Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 17 (2014) / Chapter Skim
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1 Acrylonitrile Acute Exposure Guideline Levels
1 Acrylonitrile Acute Exposure Guideline Levels
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From page 13... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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From page 14... ...
Lethality following acute inhalation exposure to acrylonitrile has been reported, but exposures were not defined. Acute exposure data are available for several laboratory species (monkey, rat, dog, rabbit, guinea pig, and cat)
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Developmental toxicity studies conducted in rats found nonlethal effects on fetal development that included decrements in fetal body weight without fetal malformations (25-100 ppm) (Saillenfait et al.
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The AEGL-2 values for acrylonitrile are based a developmental toxicity study conducted in rats, which showed that 12 ppm (6 h/day, gestation days 620) was a no-effect level for fetal toxicity, indicated by decrements in fetal body weight at higher concentrations (25-100 ppm)
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. Time scaling from the 6-h experimental point-of-departure to AEGLspecific exposure durations was performed using the equation Cn × t = k, where n = 1.1 (ten Berge et al.
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mg/m3) (ocular irritation)
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Loss of consciousness, convulsions, and respiratory arrest have been reported as outcomes of severe acute inhalation exposure to acrylonitrile (Buchter and Peter 1984)
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complained of headache, fatigue, nausea, and insomnia. There was a positive correlation with exposure duration but not with the exposure concentration or age of workers.
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. Ocular irritation was a primary effect in a 24-year old man whose face, eyes, and body were sprayed by acrylonitrile (no concentration data)
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Dong and Pan (1995) reported statistically significantly increased incidences of adverse reproductive outcomes in acrylic fiber workers exposed to an average acrylonitrile concentration of 3.7 ppm for 3.2-10.2 years when compared with unexposed controls.
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. The mutagenic potential of both acrylonitrile and its metabolite 2cyanoethylene oxide (CEO)
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They also reported lower sperm counts in the exposed versus nonexposed subjects. The workers were employed by a recently opened plant (2.8 years exposure duration for all workers)
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A control group consisted of 20 unexposed workers in administration jobs. No acrylonitrile exposure concentration or exposure duration terms were provided.
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From page 26... ...
A level of distinct odor awareness of 145 ppm was calculated for acrylonitrile. Nonlethal effects of occupational exposure to acrylonitrile include headache, nasal and ocular irritation, thoracic discomfort, nervousness, and irritability, but definitive exposure-response data are lacking.
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Exposure at 100 ppm produced only salivation and slight transient effects (redness of the skin and mucosae) while exposure at 275 ppm resulted in more severe effects (marked salivation, signs of pain)
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TABLE 1-3 Toxicity of Acrylonitrile Vapor in Dogs Exposed for 4 Hours 28 Concentration (ppm) Gender Effects 30 Female Slight salivation by end of exposure period; no other effects.
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From page 29... ...
(1981a) provided lethality data for groups of three to six male Wistar rats exposed to acrylonitrile for 30-180 min at exposure concentration varying with exposure duration (see Table 1-6)
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TABLE 1-5 Toxicity of Acrylonitrile Vapor in Rats Exposed for 4 Hours Mortality During Concentration (ppm) Exposure (%)
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1981a. A GLP-OECD guideline study sponsored by the Shanghai SECCO Petrochemical Company, Ltd., examined the acute toxicity of acrylonitrile in rats (WIL Research Laboratories 2005)
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Source: Adapted from WIL Research Laboratories 2005. TABLE 1-8 Toxicity of Acrylonitrile Vapor in Guinea Pigs Exposed for 4 Hours Exposure Mortality (%)
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. The rabbits survived for the full exposure duration, but were drowsy and listless during exposure and gained no weight gain.
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(1992) demonstrated fibrin-network formation in the lungs of six male Wistar rats exposed to acrylonitrile at 100 ppm for 5 h/day for 5 days and observed for 28 days.
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Mean body weight and maternal body weight gain was significantly decreased during treatment in both dose groups. Relative to controls, food consumption was decreased during gestation days 15-17 but increased on days 18-20.
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The no-observed-adverseeffect level (NOAEL) for maternal and developmental toxicity was 12 ppm on the basis of fetal body weight.
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(%) 1.05 0.96 1.23 1.10 0.96 Fetal body weight Male 5.95 ± 0.28 5.79 ± 0.28 5.64 ± 0.36b 5.54 ± 0.24b 5.04 ± 0.36b Female 5.66 ± 0.36 5.51 ± 0.27 5.37 ± 0.28c 5.18 ± 0.25b 4.90 ± 0.49b a Mean ± standard deviation.
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. In in vitro assays with mammalian cells, acrylonitrile induced DNA strand breaks, gene mutations, sister-chromatid exchange and chromosomal aberrations; a positive genotoxic response was not obtained for aneuploidy or unscheduled DNA synthesis in rat hepatocytes.
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In conclusion, results of in vitro and in vivo studies provide evidence that acrylonitrile is genotoxic. In in vitro models, acrylonitrile induced DNA strand breaks, sister-chromatid exchanges, chromosomal aberrations, and cell transformations.
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Clinical observations were made of body weight, mortality, clinical appearance, onset of tumors, and frequency of observed palpable tumors. All rats, regardless of time of death, were subjected to gross pathology examinations.
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. Lethality data for various exposure durations and concentrations suggest a near linear relationship (Cn × t = k, where n = 1.1)
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. Approximately 91.5% retention was reported in rats exposed at 1,800 ppm (3,900 mg/m3)
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. Generally, the toxic effects following acute inhalation exposure to acrylonitrile appear to be irritation of the respiratory tract and the metabolism of acrylonitrile to cyanide.
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4.4. Species Variability The effects of acute inhalation exposure to acrylonitrile are qualitatively similar among several animal species (monkey, dog, cat, rat, rabbit, and guinea pig)
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DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 Occupational exposure to acrylonitrile at 16-100 ppm for 20-45 min produced headache, nasal and ocular irritation, discomfort of the chest, nervous
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(1978) , in which workers routinely exposed to acrylonitrile at approximately 5 ppm experienced mild effects (initial conjunctival irritation, for which there was some accommodation)
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From page 47... ...
Typically, in the absence of this information, AEGL-1 values based on an 8-h point-of-departure would be time scaled. However, in this case, the effect is ocular irritation, which would not be expected to have a response threshold that varies with exposure duration.
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. A developmental toxicity study conducted in rats found dose-related decrements in fetal body weight that became statistically significant at 25 ppm (6 h/day, gestation days 6-20)
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(2010) used data on in vitro metabolism of acrylonitrile in rat and human liver microsomes to estimate hepatic clearance of cyanoethylene oxide.
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From page 50... ...
. Developmental toxicity studies conducted in rats found nonlethal effects on fetal development that included decrements in fetal body weight without fetal malformations (25-100 ppm)
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From page 51... ...
(2010) used data on in vitro metabolism of acrylonitrile in rat and human liver microsomes to estimate hepatic clearance of cyanoethylene oxide in rats and humans.
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From page 52... ...
The AEGL-2 values are based on a no-effect level for fetal toxicity (decreased fetal body weight) in rats exposed to acrylonitrile at 12 ppm for 6 h/day on gestation days 6-20 (Saillenfait et al.
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Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effect. TABLE 1-18 Standards and Guidelines for Acrylonitrile Exposure Duration Guideline 1 min 30 min 1h 4h 8h AEGL-1 1.5 ppm 1.5 ppm NRa NRa NRa (3.3 mg/m3)
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American Con ference of Governmental Industrial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association)
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2000. Study on the effects of occupational exposure to acrylonitrile in workers.
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I Study of the acute toxicity.
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1968. Acute Inhalation Toxicity in Rats with Acrylonitrile (Inhibit ed)
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2008. Two-generation reproductive toxicity study of inhaled acrylonitrile vapors in Crl:CD(SD)
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1990. Molecular analysis of hprt mutants induced by 2-cyanoethylene oxide in human lymphoblastoid cells.
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2005. Acute Inhalation Toxicity Study of Acrylonitrile in Albino Rats.
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leading to an odor intensity (I) of distinct odor detection (I = 3)
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for at least 10 years, 25 cases of cancer, including eight cases of respiratory cancer, were reported. A positive trend was observed for increased cancer incidence with increased exposure duration and increased duration of followup time.
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Estimated cancer risks for the AEGL-2 and AEGL-3 values are also provided, obtained by assuming a linear relationship between exposure concentration and cancer risk. TABLE B-2 Comparison of AEGL Values and Potential Cancer Riska Associated with Acute Inhalation Exposure to Acrylonitrile Exposure Duration Value 10 min 30 min 1h 4h 8h 24 h Cancer Risk (10-4)
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. The unit risk based on the LEC10 corresponds to a lifetime 1 × 10-4 risk specific exposure concentration of 9 µg/m3 (4.1 × 103 ppm)
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From page 66... ...
Estimated cancer risks for the AEGL-2 and AEGL-3 values are also provided, obtained by assuming a linear relationship between exposure concentration and cancer risk. TABLE B-4 Comparison of AEGL-values and Potential Cancer Risk Associateda with Acute Inhalation Exposure to Acrylonitrile Exposure Duration Value 10-min 30-min 1-h 4-h 8-h 24-h Cancer Risk (10-4)
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From page 67... ...
However, in this case, the effect is ocular irritation, which would not be expected to have a response threshold that varies with exposure duration. Therefore, it is prudent to not time scale and the AEGL-1 values were held constant at 1.5 ppm for the 10-min and 30-min values.
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From page 68... ...
:365-375. Critical effect: No-effect level for fetal toxicity (no decrease fetal body weight and no effects on development or reproduction end points)
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From page 69... ...
(2010) used data on in vitro metabolism of acrylonitrile in rat and human liver microsomes to estimate hepatic clearance of cyanoethylene oxide.
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From page 70... ...
for rats exposed at various concentrations of acrylonitrile for 30 min, 1, 2, 4, or 8 h. With the exception of the 4-h value, the resulting BMCL05 values show a consistent duration dependent relationship; therefore, the 30-min, 1-h, and 8-h estimates were used to derive corresponding AEGL-3 values.
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From page 71... ...
(2010) used data on in vitro metabolism of acrylonitrile in rat and human liver microsomes to estimate hepatic clearance of cyanoethylene oxide in rats and humans.
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From page 72... ...
72 Acute Exposure Guideline Levels 30-min AEGL-3: 30-min BMCL05 = 1,784 ppm 1,784 ppm ÷ 36 = 49.6 ppm (rounded to 50 ppm) 1-h AEGL-3: 1-h BMCL05 = 1,024.42 ppm 1,024.42 ppm ÷ 36 = 28.46 ppm (rounded to 28 ppm)
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. This concept states that exposure concentration and exposure duration may be reciprocally adjusted to maintain a cumulative exposure constant (k)
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From page 74... ...
However, in this case, the effect is ocular irritation, which would not be expected to have a response threshold that varies with exposure duration. Therefore, it is prudent to not time scale and the AEGL-1 values were held constant at 1.5 ppm for exposure durations of 10 and 30 min.
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From page 75... ...
Effects: Dose-related decrease in fetal body weight at 25-100 ppm. End point/Concentration/Rationale: No decrease in fetal body weight or other developmental or reproductive effect in rats at 12 ppm, 6 h/day.
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From page 76... ...
for rats exposed at various concentrations of acrylonitrile for 30 min, 1, 2, 4, or 8 h. With the exception of the 4-h value, the resulting BMCL05 values show a consistent durationdependent relationship; therefore, the 30-min, 1-h, and 8-h estimates were used to derive corresponding AEGL-3 values.
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From page 77... ...
Acrylonitrile 77 Data adequacy: Although definitive exposure-response data for lethality in humans are not available, data are available from acute and subchronic bioassays in multiple species. The animal data are sufficient for development of scientifically justified AEGL values.
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From page 78... ...
is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 3 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -30.2755 Slope = 3.91797 Asymptotic Correlation Matrix of Parameter Estimates (*
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From page 79... ...
P-value Full model -1.90954 3 Fitted model -1.99323 1 0.167371 2 0.9197 Reduced mode -8.15032 1 12.4816 2 0.001948 AIC: 5.98646 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 1,600.0000 0.0000 0.000 0 3 -0.000 2,600.0000 0.3729 1.119 1 3 -0.142 3,000.0000 0.9878 5.927 6 6 0.272 Chi-square = 0.09 d.f. = 2 P-value = 0.9541 Benchmark dose computation Specified effect = 0.05 Risk type = Extra risk Confidence level = 0.95 BMC = 2,416.07 BMCL = 1,784.1 Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 500 1000 1500 2000 2500 3000 dose 10:14 07/11 2007 FIGURE F-1 Probit model with 0.95 confidence level.
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From page 80... ...
is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 4 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -16.2084 Slope = 2.13067 Asymptotic Correlation Matrix of Parameter Estimates (*
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From page 81... ...
P-value Full model -16.7186 Fitted model -18.0178 2.5984 2 0.2728 Reduced mode -37.047 40.6567 3 <0.0001 AIC: 40.0356 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 665.0000 0.0000 0.000 0 16 -0.01652 1,270.0000 0.0544 0.870 0 16 -0.9591 1,490.0000 0.1644 2.630 4 16 0.9241 2,445.0000 0.8335 13.336 13 16 -0.2251 Chi-square = 1.82 d.f. = 2 P-value = 0.4015 Benchmark dose computation Specified effect = 0.05 Risk type = extra risk Confidence level = 0.95 BMC = 256.83 BMCL = 1,024.42 1 Probit BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 500 1000 1500 2000 2500 dose 10:17 07/11 2007 FIGURE F-2 Probit model with 0.95 confidence level.
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From page 82... ...
is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 3 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -17.8516 Slope = 2.70268 Asymptotic Correlation Matrix of Parameter Estimates (*
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From page 83... ...
P-value Full model -3.74067 Fitted model -3.74067 5.37593e-008 1 0.9998 Reduced mode -31.199 54.9175 2 <.0001 AIC: 11.4813 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 305.0000 0.0000 0.000 0 16 -4.972e-008 595.0000 0.0625 1.000 1 16 -3.32e-005 1260.0000 1.0000 16.000 16 16 0.0001623 Chi-square = 0.00 d.f. = 1 P-value = 0.9999 Benchmark dose computation Specified effect = 0.05 Risk type = extra risk Confidence level = 0.95 BMC = 588.401 BMCL = 491.304 Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 200 400 600 800 1000 1200 dose 10:21 07/11 2007 FIGURE F-3 Probit model with 0.95 confidence level.
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From page 84... ...
is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 3 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -13.5273 Slope = 2.34824 Asymptotic Correlation Matrix of Parameter Estimates: (*
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From page 85... ...
P-value Full model -9.93738 Fitted model -9.93738 2.60525e-007 1 0.9996 Reduced mode -32.8951 45.9154 2 <0.0001 AIC: 23.8748 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 130.0000 0.0000 0.000 0 16 -3.783e-008 315.0000 0.3125 5.000 5 16 -3.304e-006 635.0000 1.0000 16.000 16 16 0.0003609 Chi-square =0.00 d.f. = 1 P-value = 0.9997 Benchmark dose computation Specified effect = 0.05 Risk type = extra risk Confidence level = 0.95 BMC = 276.026 BMCL = 179.532 Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 100 200 300 400 500 600 dose 10:26 07/11 2007 FIGURE F-4 Probit model with 0.95 confidence level.
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From page 86... ...
is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 5 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -13 Slope = 2.37276 Asymptotic Correlation Matrix of Parameter Estimates (*
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From page 87... ...
P-value Full model -18.4464 Fitted model -18.9141 0.935409 3 0.8169 Reduced mode -47.991 59.091 4 <0.0001 AIC: 41.8281 Goodness of Fit Scaled Dose Estimated Probability Expected Observed Size Residual 90.0000 0.0000 0.000 0 16 -1.822e-007 135.0000 0.0000 0.000 0 16 -0.002528 210.0000 0.0392 0.628 1 16 0.479 270.0000 0.5188 8.300 7 16 -0.6506 320.0000 0.8977 14.363 15 16 0.5257 Chi-square = 0.93 d.f. = 3 P-value = 0.8184 Benchmark dose computation Specified effect = 0.05 Risk type = extra risk Confidence level = 0.95 BMC = 213.376 BMCL = 185.797 Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 50 100 150 200 250 300 dose 10:06 07/11 2007 FIGURE F-5 Probit model with 0.95 confidence level.
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From page 88... ...
* These values are 95% confidence limits Total animals = 64 Total doses = 4 Animals/dose = 16.00 Chi-square = total chi-square × animals/dose = 0.7986 Table value for Chi-square with 2 Degrees of Freedom = 5.9900 LC84 = 2502.530 LC16 = 1397.574 FED = 1.15 FS = 1.10 A = 1.07 99.99+ | 99.94+ | 99.60+ | 97.56+ | PERCENT 86.35+ EFFECT | *
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From page 89... ...
Acrylonitrile 89 Expected Lethal Dose Values LC0.1 555.726 LC1.0 834.159 LC5.0 1,114.816 LC10 1,271.215 LC25 1,541.871 LC50 1,870.153 LC75 2,268.330 LC90 2,751.283 LC99 4,192.812
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From page 90... ...
90 Accute Exposure Guideline Levels AP PPENDIX H CATE EGORY PLO OT FOR ACRY YLONITRILE E FIGUR RE H-1 Category y plot of toxicity y data and AEGL L values for acryylonitrile.
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From page 91... ...
1981a Rat m 1 2400 10 2 No mortality. Dudley and Neal 1942 Rat 1 665 30 1 Moderate transitory effects.
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From page 92... ...
Dudley and Neal 1942 Rat 1 305 120 2 Slight transitory effects. Dudley and Neal 1942 Rat 1 595 120 SL 6% mortality; marked transitory effects.
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From page 93... ...
. Dudley and Neal 1942 Guinea Pig 1 265 240 1 Slight transitory effect; reduced feed consumption for 4 d.
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From page 94... ...
Dudley and Neal 1942 Rat 1 135 480 1 Moderate transitory effects. Dudley and Neal 1942 Rat 1 210 480 SL 6% mortality; marked transitory effects.
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From page 95... ...
1993a Rat f 15 25 6 2 Fetal toxicity (fetal body weight)
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