Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 2 (2002) / Chapter Skim
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Appendix 2: Propylene Glycol Dinitrate
Appendix 2: Propylene Glycol Dinitrate
Pages 71-119
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From page 71... ...
Both the document and the AEGL values were then reviewed by the National Research Council ~C) Subcommittee on Acute Exposure Guideline Levels.
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From page 72... ...
Examination of the relationship between exposure duration and concentration for both mild and severe headaches in humans over periods of ~ to ~ h determined that the relationship is Cat x t = k. The AEGL-l 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.
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From page 73... ...
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 S-h time periods using the Cat x t = k relationship, as was done for the AEGL-l 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.
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From page 74... ...
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.
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From page 75... ...
Chemical and physical data for PGDN are listed in Table 2-2. At Tow 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.
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From page 76... ...
Gaworski et al. 1985 Conversion factors 1 ppm= 7.14 mg~m3 ATSDR 1995 1 mg/m3 = 0.14 ppm Data are for propylene glycol dinitrate (PGDN)
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From page 77... ...
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)
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From page 78... ...
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 < 0.051.
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From page 79... ...
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.
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From page 81... ...
At 0.35 ppm, all three subjects exposed for 2 h developed mild headaches, and one of three subjects exposed for ~ h developed a mild headache. Two of three subjects exposed for ~ h developed severe headaches.
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From page 82... ...
1987~. Human volunteers exposed to PGDN at various concentrations of also exhibited central nervous system effects (Stewart et al.
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From page 83... ...
2.7. Summary No deaths attributable to exposure to Otto Fuel ~ or its primary component, PGDN, were reported in the available literature, but relative risk for combined myocardial infarction and angina pectoris among torpedomen chronically exposed at unknown concentrations of Otto Fuel n and PGDN were significantly elevated compared with control groups (Forman et al.
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From page 84... ...
ANIMAL TOXICITY DATA 3.~. Acute Lethality No acute studies involving lethality and the exposure durations relevant to AEGL derivations were located.
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From page 85... ...
3.2.~. Nonhuman Primates In a range-f~nding study prior to a continuous inhalation study, squirrel monkeys (number not specified)
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From page 86... ...
Heavy iron-positive deposits consistent with mononuclear cell infiltrates and focal necrosis were present in the liver, spleen, and kidney sections of monkeys exposed at 33 ppm. Monkeys exposed at ~5 and 33 ppm also had elevated serum urea nitrogen levels and decreased serum alkaline phosphatase activity.
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From page 87... ...
Fatty deposits were observed in the livers of guinea pigs exposed at ~ 0 ppm. Guinea pigs exposed at ~ 5 ppm consistently showed foci of pulmonary hemorrhage, and vacuolar changes occurred in the liver of all guinea pigs exposed at 33 ppm.
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From page 88... ...
Daily testing involving either the cued or free operant avoidance tests showed no effects on either type of avoidance performance, and there was no disruption of the ability to discriminate between the two avoidance schedules. Three male squirrel monkeys previously trained to perform visual discrimination or visual acuity threshold tests were exposed continuously for 90 ~ to PGDN at a concentration of 262 mg/m3 (approximately 37 ppm)
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From page 89... ...
Otto Fuel ~ was not mutagenic in microbial assays involving five strains of Salmonella typhimurium or in Saccharomyces cerevisiae D4, with or without exogenous metabolic activation. The test compound was active in inducing mutations at the TK locus in L5 ~ 7SY mouse lymphoma celIs at concentrations that were clearly cytotoxic.
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From page 90... ...
. Chromosomal aberrations were not elevated compared with the control values, but the presence of ring chromosomes suggested weak activity.
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From page 91... ...
Squirrel monkeys exposed to PGDN at concentrations of 70-100 ppm for 6 h exhibited vomiting, pallor, cold extremities, semiconsciousness, and clonic convulsions. Rats exposed at 189 ppm for 4 h exhibited no overt signs of intoxication, although the mean methemogiobin level was increased to 23 .5% (Iones et al.
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From page 92... ...
About 10% oftopically applied PGDN is absorbed through the intact skin of rats, as indicated by blood pressure changes relative to subcutaneous injections (Clark and Litchfield ~ 969~. Plasma levels of PGDN of rhesus monkeys could not be detected during inhalation exposures at concentrations <0.8 ppm (Mattsson et al.
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From page 93... ...
The most commonly encountered symptom of exposure to PGDN is headache due to vasodilation of cerebral blood vessels. Nitrate and nitrite esters are vasodilators, resulting in rapid lowering of systolic and, to a lesser extent, diastolic blood pressure with a compensatory tachycardia.
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From page 94... ...
Acute exposures result in a depression of both the systolic and diastolic brood pressure. Continued exposure to Tow concentrations of nitrate esters produces a progressive rise in the diastolic blood pressure from the previously depressed level without a comparable rise in the systolic blood pressure.
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From page 95... ...
The difference in susceptibility of individuals to central nervous system depressants such as volatile anesthetics varies by no more than 2-fold as indicated by the minimum alveolar concentration (MAC) , the concentration that produces immobility in 50°/0 of patients (Kennedy and Longnecker 1996; Marshall and Longnecker 1996~.
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From page 96... ...
Older persons with arteriosclerosis or cardiac disease may have a limited ability to constrict blood vessels or to increase cardiac output in response to the vasodilatation action of PGDN and, therefore, may have a greater degree of hypotension than other individuals (ATSDR 1995~. Compensatory vasospasm following withdrawal from nitrate ester exposure has been described in chronic exposures but not following an acute exposure.
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From page 97... ...
(1974) 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.
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From page 98... ...
Occupational exposures and the study with human volunteers indicate that exposures at Tow concentrations cause headaches and signs of central nervous system depression. No headaches were reported and no equilibrium disturbances were measured during occupational exposures of healthy workers to Otto Fuel ~ (measured as PGDN)
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From page 99... ...
developed headaches during an 8-h exposure at 0.03 ppm. The highest concentrations and exposure durations that did not result in headache and the lowest concentrations and exposure durations that resulted in mild headaches are as follows: No headache 0.03 ppm for ~ h O.lppmfor34h 0.2 ppm for ~ h 0.35 ppm for T h Mild headaches 0.1 ppm after 6 h 0.2 ppm (0.21-0.26)
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From page 100... ...
DATA ANALYSIS FOR AEGL-2 6.~. Summary of Human Data Relevant to AEGL-2 Occupational and controlled human volunteer studies indicate that exposures at low concentrations of PGDN cause headaches and central nervous system depression.
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From page 101... ...
6.2. Summary of Animal Data Relevant to AEGL-2 Few data on acute exposures with effects that meet the definition of an AEGL-2 were located.
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From page 102... ...
and k = ~ ppm h. Because ofthe long exposure duration ofthe key study, the 10-min value was set equal to the 30-min value.
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From page 103... ...
For extreme central nervous system depression leading to convulsions, an intraspecies OF of 3 was considered sufficient (concentrations of anesthetics causing narcosis in infants and adults generally do not differ by more than a factor of 2 [Kennedy and Longnecker 1996; Marshall and Longnecker 19963~. The intraspecies OF of 3 is supported by the steep dose-response curve for the induction of headaches; namely, a 2-fold difference in the threshold concentration of PGDN and the concentration that induces headache in the majority of healthy individuals (Stewart et al.
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From page 104... ...
(1974) in which volunteers exposed at 0.5 ppm for 6 to ~ h showed a marked impairment of their performance on simple behavioral tests, and volunteers exposed at 0.2 ppm or greater showed a disruption of the visual evoked response and headache.
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From page 105... ...
In addition, supporting data were available. Occupational data were available to support the margin of safety associated withthe AEGL-~ values; developmental toxicity data were available from both occupational exposures and experimental animal studies; specific neurotoxicity tests were performed with both human and animal subjects; and a battery of genotoxicity and chronic toxicity bioassays were reported.
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From page 106... ...
1981. Evaluation of the neurophysiologic effects of 1,2-propylene glycol dinitrate by quantitative ataxia and oculomotor function tests.
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From page 107... ...
1981. Acute and chronic propylene glycol dinitrate exposure in the monkey.
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1985. Interspecies variability in propylene glycol dinitrate-induced methemoglobin connation.
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Appendixes
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From page 110... ...
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 x t = k 30-min and I-h AEGL-~: (0.5 ppm/3)
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From page 111... ...
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)
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From page 112... ...
in mon keys exposed at 70-100 ppm for 6 h; no effects in rats exposed at ~ 89 ppm for 4 h Scaling: Default values of n = 3 for shorter exposure dura tions and n = ~ 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 con centrations; the monkey is a good model for the hu man.
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From page 113... ...
PRoPy~NE GO DO 1 13 70-~ -: 30-~ -: 7-A -: 4-4 -: 6-6 ~-3: ~0 ~1~ x 6 h = . equal to Me SO-min value x t = k Cal x Ah =~58ppmh C = ~ ppm x t = k C3 x l h=~5Sppmh C= 13 ppm x 1=k Cal x Ah =~,OSSppm~ C=8 C x t = k C x ~ h = ~ ah C=
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From page 114... ...
That study showed that ingestion of 6.4 mg/d of nitratenitrogen did not cause an increase in the circulating methemogiobin in infants. The NOEL of 6.4 mg/d for methemogiobin formation in infants is higher than the amount of nitrogen released from PGDN even assuming complete systemic bioavailability upon inhalation and complete in viva conversion of PGDN to NO3- during exposure to the 8-h AEGL-3.
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From page 115... ...
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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From page 116... ...
. 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)
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From page 117... ...
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 (Contirlued)
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From page 118... ...
. The concentration x time product is approximately 0.5 for mild headaches and approximately 1.6 for severe headaches.
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From page 119... ...
Because of the long exposure duration of the key study, the 1 0-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.
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