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4 Oxygen Difluoride
Pages 122-160

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From page 122...
... Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
From page 123...
... Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Oxygen difluoride is an irritating, colorless gas that has been used as an oxidizing propellant for missiles (Darmer et al.
From page 124...
... , so a factor of 3 was applied to account for species differences. Although asthmatics and individuals with compromised pulmonary function may be considered to be more susceptible to the effects of oxygen difluoride vapor, necropsy findings in multiple animal species indicate that the primary target of oxygen difluoride toxicity is the lungs rather than the airways.
From page 125...
... mg/m3) rhesus monkeys (Davis 1970)
From page 126...
... noted that inhalation of oxygen difluoride produced effects similar to those caused by ozone. Respiratory tract irritation and pulmonary edema and hemorrhage were observed following exposure at 0.5 ppm for a few hours (duration was not further defined)
From page 127...
... Monkeys In a multispecies acute inhalation toxicity study, Davis (1970) exposed rhesus monkeys (two males and two females)
From page 128...
... were exposed to oxygen difluoride (>97% purity) at concentrations of 10, 20, 30, or 40 ppm for 5 min, or TABLE 4-3 Mortality in Rhesus Monkeys Exposed to Oxygen Difluoride Vapor No.
From page 129...
... . TABLE 4-5 Mortality in Rats Exposed to Oxygen Difluoride Exposure Duration (min)
From page 130...
... All rats exposed for 30 min survived exposure but showed signs of respiratory distress (details not reported) which resolved after 2 days.
From page 131...
... Comparing 1-h LC50 values reveals about a 17-fold difference between the least sensitive and most sensitive of the four species tested, with larger species appearing to be less sensitive. On the basis of experimental results from monkeys, dogs, rats, and mice, Davis (1970)
From page 132...
... This contention was based on examination of rats exposed to oxygen difluoride at 20 ppm for 5 min and then killed 0.09, 0.17, 0.58, 0.75, 1, 2, 3.5, 5, 6, 7, 14, 22.5, and 29 h after exposure. Microscopic findings in pulmonary tissue were characterized as slight congestion, focal atelectasis, hemorrhage, polymorphonuclear leukocyte infiltration, edema, and acute pneumonia.
From page 133...
... to the nonlethal effects of oxygen difluoride. Pathologic examinations of animals exposed to oxygen difluoride confirm pulmonary involvement (congestion, edema, focal atelectasis, and hemorrhage)
From page 134...
... Gross and microscopic examinations of rats exposed to oxygen difluoride at 20 ppm for 5 min revealed pulmonary damage (swelling, acute pneumonia, consolidation of lung lobes, focal atelectasis, polymorphonuclear leukocyte infiltration, and pulmonary hemorrhage and edema) that progressed with time following cessation of exposure and which did not appear to affect bronchial regions.
From page 135...
... The very old and those who are ill may also have increased susceptibility to irritants such as oxygen difluoride. TABLE 4-9 Relative Lethality of Oxygen Difluoride to Other Fluorinated Compoundsa Species Oxygen Difluoride Chlorine Pentafluoride Chlorine Trifluoride Hydrogen Fluoride Rat 2.6/2.6 = 1 122/2.6 = 47 299/2.6 = 115 1,276/2.6 = 491 Mouse 1.5/1.5 = 1 57/1.5 = 38 178/1.5 = 119 501/1.5 = 334 Dog 26/26 = 1 122/26 = 5 – – Monkey 26/26 = 1 173/26 = 6.7 230/26 = 8.8 1,774/26 = 68 a 1-h LC50 values expressed in ppm (Davis 1970; Darmer et al.
From page 136...
... 5.2. Animal Data Relevant to AEGL-1 No data regarding AEGL-1 type effects in animals exposed to oxygen difluoride are available.
From page 137...
... . In rats exposed at 20 ppm for 5 min, gross and microscopic examinations showed significant pulmonary damage, including swelling, acute pneumonia, consolidation of lung lobes, focal atelectasis, polymorphonuclear leukocyte infiltration, and pulmonary hemorrhage and edema; however, the study report did not provide adequate information to determine the severity of pulmonary damage.
From page 138...
... 7.3. Derivation of AEGL-3 Values Lethality data from studies of rhesus monkeys exposed to oxygen difluoride (Davis 1970)
From page 139...
... Although asthmatics and individuals with compromised pulmonary function may be considered more susceptible to the effects of oxygen difluoride than healthy individuals, necropsy findings in multiple animal species indicate that the primary target of oxygen difluoride toxicity is the lungs rather than airways. For this reason an intraspecies uncertainty factor of 3 was considered sufficient to account for individual variability in the toxic response to inhaled oxygen difluoride.
From page 140...
... Absence of AEGL-1 values does not imply that exposures at concentrations below the AEGL-2 values are without adverse effects. TABLE 4-13 Other Standards and Guidelines for Oxygen Difluoride Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NR NR NR NR NR AEGL-2 0.43 ppm 0.16 ppm 0.083 ppm 0.024 ppm 0.013 ppm AEGL-3 1.3 ppm 0.47 ppm 0.25 ppm 0.071 ppm 0.038 ppm a IDLH (NIOSH)
From page 141...
... Lethal response data 14-days after exposure, hematologic and clinical chemistry measurements, and gross pathology findings were used to define critical effects. Although lethality data are available to derive AEGL-3 effects, a modifying factor was applied to account for a sparse database.
From page 142...
... 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
From page 143...
... . Therefore, in accordance with the standing operating procedures for deriving AEGL values (NRC 2001)
From page 144...
... That value is also consistent with the uncertainty factor used for other direct-acting fluorinated compounds (chlorine pentafluoride, chlorine trifluoride, and hydrogen fluoride, which all appear to cause tissue irritation by direct-contact mechanisms)
From page 145...
... Oxygen Difluoride 145 1-h AEGL-3: C1.1 × 1 h = 9.15 ppm-h C = 7.48 ppm 7.48 ppm ÷ 30 = 0.249 ppm (0.25 ppm)
From page 146...
... and that the cumulative exposure constant will always reflect a specific quantitative and qualitative response. The inverse relationship of concentration and time may be valid when the toxic response to a chemical is equally dependent on the concentration and the exposure duration.
From page 147...
... The n value of 1.1 was used for deriving the AEGL values for oxygen difluoride. LogProbit_Oxygen difluoride_rat AEGL Best Fit Concentration x Time Curve 1.4 1.2 Log Concentration 1 0.8 0.6 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Log Time LogProbit_Oxygen difluoride_rat AEGL Filename: Oxygen difluoride_rat AEGL for Log Probit Model Date: 09 February 2007 Time: 12:15:08 Seq.
From page 148...
... Seq. Nr Responded Conc ppm Minutes Exposed 1 10 5 10 0 2 20 5 10 7 3 30 5 10 9 4 40 5 10 10 5 5 15 10 0 6 10 15 10 7 7 15 15 10 7 8 10 15 10 0 9 10 15 10 1 10 11 15 10 3 11 12 15 10 1 12 14 15 10 9 13 15 15 10 8 14 17 15 10 9 15 2 60 10 0 16 3 60 10 7 17 3 60 15 14 18 4 60 10 10 Used Probit Equation Y = B0 + B1*
From page 149...
... = 0.817 Upper limit (95% CI) = 1.396 Filename: Oxygen difluoride_rat AEGL for Log Probit Model Date: 09 February 2007 Time: 12:41:36 Seq.
From page 150...
... . Therefore, in accordance with the standing operating procedures for deriving AEGL values (NRC 2001)
From page 151...
... Intraspecies: 3, consistent with the uncertainty factor application for other direct-acting fluorinated compounds (chlorine pentafluoride, chlorine trifluoride, and hydrogen fluoride, which all appear to cause tissue irritation by direct-contact mechanisms)
From page 152...
... , 1-h exposure BMCL05 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ Input Data File: C:\BMDS\UNSAVED1.(d) Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt Tue Jan 30 08:44:51 2007 BMDS MODEL RUN The form of the probability function is: P[response]
From page 153...
... Prob. Expected Observed Size Residual 0.0000 0.0000 0.000 0 4 0 16.0000 0.0269 0.108 0 4 -0.3327 21.0000 0.1903 0.761 1 4 0.3039 32.0000 0.7740 3.096 3 4 -0.1148 Chi-square = 0.22 DF = 2 P-value = 0.8975 Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMC = 17.216 BMCL = 7.48236 Probit Model with 0.95 Confidence Level Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 5 10 15 20 25 30 35 dose 10:37 02/05 2007 FIGURE D-1 Probit model BMCL05.
From page 154...
... , 1-h exposure BMC01 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ Input Data File: C:\BMDS\UNSAVED1.(d) Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt Wed Jan 31 10:38:01 2007 BMDS MODEL RUN The form of the probability function is: P[response]
From page 155...
... Prob. Expected Observed Size Residual 16.0000 0.0269 0.108 0 4 -0.3327 21.0000 0.1903 0.761 1 4 0.3039 32.0000 0.7740 3.096 3 4 -0.1148 Chi-square = 0.22 DF = 1 P-value = 0.6420 Benchmark Dose Computation Specified effect = 0.01 Risk Type = Extra risk Confidence level = 0.95 BMC = 14.4341 BMCL = 4.22764 Probit Model with 0.95 Confidence Level Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 5 10 15 20 25 30 35 dose 10:39 02/05 2007 FIGURE D-2 Probit model BMC01.
From page 156...
... 156 Acute Exposure Guideline Levels LC50 and Lethality Threshold - Litchfield-Wilcoxon Davis (1970) : Rhesus monkeys, 1-h exposure to oxygen difluoride Mortality Observed % Expected % Observed-Expected Chi-Square 16.000 0/4 0 (2.30)
From page 157...
... Oxygen n Difluoride 1157 AP PPENDIX E CATEG GORY PLOT FOR F OXYGEN N DIFLUORID DE FIGUR RE E-1 Category y plot of toxicity data and AEGL L values for oxyggen difluoride.
From page 158...
... 158 TABLE E-1 Data Used in Category Plot for Oxygen Difluoride Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 0.43 10 AEGL AEGL-2 0.16 30 AEGL AEGL-2 0.083 60 AEGL AEGL-2 0.024 240 AEGL AEGL-2 0.013 480 AEGL AEGL-3 1.3 10 AEGL AEGL-3 0.47 30 AEGL AEGL-3 0.25 60 AEGL AEGL-3 0.071 240 AEGL AEGL-3 0.038 480 AEGL Darmer et al.
From page 159...
... Davis 1970 Monkey B 1 100 15 SL Mortality: 2/4 Davis 1970 Monkey B 1 120 15 SL Mortality: 2/4 Davis 1970 Monkey B 1 140 15 3 Mortality: 4/4 Davis 1970 Monkey B 1 16 60 1 Mortality: 0/4 Davis 1970 Monkey B 1 21 60 SL Mortality: 1/4 Davis 1970 Monkey B 1 32 60 SL Mortality: 3/4 Davis 1970 Mouse M 1 7.5 15 SL LC50 Davis 1970 Mouse 7.5 15 SL LC50 Davis 1970 Mouse M 1 9.5 15 SL Mortality: 12/15 Davis 1970 Mouse M 1 11.0 15 SL Mortality: 8/15 Davis 1970 Mouse M 1 11.9 15 3 Mortality: 15/15 Davis 1970 Mouse M 1 15.2 15 SL Mortality: 12/15 Davis 1970 Mouse M 1 16.5 15 SL Mortality: 14/15 Davis 1970 Mouse M 1 1.0 60 SL Mortality: 5/15 Davis 1970 Mouse M 1 2.2 60 SL Mortality: 8/15 Davis 1970 Mouse M 1 2.2 60 SL Mortality: 8/15 Davis 1970 Mouse M 1 4.2 60 3 Mortality: 15/15 Davis 1970 Rat M 1 9.5 15 1 Mortality: 0/10 Davis 1970 Rat M 1 10.4 15 SL Mortality: 1/10 Davis 1970 Rat M 1 11.0 15 SL Mortality: 3/10 Davis 1970 Rat M 1 11.9 15 SL Mortality: 1/10 Davis 1970 Rat M 1 12.7 15 SL LC50 Davis 1970 Rat M 1 13.8 15 SL Mortality: 9/10 Davis 1970 Rat M 1 15.2 15 SL Mortality: 8/10 159 (Continued)
From page 160...
... 160 TABLE E-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Davis 1970 Rat M 1 16.5 15 SL Mortality: 9/10 Davis 1970 Rat M 1 2.2 60 1 Mortality: 0/10 Davis 1970 Rat M 1 2.2 60 1 Mortality: 0/10 Davis 1970 Rat 2.6 60 SL LC50 Davis 1970 Rat M 1 2.7 60 SL Mortality: 7/10 Davis 1970 Rat M 1 3.0 60 SL Mortality: 14/15 Davis 1970 Rat M 1 4.0 60 3 Mortality: 10/10 Harrison and Mackenzie 1973 Rat M 1 4.5 30 1 Respiratory distress Harrison and Mackenzie 1973 Rat M 1 4.5 60 3 Mortality: 4/4 Harrison and Mackenzie 1973 Rat 4.5 60 3 100% mortality Lester and Adams 1965 Rat B 1 17.6 5 SL LC50 Lester and Adams 1965 Rat B 1 2.3 15 SL BMCL05 Lester and Adams 1965 Rat B 1 3.6 15 SL BMC01 Lester and Adams 1965 Rat B 1 8.0 15 SL LC50 Lester and Adams 1965 Rat B 1 9.7 15 SL Mortality: 7/10 Lester and Adams 1965 Rat B 1 14.6 15 SL Mortality: 7/10 Vernot et al.


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