposed group than in either unexposed group. Relative risk was significant for myocardial infarction and angina pectoris compared with the fire-control-technician group but not compared with the torpedomen control group. When incidences of myocardial infarction and angina pectoris were com- bined, the relative risk was significant compared with the unexposed torpe- domen group and the unexposed fire-control-technician group. Cardiovascular deaths occurred in the unexposed groups but not in the group potentially ex- posed to PGDN. There were few hospitalizations in the study and only four for myocardial infarction and two for angina pectoris in the potentially exposed group over the 10-year period. Effects in Animals Acute Toxicity Rats treated with lethal oral or subcutaneous doses of PGDN were pros- trate, anoxic, and cold and had signs of methemoglobinemia and respiratory depression (Clark and Litchfield 1969). At high oral or parenteral doses, deaths from anoxia due to almost complete conversion of hemoglobin to methemoglo- bin have been observed (ACGIH 1991). Death consistent with anoxia occurred up to 48 h after PGDN administration (Clark and Litchfield 1969). PGDN is a potent vasodilator in animals, inducing a maximal fall in blood pressure usually 30 min after injection (ACGIH 1991). Oral doses of PGDN that were lethal to half the animals ranged from 250 to 1,190 mg/kg in rats (NRC 2002). Jones et al. (1972) reported deaths in preliminary, range-finding studies in which single animals were exposed to PGDN that was chemically stabilized. An unspecified number of squirrel monkeys exposed to PGDN at about 70-100 ppm for 6 h developed vomiting, pallor, coldness of the extremities, semiconscious- ness, and clonic convulsions (Jones et al. 1972). The clinical signs disappeared within 30-45 min after removal from the exposure chambers. Six rats (strain unknown) that were exposed to PGDN as a mist at 1,350 mg/m3 for 4 h did not show adverse clinical signs during the exposure or within 14 days after it, although the mean methemoglobin concentration immediately after exposure was 23.5% (Jones et al. 1972). The potential for PGDN to impair motor activity in animals was investi- gated as a model of human responses by injecting PGDN into the cerebrospinal fluid of rats (Bogo et al. 1987). Groups of 13-14 anesthetized male Sprague- Dawley rats that had been trained on the accelerod (used to test motor perform- ance) were given injections of saline (control) or 5 or 10 μL of PGDN (0.01 or 0.02 μL/kg; about 0.007 or 0.014 μg/kg) directly into the cisterna magna of the brain. Motor performance was tested 12 min after injection, hourly for 6 h, and at 24 h in rats that had not been grossly traumatized by the injection procedure. No change in motor performance was observed in rats given 5 μL of PGDN

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147 Propylene Glycol Dinitrate compared with the control group. A significant decrease in motor performance was observed during the first 2 h in rats given 10 μL. The authors suggested that the study confirmed the reported effects of PGDN on human motor perform- ance. Two male rhesus monkeys trained in free operant avoidance tests were exposed to PGDN at 2-33 ppm and observed for successful completion of the avoidance test and VER (Mattsson et al. 1981). The test used a multiple- avoidance schedule to evaluate performance: the monkeys were subjected to a series of discrete, cued-avoidance trials for 10 min, allowed to rest for 3 min, and then subjected to a 10-min session of free operant avoidance. For the VER, the A-B-C complex, comparable with the 3-4-5 complexes in the Stewart et al. (1974) study, was measured in response to flashes from a strobe light. The mon- keys were tested individually, each at several concentrations at 1-week intervals. One monkey was exposed at 2 ppm three times and also at 7 and 20 ppm. The other monkey was exposed at 3, 10, and 33 ppm. Exposure duration was 4 h. Halothane at one-tenth the concentration that produces anesthesia in monkeys served as a reference depressant. Free operant behavior was not affected by any PGDN concentration, but the VER was significantly (p < 0.05) altered by expo- sure to PGDN. The C wave increased by 20% in amplitude at 2 ppm and de- creased by 25% at higher concentrations; there were no changes in amplitude of the A and B waves or in the latency of the waveforms. No changes occurred in one of three trials at 2 ppm and in the trial at 10 ppm. During the course of the training, Mattsson et al. found that the C wave could be increased or decreased by 30-40% by changing the environment or the tension of the operant-response lever; therefore, the authors suggested that the changes observed during the ex- posures might have been caused by the irritating or distracting properties of the vapor. Halothane produced significant increases in the A, B, and C waves and slowed the latency of the B and C waves but did not change free operant avoid- ance behavior. Repeated Exposures and Subchronic Toxicity Inhalation exposure of eight male Sprague-Dawley-derived rats to PGDN at about 10 ppm 7 h/day, 5 days/week for a total of 30 exposures did not result in death or adverse clinical signs (Jones et al. 1972). Weight gain, hematologic values, and histopathologic examinations of heart, lungs, liver, spleen, and kid- neys did not reveal adverse effects immediately after exposure (four rats) or 2 weeks later (four additional rats). Jones et al. (1972) exposed four species of animals—nine male Squirrel monkeys, two male beagles, 15 male and 15 female Sprague-Dawley-derived rats, and 15 male and 15 female Hartley-derived guinea pigs per exposure con- centration—to PGDN at 10, 16, or 35 ppm continuously (24 h/day) for 90 days. Equal numbers of control animals were exposed in a similar manner to uncon- taminated air in parallel with each exposure concentration. Total leukocytes,

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148 Exposure Guidance Levels for Selected Submarine Contaminants hemoglobin, and microhematocrit were determined before and at the conclusion of exposures. Necropsies were conducted after the last exposures, and tissue sections—heart, lungs, spleen, liver, and kidneys from all species; brain and spinal cord from dogs and monkeys; and adrenal glands from dogs—were exam- ined microscopically. Selected biochemical measures, serum nitrate, and methemoglobin (including samples taken each week from two animals of each species exposed at the highest concentration) were also evaluated. • At 35 ppm, one monkey died on day 31, possibly because of a com- plication of an abdominal filarial parasitic Dipetalonema infection (although other monkeys showed similar parasite infestation). The remaining monkeys did not show abnormal clinical signs during the exposures. Body-weight gains of surviving animals were normal. Fatty infiltration of the liver was present in monkeys exposed at 10 ppm. Heavy iron-positive deposits, commonly associ- ated with mononuclear-cell infiltrates and focal necrosis, were present in the liver, spleen, and kidneys at 35 ppm. Monkeys exposed at 16 and 35 ppm also had increased serum urea nitrogen and decreased serum alkaline phosphatase. Monkeys exposed at 35 ppm developed methemoglobinemia (methemoglobin concentration, 17%) by day 14, but this declined to about control values by day 42. • All dogs gained weight at a normal rate. At 35 ppm, hemoglobin and hematocrit were decreased by 63% and 37% in the two dogs. Hemosiderin de- posits were observed in the livers of dogs in the 10-ppm group. Hemosiderin deposits and fatty changes were reported in the livers of the 16-ppm group. Heavy hemosiderin deposits and focal necrosis were observed in the livers of dogs in the 35-ppm group. At 35 ppm, iron-positive deposits were observed in the spleen and kidneys. Methemoglobinemia reached 23% on day 14 at 35 ppm; it declined thereafter but did not return to control values. • Fatty infiltration was observed in the livers of some of the rats ex- posed at 10 ppm but not at higher concentrations. Female rats, but not male rats, exposed at 35 ppm showed focal necrosis of the liver and acute renal tubular necrosis. Methemoglobin concentrations of two rats exposed at 35 ppm in- creased to 9.9 and 12.8% on day 14 but decreased with continued exposure (on day 42 methemoglobin concentrations were 2.3 and 7.3 %). • Fatty infiltration was observed in the livers of some of the guinea pigs exposed at 10 ppm. Guinea pigs exposed at 16 ppm consistently showed foci of pulmonary hemorrhage, and vacuolar changes occurred in the livers of all guinea pigs exposed at 35 ppm. Methemoglobin concentrations increased in two guinea pigs in the 35-ppm group, reaching 4.8 and 9.3 % on day 42. Three trained male squirrel monkeys were exposed to PGDN continuously for 90 day at 39 ppm (Jones et al. 1972). A fourth trained monkey was exposed to filtered room air under the same conditions and served as the control. The animals were removed from the exposure chambers for a 2-h period once a week

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149 Propylene Glycol Dinitrate to perform visual-discrimination or visual-acuity threshold tests. The only sign or change in the monkeys during exposure was mydriasis, which increased from slight to moderate. There were no changes in avoidance behavior in the mon- keys as determined by the visual tests, and body weight was unaffected by the PGDN exposure. Pairs of rhesus monkeys were exposed to ambient air or PGDN vapors 23 h/day for 125 days at concentrations that were increased incrementally from 0.3 to 4.2 ppm (Mattsson et al. 1981). Cued or free operant avoidance testing con- ducted daily showed no effects on either type of avoidance performance. There was no disruption of the ability of the monkeys to discriminate between the two avoidance schedules. The monkeys were tested for a further 16-day period after PGDN exposure and then necropsied. Samples of lungs, liver, spleen, kidneys, and lymph nodes were collected for microscopic analysis; however, no signifi- cant gross or microscopic lesions were identified in the samples. Chronic Toxicity A 1-year inhalation study (6 h/day, 5 days/week) was conducted to evalu- ate the carcinogenic potential of Otto fuel II at 0, 0.2, or 36 ppm on the basis of analysis for PGDN (Gaworski et al. 1985). Analysis indicated that the average material composition of the Otto fuel II tested was 74.3 ± 1.2% PGDN, 1.9 ± 0.6% 2-nitrodiphenylamine, and 23.8 ± 1.2% di-n-butyl sebacate with a trace contaminant (o-chloronitrobenzene) from the manufacture of 2-nitrodiphenyl- amine. Dogs (three male and three female beagles per group), rats (75 male and 75 female F344 rats per group), and mice (75 male and 75 female C57BL/6 mice per group) were exposed at 0.2 ppm, and 100 male and 100 female rats and mice were exposed at 36 ppm. Dogs were exposed to Otto fuel II for 14 months, and rodents for 12 months. Ten male and 10 female rodents from each exposure group were necropsied after the 1-year exposure, and the remaining animals were held for a 1-year observation period before being necropsied. Dogs appeared to be the most sensitive species tested, with measurable re- ductions in red blood cells, hematocrit, and hemoglobin (Gaworski et al. 1985). Decreases in hematocrit and hemoglobin in dogs were evident after only 2 weeks of exposure at 0.2 ppm, and a decrease in red-cell count after 4 weeks of exposure. Reticulocyte counts were also decreased in spite of the reduction in red-cell measures. After a 60-day recovery period, the red-cell changes im- proved, although reticulocyte counts did not increase. Heinz bodies were not observed in red cells of the dogs. A mild increase in methemoglobin was ob- served in dogs exposed at 0.2 ppm and rats exposed at 36 ppm. No other signifi- cant effects were noted in rats exposed at either concentration. Microscopic ex- amination of tissues collected from dogs, rats, and mice exposed to Otto fuel II did not suggest any significant exposure-related nonneoplastic changes.

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150 Exposure Guidance Levels for Selected Submarine Contaminants Reproductive Toxicity in Males Litton Bionetics (1979) reported that Otto fuel II was not active in a domi- nant lethal assay conducted in male mice. No lesions in the reproductive tract of male dogs, rats, or mice were identified in a 1-year inhalation bioassay con- ducted with Otto fuel II (Gaworski et al. 1985). See the section “Chronic Toxic- ity” above for details. Immunotoxicity No study specifically directed at the immunotoxicity of PGDN has been reported. Genotoxicity The genotoxicity of Otto fuel II was evaluated in a series of assays con- ducted by Litton Bionetics (1979). Otto fuel II was not mutagenic in microbial assays with five strains of Salmonella typhimurium or in Saccharomyces cere- visiae D4, with or without metabolic activation. It was positive for induction of mutations at the TK locus in L5178Y mouse lymphoma cells at concentrations that were cytotoxic. Otto fuel II did not induce sister-chromatid exchanges in L5178T mouse lymphoma cells, with or without metabolic activation. In a bone marrow cytogenetic analysis in mice in which Otto fuel II was administered acutely and repeatedly (five doses), chromosomal aberrations were not increased compared with the control, but the presence of ring chromosomes suggested weak activity. Otto fuel II was not positive in a dominant lethal assay in mice. Carcinogenicity Two-year carcinogenicity studies of PGDN have not been conducted; however, as discussed above in the section “Chronic Toxicity,” 1-year inhalation studies with a 1-year follow-up have been conducted with Otto fuel II. In the 1- year inhalation study (6 h/day, 5 days/week), dogs were exposed to PGDN at 0 or 0.2 ppm for 14 months (three males and three females in each of the control and exposed groups), and F-344 rats and C57BL/6 mice were exposed at 0, 0.2, or 36 ppm for 12 months (100 males and 100 females in each of the control and high-concentration groups and 75 of each sex in the low-concentration group) (Gaworski et al 1985). Osteosarcomas were reported in one of the 55 male rats exposed at 0.2 ppm (1.8%) and two of the 85 exposed at 36 ppm (2.4%), and an osteoma was reported in one of the 61 female rats exposed at 0.2 ppm (1.6%). Although bone tumors are considered rare in rats, the low incidence of bone tumors did not fit a dose-response pattern particularly in light of the large differ-

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151 Propylene Glycol Dinitrate ence in exposure concentrations. Consequently, the bone tumors were not con- sidered to be related to exposure to PGDN as a component of Otto fuel II. No significant tumor incidence was observed in mice exposed to PGDN. TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS After exposures of human volunteers to Otto fuel II (99% PGDN vapor) at 1.5 ppm for 1-3 h, the blood concentration of PGDN was less than 5 ppb, the analytic limit of detection (Stewart et al. 1974). A 1-h exposure to Otto fuel II at 1.5 ppm resulted in PGDN at 20-35 ppb in expired breath; no PGDN was de- tected in breath 15 min after exposure. Those few data suggest that PGDN is likely to be cleared from the blood via exhalation soon after exposure ceases even though headaches persist for longer periods. PGDN was not detected in the plasma of rhesus monkeys during inhala- tion exposures at 0.3 ppm for 14 days or after an additional 56 days of exposure at 0.8 ppm (Mattsson et al. 1981). During a later exposure for 20 days at 1.6 ppm, plasma PGDN was about 35 μg/mL. During a final 14-day exposure at 4.2 ppm, plasma PGDN was about 170 μg/mL. PGDN is rapidly cleared from the blood; within 24 h of termination of exposure, it was not detectable. Dermal absorption of PGDN is also possible because mortality, increased methemoglobin, and increased urinary nitrogen concentrations have been re- ported in rabbits after repeated applications to skin at 4 g/kg (Jones et al. 1972). About 10% of topically applied PGDN is estimated to be absorbed through the intact skin of rats by 30 min after application (Clark and Litchfield 1969). According to Kylin et al. (1966, cited in NRC 2002), metabolism of PGDN is rapid and follows first-order kinetics. It is metabolized in the liver and red blood cells. Mononitrates and inorganic nitrate are produced, and the inor- ganic nitrate is eliminated in urine. Clark and Litchfield (1969) studied the metabolism of PGDN in vitro and in vivo in Alderley Park rats. PGDN, mononitrates, inorganic nitrite, and inor- ganic nitrate were detected at various times during both experiments. For the in vivo study, rats received subcutaneous injections of PGDN at 65 mg/kg. PGDN peaked within 30 min of injection and declined to become undetectable by 8-12 h. The primary metabolite detected in the blood was propylene glycol 2- mononitrate, which was metabolized further to inorganic nitrate (56% of admin- istered dose as measured in urine). Excretion was considered complete by 24 h because metabolites were not detected above control values after that point. For the in vitro study, rat blood was incubated with PGDN at 50 μg/mL. At 1 h, 50% of PGDN had been metabolized; 50% of the remainder was metabolized in the next hour. At 3 h, the primary metabolites were propylene glycol 2-mononitrate and inorganic nitrate; small amounts of unmetabolized PGDN, propylene glycol 1-mononitrate, and inorganic nitrite were present. The time courses of in vivo and in vitro metabolism of PGDN were similar.

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152 Exposure Guidance Levels for Selected Submarine Contaminants The proposed metabolism of PGDN involves the reduction of a nitrate group to yield an unstable organic nitrite-nitrate intermediate followed by hy- drolysis to yield the mononitrate and inorganic nitrite and oxidation of the latter in the blood to inorganic nitrate, which is excreted in urine (NRC 2002). At relatively low concentrations, PGDN or its metabolites produce effects on red blood cells, the vasculature, and the CNS in some species of experimental animals. Except in the dog, effects on red blood cells are seen at high exposure concentrations. There are species differences in susceptibility to methemoglobin formation (Wyman et al. 1985). In a series of in vitro assays using blood, hemo- lysates, and partially purified hemoglobin solutions, formation of methemoglo- bin was greatest in the dog and less in the guinea pig, followed by the rat; the human was either the least sensitive or as sensitive as the rat. The primary de- terminant of methemoglobin formation appeared to be the structure of each spe- cies’ hemoglobin and not the reactivity of blood enzymes. With chronic inhala- tion exposure to PGDN at 33 ppm, dogs and monkeys were more susceptible to formation of methemoglobin than rats and guinea pigs, the dog being the most susceptible and reaching a peak of about 20% during the second week of con- tinuous inhalation exposure (Jones et al. 1972). In a 1-year inhalation exposure of dogs to PGDN at 0.2 ppm and rats at 36 ppm, similar low concentrations of methemoglobin were induced (Gaworski et al. 1985). After exposure of humans to Otto fuel II, PGDN-induced methemoglobin was not observed in subjects exposed at up to 1.5 ppm for a few hours (Stewart et al. 1974). PGDN has effects on both the cardiovascular system and the CNS. The most commonly encountered symptom of human exposure to PGDN is headache due to dilation of cerebral blood vessels. Nitrate and nitrite esters are vasodila- tors and result in rapid lowering of systolic and, to a smaller extent, diastolic blood pressure with compensatory tachycardia. Administration of nitrites pro- duces dilation of meningeal blood vessels (via relaxation of vascular smooth muscle), which is the basis of the transient pulsating headache (Nickerson 1975). Headache of presumed vascular origin is a frequent complaint after ad- ministration of therapeutic doses of the structurally similar nitrate triester nitro- glycerin for angina. Dilation of the dural arteries is the probable cause of head- aches and nasal congestion experienced by torpedo-maintenance workers in the study of Horvath et al. (1981). Vascular effects after exposure to PGDN have been attributed to the for- mation of nitric oxide, which is produced either directly from the nitroester or liberated by decomposition of intermediates (Feelisch and Noack 1987). In ani- mal studies, intravenous administration of PGDN has resulted in changes that initially decrease and then increase cerebral blood flow (Godin et al. 1995). Pe- ripheral vasodilation after parenteral administration of PGDN can precipitate a rapid fall in systolic blood pressure (Clark and Litchfield 1969; Godin et al. 1995). However, no drop in blood pressure was observed in rats during a 30- to 45-min exposure to a saturated PGDN vapor generated from Otto fuel II (Godin et al. 1993) or in human volunteers who inhaled PGDN at 0.5 ppm for 7.3 h

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153 Propylene Glycol Dinitrate (Stewart et al. 1974). Rather, a mean increase in diastolic blood pressure of 12 mmHg was associated with severe and throbbing headaches in human volunteers (Stewart et al. 1974). A drop in blood pressure and decreasing cardiac stroke volume can result in brain ischemia, causing the dizziness and weakness re- ported by one subject after exposure at 0.5 ppm for 6 h (Stewart et al. 1974) and by occupationally exposed workers (Horvath et al. 1981). Although no deaths or cardiac problems have been reported after exposures to PGDN, workers in the explosives industry have reportedly had cardiovascular events after repeated occupational exposures and depression of systolic and diastolic blood pressure after acute exposures (Carmichael and Lieben 1963). Continued exposure to nitrate esters at low concentrations can narrow the pulse-pressure differential between systole and diastole because of a progressive rise in diastolic blood pressure. When combined with high pulse rate, which occurs after cessation of exposure to nitrate esters, that may contribute to acute myocardial ischemia. Another mechanistic consideration is that PGDN also acts as a CNS de- pressant in humans and results in changes in the VER, disturbances in postural balance, and changes in oculomotor performance (Stewart et al. 1974; Horvath et al. 1981). The PGDN concentrations in those studies did not greatly influence cognitive functions, and higher concentrations of PGDN had little or no effect on monkeys trained in avoidance tests (Jones et al. 1972; Mattsson et al. 1981). The mechanism of CNS depression induced by PGDN exposure is poorly under- stood but may be the same as that of CNS depression induced by volatile anes- thetics, such as halothane (Mattsson et al. 1981). Susceptibility of humans to CNS depressants, such as volatile anesthetics, varies by no more than a factor of 2 as indicated by the concentration that produces immobility in 50% of patients (Kennedy and Longnecker 1996, cited in NRC 2002; Marshall and Longnecker 1996, cited in NRC 2002). NRC (2002) concluded that the adult human population did not appear to be overly susceptible to PGDN on the basis of a literature review. Although laboratory animals are susceptible to methemoglobinemia at high PGDN con- centrations, occupational and human experimental studies show that humans are not similarly affected. Those findings are supported by the in vitro studies in which human hemoglobin was shown to be generally less sensitive to formation of methemoglobin on PGDN exposure than that of other animal species. Al- though one might assume that humans vary widely in their susceptibility to the induction of headaches, Stewart et al. (1974) showed that the concentrations of PGDN at which mild headaches were induced in various subjects were relatively similar for an 8-h exposure (0.1 ppm for the most susceptible person vs 0.21- 0.26 ppm for about half the subjects). Severe headaches were induced in all sub- jects at 1.5 ppm between 30 and 90 min. The data supported a linear relationship between concentration and time for headache induction (that is, n = 1 for the function Cn × t = k, where C = concentration, t = time, and k = constant).

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154 Exposure Guidance Levels for Selected Submarine Contaminants INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established or proposed acceptable expo- sure limits or guidelines for inhaled PGDN. Table 6-2 summarizes selected val- ues. COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for PGDN are summarized in Table 6-3. The current U.S. Navy values are provided for comparison. 1-Hour EEGL Human experimental studies were used as the basis of the 1-h EEGL. Acute effects due to exposure to PGDN during maintenance of torpedos that contain Otto fuel II were evaluated in chronically exposed workers by compar- ing test values before and after completion of a torpedo maintenance procedure that lasted 30-60 min (Horvath et al 1981). None of the effects reported during the study was interpreted as indicating significant impairment during exposure to Otto fuel II. Stewart et al. (1974) exposed primarily young male volunteers to PGDN vapors at various concentrations for 1 h or longer. Three of six volun- teers or research staff members who were exposed to PGDN at 0.5 ppm for 1- 1.25 h developed mild headache but had no other adverse effects. At 1.5 ppm, eight subjects reported mild eye irritation within 40 min of exposure, which re- solved on cessation of exposure. All the volunteers developed severe frontal headaches after only 30-90 min of exposure, so all exposures were terminated after 3 h, at which time the headaches were described as nearly incapacitating. The headaches persisted for 1-7.5 h in the absence of continued exposure. Only the Flanagan coordination test was considered abnormal while the subjects were experiencing severe headaches. The VER in all volunteers showed a dramatic increase (of 10-70%) in amplitude in the peak-to-peak voltage of the 3-4-5 com- plex after 45-90 min of exposure; the amplitude shifted toward normal after ces- sation of exposure but was still altered 48 h after exposure. Those data indicate a threshold after a 1-h exposure to PGDN at 0.5-1.5 ppm for the induction of severe headaches that can be incapacitating and impair function. The available data and the small group used in the study of Stewart et al. (1974) do not allow a more precise definition of the threshold. On the basis of those human data, a point of departure for development of a 1-h EEGL is 0.5 ppm. Exposure at that concentration should avoid induction of severe headaches in naval personnel. Although one of three volunteers developed a mild headache

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155 Propylene Glycol Dinitrate TABLE 6-2 Selected Inhalation Exposure Levels for Propylene Glycol Dinitrate from the National Research Council and Other Agenciesa Exposure Level Organization Type of Level (ppm) Reference Occupational ACGIH TLV-TWA 0.05 ACGIH 1991 NIOSH REL-TWA, skin 0.05 NIOSH 2005 General public ATSDR Acute MRL 0.003 ATSDR 2008 Chronic MRL 0.00004 NAC/NRC AEGL-1 (1-h) 0.17 NRC 2002 AEGL-2 (1-h) 1 AEGL-1 (8-h) 0.03 AEGL-2 (8-h) 0.13 a Comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regula- tory Standards or Guidance Levels”). Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Dis- ease Registry; MRL, minimal risk level; NAC, National Advisory Committee; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; REL, recommended exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average. TABLE 6-3 Emergency and Continuous Exposure Guidance Levels for Propylene Glycol Dinitrate Current U.S. Navy Committee Recommended Exposure Level Values (ppm) Values (ppm) EEGL 1-h 0.15 0.2 24-h 0.02 0.02 CEGL 90-day 0.01 0.004 Abbreviations: CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level. during a 1-h exposure at 0.5 ppm, the headache was not considered sufficient to impair function. No interspecies or intraspecies uncertainty factors need to be applied because the data are from human exposures and the proposed 1-h EEGL is below the concentration expected to induce severe headaches in 1 h. However,

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156 Exposure Guidance Levels for Selected Submarine Contaminants because so few data on acute human exposures to PGDN are available, an uncer- tainty factor of 3 is considered appropriate in determining a 1-h EEGL value. Thus, the recommended 1-h EEGL is 0.2 ppm. 24-Hour EEGL During exposures of healthy male volunteers to PGDN at 0.03 or 0.1 ppm for up to 8 h, mild headaches or no headaches were reported (Stewart et al. 1974). Exposure to PGDN at 0.2 ppm for 8 h resulted in reports of headaches in seven of nine volunteers. According to the data of Stewart et al. (1974), the con- centration-time product is about 0.5 ppm-h for mild headaches induced by PGDN and about 1.6 ppm-h for severe headaches (NRC 2002). The concentra- tion-time relationship derived from Stewart et al. (1974) is linear. Thus, the threshold for mild headaches after a 24-h exposure to PGDN is calculated to be 0.02 ppm and for severe headache is 0.07 ppm. Because severe headaches are considered to be incapacitating, a 24-h EEGL of 0.02 ppm is proposed for PGDN. No interspecies or intraspecies uncertainty factors need to be applied because the data are from human exposures and the proposed 24-h EEGL is be- low the concentration expected to induce severe headaches in 24 h. 90-Day CEGL The committee considered animal and human data in deriving a 90-day CEGL. In a 1-year inhalation study (6 h/day, 5 days/week) with Otto fuel II, dogs were exposed to PGDN at 0 or 0.2 ppm for 14 months, and F-344 rats and C57BL/6 mice were exposed at 0, 0.2, or 36 ppm for 12 months (Gaworski et al. 1985). Dogs developed changes in red-blood-cell measures (decreased hema- tocrit and hemoglobin) that were evident after only 2 weeks of exposure and decreased red-blood-cell count after 4 weeks of exposure. Reticulocyte counts were also decreased in spite of the reduction in red-cell measures. After a 60-day recovery period, the changes in red blood cells improved, although reticulocyte counts did not increase. A mild increase in methemoglobin was observed in dogs exposed at 0.2 ppm and rats exposed at 36 ppm. No other significant ef- fects were noted in rats or mice exposed at either concentration. Microscopic examination of tissues collected from dogs, rats, and mice did not suggest any significant exposure-related changes. No comparable data on human exposures are available for analysis. How- ever, as discussed above, humans exposed to PGDN at 0.1 ppm reported mild headaches and at 0.2 ppm severe headaches (Stewart et al. 1974). Some toler- ance of induction of headaches developed with repeated exposure at 0.2 ppm. Changes in VER were duration-related, and this indicates a cumulative effect at 0.2 ppm. Human exposure at 0.5 ppm for 8 h resulted in nausea, dizziness, and

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157 Propylene Glycol Dinitrate more markedly altered VER. The results are supported by an occupational study of humans (Horvath et al. 1981) and studies of monkeys (Mattsson et al. 1981). The 1-year dog and acute human studies indicate lowest observed- adverse-effect levels (LOAELs) of PGDN of 0.2 ppm and 0.1 ppm, respectively, and a human acute NOAEL for mild headache of 0.03 ppm (Stewart et al. 1974). Of the species tested for hematologic effects in an in vitro study (Wyman et al. 1985), a 90-day continuous-exposure study (Jones et al. 1972), and a 1-year ex- posure study (Gaworski et 1985), the dog was the most sensitive for develop- ment of red-blood-cell effects due to PGDN exposure. A 90-day CEGL based on hematologic effects in dogs is probably conservative in that in vitro studies indi- cate that human red blood cells are less sensitive to PGDN than those of the other species tested; however, comparable subchronic-exposure data on humans are not available. Therefore, in the absence of a NOAEL for subchronic effects of PGDN exposure, a point of departure of 0.2 ppm for development of a 90-day CEGL is proposed on the basis of hematologic effects in dogs exposed 6 h/day, 5 days/week. A value of 10 is used to extrapolate the LOAEL to a NOAEL, and the resulting value is then time-scaled from 6 h/day, 5 days/week to 24 h/day, 7 days/week: (0.2 ppm/10)(6/24)(5/7) = 0.02 ppm × 0.18 = 0.004 ppm. Thus, the recommended 90-day CEGL is 0.004 ppm. No interspecies adjustment factor is considered necessary because the dog is the species most sensitive to hema- tologic effects of PGDN. And no intraspecies adjustment factor is considered necessary because the available data do not indicate a significant degree of vari- ability among young men exposed to PGDN. DATA ADEQUACY AND RESEARCH NEEDS Although there have been short-term human exposure studies and 90-day and chronic animal toxicity studies of PGDN, the short-term and subchronic effects of PGDN are somewhat uncertain. The human data are limited to a study in which volunteers were briefly exposed to PGDN vapors (Stewart et al. 1974). The animal data on PGDN are from inhalation studies (Gaworski et al. 1985; Jones et al. 1972; Mattsson et al. 1981) that did not identify NOAELs for hema- tologic and male reproductive effects. Acute human PGDN-exposure studies that use more modern imaging techniques for cerebral blood flow and neu- rologic function are recommended. Depending on the results of the acute human studies, animal inhalation studies to determine NOAELs for neurologic, hema- tologic, and reproductive effects are recommended. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological

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158 Exposure Guidance Levels for Selected Submarine Contaminants Exposure Indices (BEIs), 6th Ed. American Conference of Governmental Hygien- ists, Cincinnati, OH. ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological Pro- file for Otto Fuel II and Its Components. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Regis- try, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp77. html [accessed Apr. 14, 2009]. ATSDR (Agency for Toxic Substances and Disease Registry). 2008. ATSDR Minimal Risk Levels (MRLs). U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. December 2008 [online]. Available: http://www.atsdr.cdc.gov/mrls/pdfs/atsdr_mrls_december_2008.pdf [accessed Apr. 14, 2009]. Bogo, V., T.A. Hill, and J. Nold. 1987. Motor performance effects of propylene glycol dinitrate in the rat. J. Toxicol. Environ. Health 22(1):17-27. Carmichael, P., and J. Lieben. 1963. Sudden death in explosives workers. Arch. Environ. Health 7:424-439. Clark, D.G., and M.H. Litchfield. 1969. The toxicity, metabolism, and pharmacologic properties of propylene glycol 1,2-dinitrate. Toxicol. Appl. Pharmacol. 15:175- 184. Feelisch, M., and E.A. Noack. 1987. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur. J. Phar- macol. 139(1):19–30. Forman, S.A. 1988. A review of propylene glycol dinitrate toxicology and epidemiology. Toxicol. Lett. 43(1-3):51-65. Forman, S.A., J.C. Helmkamp, and C.M. Bone. 1987. Cardiac morbidity and mortality associated with occupational exposure to 1,2 propylene glycol dinitrate. J. Occup. Med. 29(5):445-450. Gaworski, C.L., H.F. Leahy, W.J. Bashe, J.D. Macewen, E.H. Vernot, and C.C. Haun. 1985. A One-Year Inhalation Toxicity Study of OTTO Fuel II. AAMRL-TR-85- 071. ADA163162. Naval Medical Research Institute Report No. 85-86. Harry G. Armstrong Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. Godin, C.S., E.C. Kimmel, J.M. Drerup, H.F. Leahy, and D.L. Pollard. 1993. Effect of exposure route on measurement of blood pressure by tail cuff in F-344 rats ex- posed to OTTO Fuel II. Toxicol. Lett. 66(2):147-155. Godin, S.C., J. He, J.M. Drerup, and J. Wyman. 1995. Effect of propylene glycol 1,2- dinitrate on cerebral blood flow in rats: A potential biomarker for vascular head- ache? Toxicol. Lett. 75(1-3):59-68. Helmkamp, J.C., S.A. Forman, M.S. McNally, and C.M. Bone. 1984. Morbidity and Mortality Associated with Exposure to Otto Fuel II in the U.S. Navy 1966–1979. AD-A148 726. Report No. 84-35. Naval Health Research Center, San Diego, CA. Horvath, E.P., R.A. Ilka, J. Boyd, and T. Markham. 1981. Evaluation of the neurophysi- ologic effects of 1,2-propylene glycol dinitrate by quantitative ataxia and oculomo- tor function tests. Am. J. Ind. Med. 2(4):365-378. HSDB (Hazardous Substances Data Bank). 2005. 1, 2-Propanediol Dinitrate (CASRN: 6423-43-4). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/ [accessed Apr. 14, 2009]. Jones, R.A., J.A. Strickland, and J. Siegel. 1972. Toxicity of propylene glycol 1,2- dinitrate in experimental animals. Toxicol. Appl. Pharmacol. 22(1):128-137.

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159 Propylene Glycol Dinitrate Kennedy, S.K., and D.E. Longnecker. 1996. History and principles of anesthesiology. P. 302 in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th Ed., J.G. Hardman et al., eds. New York: McGraw-Hill. Kylin, B., A. Englund, H. Ehrner-Samuel, and S. Yllner. 1966. A comparative study on the toxicology of nitroglycerine, nitroglycol and propylene glycol dinitrate. Pp. 191-195 in Proceedings of the 15th International Congress on Occupational Health, September 19–24, 1966, Vienna, Austria, Vol. 3. Hygiene, Toxicology, Occupational Disease. Vienna: Verlag der Wiener Medizinischen Akademie. Litton Bionetics, Inc. 1979. Mutagenicity Evaluation of Otto Fuel Number 2 in the Ames Salmonella/Microsome Plate Test. Segment report. ADA112227. Prepared by Lit- ton Bionetics, Inc., Kensington, MD, to U.S. Department of the Navy, Office of Naval Research, Arlington, VA. Marshall, B.E., and D.E. Longnecker. 1996. General anesthetics. P. 307 in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th Ed., J.G. Hardman et al., eds. New York: McGraw-Hill. Mattsson, J.L., R.W. Young, C.R. Curran, C.G. Franz, M.J. Cowan, Jr., and L.J. Jenkins, Jr. 1981. Acute and chronic propylene glycol dinitrate exposure in the monkey. Aviat. Space Environ. Med. 52(6):340-345. Nickerson, M. 1975. Vasodilator drugs. Pp. 727-743 in The Pharmacological Basis of Therapeutics, 5th Ed., L. Goodman, and A. Gilman, eds. New York: MacMillan. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH). No. 2005-149. National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/npg/ [accessed Jan. 27, 2009]. NRC (National Research Council). 1982. Evaluation of the Health Risks of Ordnance Disposal Waste in Drinking Water. Washington, DC: National Academy Press. NRC (National Research Council). 2002. Propylene glycol dinitrate. Pp. 71-119 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: The National Academies Press. NSWC (Naval Surface Warfare Center). 1995. Otto Fuel II – 1356-00-842-0630. Mate- rial Safety Data Sheet (MSDS) [online]. Available: http://hazard.com/msds/f2/cfs/ cfsyc.html [accessed April 14, 2009]. Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151. 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(3): 377-395. Wyman, J.F., B.H. Gray, L.H. Lee, J. Coleman, C. Flemming, and D.E. Uddin. 1985. Interspecies variability in propylene glycol dinitrate-induced methemoglobin for- mation. Toxicol. Appl. Pharmacol. 81(2):203-212.