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6
Tetranitromethane1
Acute Exposure Guideline Levels
SUMMARY
Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/ AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 min to 8 h. Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and
1
This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory) and National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member Kyle Blackman (Chemical Reviewer). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; NRC 2001).
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are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels 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 unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
EXECUTIVE SUMMARY
Tetranitromethane (TNM) is a highly explosive chemical used as an oxidizer in rocket propellants, to increase the cetane number of diesel fuels, and as a reagent to detect double bonds in organic molecules. TNM is formed as an impurity during the manufacture of trinitrotoluene (TNT). Inhaled TNM caused respiratory and ocular irritation in humans and animals, and lung tumors in rats and mice.
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AEGL-1 values were not developed due to insufficient data. No studies were located with end points clearly within the scope of AEGL-1.
AEGL-2 values were derived from a 4-h rat LC50 study (Kinkead et al. 1977), in which rats exposed to 10 ppm (lowest concentration tested) had mild lung congestion whereas 3/10 died with lung lesions at the next higher concentration tested of 15 ppm. Because 10 ppm is a lethality NOEL in this study and is near the point of departure for AEGL-3, a modifying factor of 3 was applied to 10 ppm obtain a concentration (3.3 ppm) that would cause only mild reversible lung irritation. Scaling across time was performed using the exponential equation Cn × t = k, which has been shown to describe the concentration-exposure time relationship for many irritant and systemically acting vapors and gases, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data were unavailable to derive n empirically for TNM, and n = 3 and n = 1 were used to extrapolate to <4 h and >4 h, respectively, except that the 30-min value was adopted as the 10-min value, to provide AEGL values protective of human health (NRC 2001). A total uncertainty factor of 10 was used: 3 for interspecies extrapolation because the key study tested the most sensitive species, and 3 to account for sensitive humans because mild reversible lung irritation from a gas with a steep dose-response is not likely to vary greatly among humans.
AEGL-3 values were derived from the same 4-h rat LC50 study as the AEGL-2 values (Kinkead et al. 1977). The point of departure for AEGL-3 was the calculated lethality BMDL05 of 11 ppm, which is consistent with the empirical lethality NOEL of 10 ppm in the key study and in a repeat-exposure study with rats and mice (6 h/day for 14 days; NTP 1990). Scaling across time was performed as for the AEGL-2, i.e., using Cn × t = k, where n = 3 or n = 1. A total uncertainty factor of 10 was applied: 3 for interspecies extrapolation (key study tested the most sensitive species), and 3 for human variability (NOEL for lethality from extreme lung irritation from a gas with a steep dose-response is not likely to vary greatly among humans).
A cancer inhalation slope factor was derived for TNM and used to estimate the 10-4 excess cancer risk from a single 30-min to 8-h exposure, as shown in Appendix B. TNM concentrations associated with a 10−4 excess cancer risk were 2.5 to 10-fold greater than the toxicity-based AEGL-2 values for 30 to 480 min. The noncarcinogenic end points were considered to be more appropriate for AEGL-2 derivation because (1) they appeared to be the more sensitive end points, (2) AEGL values are
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applicable to rare events or single, once-in-a-lifetime exposures, and the data indicate that TNM neoplasms resulted from chronic exposure, and (3) a direct comparison of estimated TNM cancer risk and AEGL values is not appropriate due to large differences in methodology used to obtain these numbers.
The calculated values are listed in the Table 6-1.
1.
INTRODUCTION
Tetranitromethane (TNM) is a highly explosive liquid not known to occur naturally. It is prepared by the nitration of acetic anhydride with anhydrous nitric acid (Budavari et al. 1996; IARC 1996). TNM is also formed as an impurity during the manufacture of TNT (trinitrotoluene) and up to 0.12% may be present in crude TNT (Sievers et al. 1947). TNM is used as an oxidizer in rocket propellants, to increase the cetane number of diesel fuels, as a reagent to detect double bonds in organic molecules, and for the nitration of tyrosine in proteins and peptides (Budavari et al. 1996; ACGIH 1996). HSDB (2005a) lists only one current U.S. producer of TNM, although the amount produced was not available. U.S. production of TNM was reported to be >1,000 pounds in 1977 (HSDB 2005a).
TABLE 6-1 Summary of AEGL Values for Tetranitromethane (TNM)
Level
10 min
30 min
1 h
4 h
8 h
End point (Reference)
AEGL-1a (Nondisabling)
Not recommended due to insufficient data.
AEGL-2 (Disabling)
0.66 ppm
(5.3 mg/m3)
0.66 ppm
(5.3 mg/m3)
0.52 ppm
(4.2 mg/m3)
0.33 ppm
(2.6 mg/m3)
0.17 ppm
(1.4 mg/m3)
Mild reversible lung irritation in rats (Kinkead et al. 1977).
AEGL-3 (Lethal)
2.2 ppm
(18 mg/m3)
2.2 ppm
(18 mg/m3)
1.7 ppm
(14 mg/m3)
1.1 ppm
(8.8 mg/m3)
0.55 ppm
(4.4 mg/m3)
NOEL for lethality in rats (Kinkead et al. 1977).
aA value for the human odor threshold was not located.
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In humans, exposure to impure TNM has been reported to cause irritation of the eyes, nose, throat, dizziness, chest pain, dyspnea, methemoglobinuria, and cyanosis (Budavari et al. 1996). In animals, TNM caused respiratory and eye irritation and lung vascular congestion, pulmonary edema, bronchopneumonia, and lung tumors in rats and mice (Kinkead et al. 1977; NTP 1990). The NTP (2002) Report on Carcinogens, Tenth Edition states that TNM is “reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals.” The ACGIH places TNM in carcinogenicity class A3, i.e. a “confirmed animal carcinogen with unknown relevance to humans” (ACGIH 2004). IARC considers TNM to be “possibly carcinogenic to humans” and places it in group 2B, based on sufficient evidence in experimental animals and inadequate evidence in humans (IARC 1996). A carcinogenicity risk assessment of TNM is currently (July 2005) not listed on the Environmental Protection Agency (EPA) online IRIS database. Chemical and physical properties of TNM are listed in Table 6-2.
TABLE 6-2 Physical and Chemical Data of TNM
Parameter
Value
Reference
Synonyms
TNM; NCI-C55947
HSDB 2005a
Chemical formula
C(NO2)4
Budavari et al. 1996
Molecular weight
196.03
Budavari et al. 1996
CAS Registry Number
509-14-8
Verschueren 1996
Physical state
Liquid
Budavari et al. 1996
Solubility in water
Insoluble (soluble in alcohol, ether)
Budavari et al. 1996
Vapor pressure
13 mm Hg at 25°C
Verschueren 1996
Vapor density (air = 1)
6.8; 0.8
Verschueren 1996; HSDB 2005a
Liquid density (water = 1)
1.65 at 13/4°C
Verschueren 1996
Melting point
13.8°C
Budavari et al. 1996
Boiling point
126°C at 760 mm
Budavari et al. 1996
Flammability/ explosive limits
Limits not found; combustible liquid, difficult to ignite
NIOSH 2005a
Conversion factors
1 mg/m3 = 0.125 ppm; 1 ppm = 8.02 mg/m3
ACGIH 1996
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2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
Koelsch (1917) described three cases of occupational exposure to high, undefined concentrations of TNM (fumes evolved during TNT production) in one plant; two of the exposures proved fatal. A man who had worked for 14 days with impure TNT containing TNM developed severe chest pains during the night, and the next day at work had respiratory distress, chest tightness, and foamy sputum. The following day he died of pulmonary edema and had methemoglobinemia. A second worker in the same plant developed marked respiratory tract irritation after 14 days of exposure and subsequently developed fatal pneumonia. In the third case, a female worker inhaled a large amount of TNM and ran out of the room, fell unconscious, and was revived several hours later after treatment with oxygen and skin stimulation. The next day, recovery was almost complete.
2.2.
Nonlethal Toxicity
Workers exposed to undefined concentrations of TNM that were emitted as fumes from crude TNT complained of nasal irritation, burning of the eyes, dyspnea, expectoration, coughing, chest tightness, and dizziness, with continued exposure leading to drowsiness, headache, anemia, marked cyanosis, respiratory distress, and bradycardia (Sievers et al. 1947).
A survey of workers exposed to unknown concentrations of TNM found it was irritating to the mucous tissue of the eyes, nose, and respiratory passages, but was seldom irritating to the skin (Hager 1949). Symptoms from acute exposure included salivation and upper respiratory passage irritation, whereas prolonged exposure resulted in headaches, weariness, sleepiness, slowed pulse, “formation of hemoglobin (not further details provided)”, disturbance of internal respiration, and effects (not specified) on the CNS and heart.
The AIHA (1964), in its recommendation for industrial hygiene practice, stated that “concentrations in excess of 1 ppm will cause lacrimation and upper respiratory irritation” and “concentrations as low as 0.4 ppm may cause mild irritation,” and cited Sievers et al (1947) as the
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source of this information. The data in Sievers (1947), however, were obtained with cats using impure TNM (see Section 3.1.3), and it is unclear whether humans would be similarly sensitive as cats.
2.2.1.
Odor Threshold/Odor Awareness
No data was found regarding the human odor threshold for TNM, or of concentrations that are detected by humans.
2.3.
Neurotoxicity
No human neurotoxicity studies were located with TNM exposure by any route.
2.4.
Developmental/Reproductive Toxicity
No human genotoxicity data were located.
2.5.
Genotoxicity
No human genotoxicity data were located.
2.6.
Carcinogenicity
No human carcinogenicity data were located.
2.7.
Summary
No quantitative human TNM inhalation exposure studies, including an odor threshold, were located. Based on animal studies using impure TNM, the AIHA (1964) stated that “concentrations in excess of 1 ppm will cause lacrimation and upper respiratory irritation” and “concentrations as low as 0.4 ppm may cause mild irritation.” Symptoms experi-
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enced by workers exposed to unknown concentrations of impure TNM (emitted during TNT production) included irritation to the mucous tissue of the eyes, nose, and respiratory passages, dyspnea, expectoration, coughing, chest tightness, and dizziness (Sievers et al. 1947; Hager 1949). Continued exposure led to drowsiness, headache, anemia, marked cyanosis, respiratory distress, and bradycardia. Two workers exposed for several weeks to a high, undefined concentration of impure TNM had respiratory irritation and distress, chest tightness, foamy sputum, and methemoglobinemia, and shortly thereafter died of pneumonia or pulmonary edema (Koelsch 1917). It is unclear whether TNM inhalation caused methemoglobinemia since exposure was to impure TNM containing TNT; the latter has been reported to cause similar effects in humans (fatigue, weakness, eye irritation, anorexia, nausea, methemoglobinemia) (HSDB 2005b). Kinkead et al. (1977) showed that oral, but not intravenous, administration of TNM caused methemoglobinemia in rats and mice, indicating that metabolism of TNM to nitrite ion by intestinal bacteria was necessary for methemoglobin formation.
No human developmental or reproductive studies, genotoxicity data, or oncogenicity data were located with TNM exposure by any route.
3.
ANIMAL TOXICITY DATA
3.1.
Acute Lethality
3.1.1.
Rats
Fischer 344/N rats (5/sex/dose) were exposed (whole body) 6 h/day for 2 weeks (5 days/week) to 2, 5, 10, or 25 ppm TNM in a study conducted by the National Toxicology Program (NTP 1990). TNM vapor was generated from a gas dispersion bottle by bubbling nitrogen through liquid TNM. TNM concentration in the exposure chambers was monitored every 10-15 min with a Miran Infrared Gas Analyzer. All animals were observed, weighed, and necropsied. The lung, heart, liver, spleen, trachea, thymus, testes, ovary, kidney, and brain were examined microscopically in 1 rat/sex at 5, 10, and 25 ppm, no rats at 2 ppm, and 2 rats/sex of the control group. All rats exposed to 25 ppm died on the first day and had grossly visible yellow exudate around the mouth and nose,
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edematous and/or reddened lungs, and microscopic diffuse lung edema. At 10 ppm, one male died on day 8 and had diffuse pneumonitis. The 10 ppm rats lost weight (males, 34%; females, 21% loss of their initial body weights), were lethargic (2 males, days 1 and 2), had rough coats (2 males, 2 females, day 7), lacrimation (1 male, day 1), conjunctivitis (2 females, day 1), and nose bleed (1 female, day 14). Reddened lungs were found in one (1/1) male. No clinical observations or pathology were reported at 0, 2, or 5 ppm.
The U.S. Army sponsored a series of inhalation studies of atmospheric pollutants generated from the manufacture of munitions, including TNM (Kinkead et al. 1977). Male Sprague-Dawley CFE rats (10/concentration) were exposed for 4 h to 10-23 ppm TNM and were observed for 2 weeks and then sacrificed. All animals were grossly examined. TNM concentrations were monitored by a colorimetric method and a Technicon AutoAnalyzer I system. The mortality results are summarized in Table 6-3 (Section 3.6.). The exposure concentrations and [death rates] were as follows: 23 ppm [10/10]; 21 ppm [10/10]; 19 ppm [6/10], 18 ppm [3/10]; 15 ppm [3/10]; 10 ppm [0/10]. The LC50 was calculated by the authors to be 17.5 ppm (using the probit method of Finney 1952). Deaths typically occurred within 12 h of exposure. The severity of toxic responses increased with exposure concentration. The rats were lethargic, had a noticeably slowed rate and depth of respiration, and had nose and eye irritation “at the toxic levels” (not specified). Animals exposed to 10 ppm lost weight the first 4 days after exposure but thereafter recovered, whereas rats exposed to greater TNM concentrations had poor weight gain throughout the study. Rats that died prematurely had moderate to severe lung congestion and hemorrhage; rats surviving the 2 weeks had mild lung congestion.
Kinkead et al. (1977) also exposed male rats (100/group) to 0, 3.5, 5, or 7.5 ppm TNM continuously for 2 weeks. TNM concentrations were initially measured by a colorimetric method and a Technicon AutoAnalyzer I system, but after 2 days were instead continuously monitored with a Wilkes Miran IR infrared analyzer. Rats exposed to all concentrations were lethargic and had dyspnea, kyphosis (abnormal backward curvature of the spine), lowered body weight gains, and yellowed fur, with severity of effects increasing with exposure concentration. TNM did not alter blood methemoglobin levels. At 3.5 ppm, no rats died; at 5.0 ppm, two rats died after 7 days and 16 died after 2 weeks; and at 7.5 ppm one rat
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TABLE 6-3 Tetranitromethane Single-Exposure Animal Studies
Species
Exposure Time
Exposure Conc. (ppm) [mortality]
End Points and Comments
Reference
Rat
36.3 min
60 min
5.8 h
1,320
300
33
Estimated time at which 50% of rats will not survive given concentration (ET50). Rats had closed eyes, gasping, lacrimation, rhinorrhea, red lungs with epithelial cell destruction, vascular congestion, edema
Horn 1954
Rat
2 weeks continuous
3.5 [0/100]
5.0 [16/100]
7.5 [65/100]
Dose-related increase in bronchitis and lung edema; other non-specific lung (irritation) lesions; kyphosis
Kinkead et al. 1977
Rat
4 h
23 [10/10]
21 [10/10]
19 [6/10]
18 [3/10]
15 [3/10]
10 [0/10]
LC50 = 17.5 ppm. Males only. Most deaths occurred within 12 h. Rats were lethargic, had slowed respiration, nose and eye irritation, poor weight gain, and lung congestion and hemorrhage; severity increased with test concentration
Kinkead et al. 1977
Mouse
4 h
76 [10/10]
63 [5/10]
55 [4/10]
47 [3/10]
42 [3/10]
32 [1/10]
17 [0/10]
14 [0/10]
LC50 = 54.4 ppm. Males only. Most deaths occurred within 12 h. Mice were lethargic and had slowed respiration and nose and eye irritation, lung congestion and hemorrhage, and poor weight gain
Kinkead et al. 1977
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Species
Exposure Time
Exposure Conc. (ppm) [mortality]
End Points and Comments
Reference
Mouse
2 h
75
114
LC50 (no further information available)
LC100 (no further information available)
Korbakova 1960
Cat
6 h
4-5.5 h
1-2.25 h
0.1-0.4
7.2-5.2
7
TNM was emitted during TNT production and possibly contained impurities. At 0.1-0.4 ppm cats had slight lacrimation. At higher concentrations, cats were irritated, restless, dyspneic, weak, and had hemorrhagic and edematous lungs, congested kidneys and liver, ~5-20% methemoglobin; death occurred at end of stated exposure time
Sievers et al. 1947
Cat
20 min
10
100
“Seriously ill;” died after 10 days
Death 1 h after exposure
Flury and Zernik 1931
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ten Berge, W.F., a. Zwart and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapors and gases. J. Hazard. Materials. 13:302-309.
U.S. EPA (Environmental Protection Agency). 1994. Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066F, October 1994.
U.S. EPA (Environmental Protection Agency). 1999. Guidelines for carcinogen risk assessment. Risk assessment forum, Washington D.C. NCEA-F-0644, July 1999 Review draft.
Verschueren, K. (Ed.) 1996. Tetranitromethane. In: Handbook of Environmental Data on Organic Chemicals, Third Edition. Van Nostrand Reinhold Co., New York, pp. 1702-1703.
Würgler F.E., U. Friederich, E. Fürer, and M. Ganss. 1990. Salmonella/mammalian microsome assay with tetranitromethane and 3-nitro-L-tyrosine. Mutat. Res. 244: 7-14.
Zeiger, E., B. Anderson, S. Haworth, et al. 1987. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ. Mutagen. 9:1-110.
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APPENDIX A
Derivation of AEGL Values
AEGL-1
AEGL-1 values were not developed due to insufficient data. No studies were located with end points clearly within the scope of AEGL-1.
AEGL-2
Key study: Kinkead et al. (1977). Male Sprague-Dawley CFE rats (10/concentration) were exposed for 4 h and observed for 2 weeks. The exposure concentrations and [death rates] were: 23 ppm [10/10]; 21 ppm [10/10]; 19 ppm [6/10], 18 ppm [3/10]; 15 ppm [3/10]; 10 ppm [0/10]. The rats were lethargic, had a noticeably slowed rate and depth of respiration, nose and eye irritation, and weight loss. The severity of toxicity increased with exposure concentration. Rats that died prematurely had moderate to severe lung congestion and hemorrhage; rats surviving the 2 weeks had mild lung congestion. Because 10 ppm is a lethality NOEL in this study and is near the point of departure for AEGL-3, a modifying factor of 3 was applied to 10 ppm obtain a concentration (3.3 ppm) that would cause only mild reversible lung irritation.
Toxicity end point: Mild reversible lung irritation from a 4-h exposure to 3.3 ppm.
Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n empirically for TNM, so used n = 3 and n = 1 to extrapolate to <4 h and >4 h, respectively, except adopted 30-min value as 10-min value to protect human health (see Section 4.4.3.).
Uncertainty factors: Total Uncertainty Factor: 10
Interspecies: 3: Key study tested most sensitive species.
Intraspecies: 3: Mild reversible lung irritation from a gas with a steep dose-response is not likely to vary greatly among humans.
Calculations:
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Calculations:
AEGL-3
Key study: Kinkead et al. (1977). Male Sprague-Dawley CFE rats (10/concentration) were exposed for 4 h and observed for 2 weeks. The exposure concentrations and [death rates] were: 23 ppm [10/10]; 21 ppm [10/10]; 19 ppm [6/10], 18 ppm [3/10]; 15 ppm [3/10]; 10 ppm [0/10]. The rats were lethargic, had a noticeably slowed rate and depth of respiration, nose and eye irritation, and weight loss. The severity of toxicity increased with exposure concentration. Rats that died prematurely had moderate to severe lung congestion and hemorrhage; rats surviving the 2 weeks had mild lung congestion. A BMDL05 of 11 ppm was calculated using the log/probit model from EPA’s Benchmark Dose Software, Version 1.3.2. with the Kinkead et al. (1977) lethality data.
Toxicity end point: NOEL for lethality (from extreme lung irritation), based on the calculated lethality BMDL05 of 11 ppm.
Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n empirically for TNM, so used n = 3 and n = 1 to extrapolate to <4 h and >4 h, respectively, except adopted 30 min value as 10-min value to protect human health (see Section 4.4.3.).
Uncertainty factors: Total Uncertainty Factor: 10
Interspecies: 3: Key study tested most sensitive species
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Intraspecies: 3: NOEL for lethality from extreme lung irritation from a gas with a steep dose-response is not likely to vary greatly among humans.
Calculations:
Calculations:
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APPENDIX B
CANCER ASSESSMENT
A preliminary cancer assessment of tetranitromethane (TNM) was performed using the NTP (1990) study, in which male and female mice were exposed to 0, 0.5, or 2 ppm TNM and male and female rats were exposed to 0, 2, or 5 ppm TNM for 6 h/day, 5 days/week, for 103 weeks. All TNM exposures caused alveolar/bronchiolar adenoma or carcinoma, and 5 ppm rats also had squamous cell carcinoma. The highest tumor incidence was alveolar/bronchiolar adenoma or carcinoma in female mice (4/49, 24/50, 49/50 for 0, 0.5, and 2 ppm TNM), which was used to generate the inhalation unit risk after adjusting for discontinuous exposure (6 h/day, 5 day/week), converting to mg/m3, and extrapolating to a human equivalent concentration (HEC) using the relationship below (EPA 1994, pp. 44 and 50), where MV = min volume and SA = lung alveolar plus bronchiolar surface area, M = mouse, and H = human:
The resulting HEC of 1.95 mg/m3 and 7.82 mg/m3 (for 0.5 and 2 ppm, respectively) were used to calculate the BMDL10 of 0.255 mg/m3 using EPA’s Benchmark Dose Software, Version 1.3.2. and the multistage model (EPA 1999). The inhalation unit risk (or slope factor, i.e. q1*) of 0.392 per (mg/m3) was obtained by dividing 0.10 (i.e., 10% risk) by the BMDL10.
For a lifetime cancer risk of 10-4, air concentration is
10-4/0.392 (mg/m3)-1 = 2.55 × 10-4 mg/m3. For 10-4 risk from lifetime (24-h/day) exposure, total TNM exposure would be:
An additional adjustment factor of 6 is applied to allow for uncertainties in assessing potential cancer risks under short term exposures with the multistage model (Crump and Howe 1984):
6.53 mg/m3 ÷ 6 = 1.09 mg/m3 or 0.14 ppm for 24 h exposure
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For exposures less than 24 h, the fractional exposure (f) becomes 1/f 24 h (NRC 1985) (extrapolation to 10 min was not performed due to unacceptably large inherent uncertainty):
Exposure Duration
AEGL-2 Values (ppm) Based on Toxicity End Points
TNM Exposure Conc. (ppm) with an Excess Cancer Risk of
10-4
10-5
10-6
0.5 h
0.66
6.72
0.67
0.067
1 h
0.52
3.36
0.34
0.0336
4 h
0.33
0.84
0.084
0.0084
8 h
0.17
0.42
0.042
0.0042
Because animal doses were converted to an air concentration that results in an equivalent human inhaled dose for the derivation of the cancer slope factor, no reduction of exposure levels is applied to account for interspecies variability.
TNM concentrations associated with a 10-4 excess cancer risk for a single 30 to 480 min exposure were 2.5 to 10-fold greater than the toxicity-based AEGL-2 values for 30 to 480 min. The noncarcinogenic end points were considered to be more appropriate for AEGL-2 derivation because AEGL values are applicable to rare events or single, once-in-a-lifetime exposures, and the data indicate that TNM neoplasms resulted from chronic exposure. A direct comparison of estimated TNM cancer risk and AEGL values is not appropriate due to large differences in methodology used to obtain these numbers (the TNM concentration with a 10-4 excess cancer risk was estimated by linearly extrapolating from lifetime exposure [25,600 days] to 0.5-8 h, whereas the AEGL-2 values were based on results from a single exposure for 10 min to 4 h).
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APPENDIX C
ACUTE EXPOSURE GUIDELINES FOR TETRANITROMETHANE (CAS Reg. No. 107-15-3)
DERIVATION SUMMARY
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
Not recommended due to insufficient data.
Reference:
Test Species/Strain/Number:
Exposure Route/Concentrations/Durations:
Effects:
End point/Concentration/Rationale:
Uncertainty Factors/Rationale:
Total uncertainty factor:
Interspecies:
Intraspecies:
Modifying Factor:
Animal to Human Dosimetric Adjustment:
Time Scaling:
Data Adequacy:
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
0.66 ppm
0.66 ppm
0.52 ppm
0.33 ppm
0.17 ppm
Reference: Kinkead, E.R., J.D. MacEwen, C.C. Haun, et al. 1977. Toxic hazards evaluation of five atmospheric pollutants from Army ammunition plants. Wright-Patterson Air Force Base, OH: Air Force Systems Command, Aerospace Medical Division, Aerospace Medical Research Laboratory Technical Report AMRL-TR-77-25.
Test Species/Strain/Number: Male Sprague-Dawley CFE rats (10/concentration).
Exposure Route/Concentrations/Durations: Inhalation of 10, 15, 18, 19, 21, or 23 ppm for 4 h.
Effects: Mortality: 23 ppm [10/10]; 21 ppm [10/10]; 19 ppm [6/10], 18 ppm [3/10]; 15 ppm [3/10]; 10 ppm [0/10]. The rats were lethargic, had slowed rate and depth of respiration, and had nose and eye irritation.
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All groups had weight loss, which was reversible only at 10 ppm. Rats that died prematurely had moderate to severe lung congestion and hemorrhage; rats surviving the 2 weeks had mild lung congestion. The severity of toxicity increased with exposure concentration. Because 10 ppm is a lethality NOEL in this study and is near the point of departure for AEGL-3, a modifying factor of 3 was applied to 10 ppm obtain a concentration (3.3 ppm) that would cause only mild reversible lung irritation.
End point/Concentration/Rationale: Mild reversible lung irritation from exposure to 3.3 ppm for 4 h.
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3—Key study tested most sensitive species
Intraspecies: 3—Mild reversible lung irritation from a gas with a steep dose-response is not likely to vary greatly among humans.
Modifying Factor: 3—applied to 10 ppm to obtain a concentration (3.3 ppm) causing only mild reversible lung irritation.
Animal to Human Dosimetric Adjustment: Not performed.
Time Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n empirically for TNM, so used n = 3 and n = 1 to extrapolate to <4 h and >4 h, respectively, except adopted 30-min value as 10 min value to be protective of human health (see section 4.4.3.).
Data Adequacy: The relevant data set was small but contained two mutually supportive and well-conducted studies (Kinkead et al. 1977 and NTP 1990). Use of 3.3 ppm as the Point of departure was supported by the repeat-exposure study with rats and mice (6 h/day for 14 days; NTP 1990) in which 2 ppm caused no effects in either species and 5 ppm caused no effects in rats and only decreased body weights in mice (no histopath at 2 ppm and only for 1/5 animals/sex at 5 ppm, however).
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
2.2 ppm
2.2 ppm
1.7 ppm
1.1 ppm
0.55 ppm
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Reference: Kinkead, E.R., J.D. MacEwen, C.C. Haun, et al. 1977. Toxic ammunition plants. Wright-Patterson Air Force Base, OH: Air Force Systems Command, Aerospace Medical Division, Aerospace Medical Research Laboratory Technical Report AMRL-TR-77-25.
Test Species/Strain/Number: Male Sprague-Dawley CFE rats (10/concentration).
Exposure Route/Concentrations/Durations: Inhalation of 10, 15, 18, 19, 21, or 23 ppm for 4 h.
Effects: Mortality: 23 ppm [10/10]; 21 ppm [10/10]; 19 ppm [6/10], 18 ppm [3/10]; 15 ppm [3/10]; 10 ppm [0/10]. The rats were lethargic, had slowed rate and depth of respiration, and had nose and eye irritation. All groups had weight loss, which was reversible only at 10 ppm. Rats that died prematurely had moderate to severe lung congestion and hemorrhage; rats surviving the 2 weeks had mild lung congestion. The severity of toxicity increased with exposure concentration.
End point/Concentration/Rationale: The calculated lethality BMDL05 of 11 ppm was the NOEL for lethality (from extreme lung irritation).
Uncertainty Factors/Rationale:
Uncertainty factors: Total Uncertainty Factor: 10
Interspecies: 3—Key study tested most sensitive species.
Intraspecies: 3—NOEL for lethality from extreme lung irritation from a gas with a steep dose-response is not likely to vary greatly among humans.
Modifying Factor: None.
Animal to Human Dosimetric Adjustment: Not performed.
Time Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n empirically for TNM, so used n = 3 and n = 1 to extrapolate to <4 h and >4 h, respectively, except adopted 30-min value as 10-min value to be protective of human health (see section 4.4.3.).
Data Adequacy: The relevant data set was small but contained two mutually supportive and well-conducted studies (Kinkead et al. 1977 and NTP 1990). Use of the calculated lethality BMDL05 of 11 ppm as the Point of departure was supported by the empirical lethality NOEL of 10 ppm in the key study and in a repeat-exposure study with rats and mice (6 h/day for 14 days; NTP 1990).
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APPENDIX D
Category Plot for Tetranitromethane
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FIGURE D-1 Chemical toxicity—TSD all data, tetranitromethane. Note that the above plot includes several multiple-exposure (6 h/day, 5 days/week) studies for which a single 6 h/day exposure was input into the table (the NTP [1990] 2-week rat and mouse studies, and the Horn [1954] 6-month rat and dog studies).
Representative terms from entire chapter:
selected airborne